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Freibaum JS, Leathem RP, Braaton W, Krummey SM. Unraveling CD8 + T Cell Alloimmunity: Insights into the Direct Pathway of Antigen Recognition from Modern Experimental Tools. Am J Transplant 2025:S1600-6135(25)00263-1. [PMID: 40373878 DOI: 10.1016/j.ajt.2025.05.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 04/16/2025] [Accepted: 05/06/2025] [Indexed: 05/17/2025]
Abstract
Early experimental investigations of alloimmunity demonstrated that the T cell response against allogeneic antigens is robust and results from a high precursor frequency of responding clones. Seminal studies using cell culture-based methods led to an overall model in which CD8+ T cells are able to recognize self-peptide complexed to allogeneic peptide MHC, termed the direct allogeneic antigen recognition pathway. Recently, three groups used modern experimental approaches, including MHC class I tetramers, to further investigate the nature of direct allogeneic antigen recognition by CD8+ T cells in mice and humans. In a model of liver-induced transplant tolerance, Son et al showed that the MHC class I alloimmune CD8+ T cell response is peptide dependent. Cohen et al elucidated the H-Ld QL9 allogeneic epitope and showed that reactive CD8+ T cells were peptide discriminating. Zhang et al engineered artificial antigen presenting cells to show that human alloreactive CD8+ T cells against HLA-A antigens were MHC restricted, and demonstrated a public HLA-A2 CD8+ T cell response in four donors. Through new experimental tools, these studies offer granular evidence of the mechanisms by which CD8+ T cells recognize allogeneic antigen, and provide a framework for future approaches to selectively target them.
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Affiliation(s)
- Joel S Freibaum
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA
| | - Riley P Leathem
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA
| | - William Braaton
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA
| | - Scott M Krummey
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA.
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Mai Z, Chen X, Lu Y, Zheng J, Lin Y, Lin P, Zheng Y, Zhou Z, Xu R, Guo B, Cui L, Zhao X. Orchestration of immunoregulatory signaling ligand and receptor dynamics by mRNA modifications: Implications for therapeutic potential. Int J Biol Macromol 2025; 310:142987. [PMID: 40210040 DOI: 10.1016/j.ijbiomac.2025.142987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Revised: 03/26/2025] [Accepted: 04/07/2025] [Indexed: 04/12/2025]
Abstract
RNA modifications are pivotal regulators of gene expression, significantly influencing immune responses by modulating the stability and translation of mRNAs encoding key immunoregulatory ligands and receptors. Among these modifications, N6-methyladenosine (m6A) is the most abundant and well-characterized, orchestrating immune evasion, T-cell exhaustion, and cytokine production by dynamically regulating transcripts such as PD-L1, IFN-γ, and TGF-β. These modifications critically impact the function and availability of proteins essential for maintaining immune homeostasis and shaping adaptive immune responses. This review comprehensively examines established and emerging roles of mRNA modifications in regulating immunoregulatory signaling, including co-inhibitory and co-stimulatory molecules, chemokines, cytokines, and transforming growth factor-β. We highlight how m6A writers, erasers, and readers finely regulate immune checkpoints and inflammatory pathways across cancer, infection, and autoimmune diseases. Furthermore, the review provides a critical analysis of current discrepancies in the field, emphasizing factors contributing to inconsistencies and offering insights into the complex nature of epigenetic regulation. Challenges and limitations in this rapidly evolving area are also discussed. Advancing detection technologies and developing specific inhibitors targeting RNA-modifying proteins will be crucial for precisely modulating immune responses, paving the way for innovations in precision medicine and immunotherapy.
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Affiliation(s)
- Zizhao Mai
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou 510280, Guangdong, China
| | - Xu Chen
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou 510280, Guangdong, China
| | - Ye Lu
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou 510280, Guangdong, China
| | - Jiarong Zheng
- Department of Dentistry, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China
| | - Yunfan Lin
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou 510280, Guangdong, China
| | - Pei Lin
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou 510280, Guangdong, China
| | - Yucheng Zheng
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou 510280, Guangdong, China
| | - Zihao Zhou
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou 510280, Guangdong, China
| | - Rongwei Xu
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou 510280, Guangdong, China
| | - Bing Guo
- Department of Dentistry, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China
| | - Li Cui
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou 510280, Guangdong, China; School of Dentistry, University of California, Los Angeles, Los Angeles 90095, CA, USA.
| | - Xinyuan Zhao
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou 510280, Guangdong, China.
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Belal AA, Santos Jr AH, Kazory A, Koratala A. Providing care for kidney transplant recipients: An overview for generalists. World J Nephrol 2025; 14:99555. [PMID: 40134644 PMCID: PMC11755230 DOI: 10.5527/wjn.v14.i1.99555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 12/25/2024] [Accepted: 01/02/2025] [Indexed: 01/20/2025] Open
Abstract
Kidney transplantation is the preferred treatment for patients with advanced chronic kidney disease and end-stage kidney disease, offering superior quality of life and survival compared to dialysis. This manuscript provides an updated overview of post-transplant care, highlighting recent advancements and current practices to assist generalists in managing these patients. It covers key areas such as immunosuppression strategies, drug interactions, and the management of transplant-specific acute kidney injury. The focus includes the use of sodium-glucose cotransporter-2 inhibitors and cell-free DNA monitoring for evaluating allograft health and immune-mediated injury. The manuscript reviews the fundamentals of immunosuppression, including both induction and maintenance therapies, and underscores the importance of monitoring kidney function, as well as addressing hypertension, diabetes, and infections. It also provides recommendations for vaccinations and cancer screening tailored to kidney transplant recipients and emphasizes lifestyle management strategies, such as exercise and sodium intake, to reduce post-transplant complications.
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Affiliation(s)
- Amer A Belal
- Department of Nephrology, Hypertension and Renal Transplantation, University of Florida, Gainesville, FL 32610, United States
| | - Alfonso H Santos Jr
- Department of Nephrology, Hypertension and Renal Transplantation, University of Florida, Gainesville, FL 32610, United States
| | - Amir Kazory
- Department of Nephrology, Hypertension and Renal Transplantation, University of Florida, Gainesville, FL 32610, United States
| | - Abhilash Koratala
- Department of Nephrology, Medical College of Wisconsin, Milwaukee, WI 53226, United States
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Cieplińska K, Niedziela E, Rdzanek AK, Słuszniak A, Chrapek M, Pałyga I, Kowalska A. Association between clinical activity score and serum sPD-1 and sPD-L1 levels during systemic glucocorticoid treatment for active moderate-to-severe thyroid eye disease. Cytokine 2025; 187:156862. [PMID: 39842384 DOI: 10.1016/j.cyto.2025.156862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 01/04/2025] [Accepted: 01/16/2025] [Indexed: 01/24/2025]
Abstract
BACKGROUND CD4+ T lymphocytes are key immune cells involved in orbital inflammation in thyroid eye disease (TED). Inhibition of their activity is important in treatment of TED, but effective drugs targeting these cells are lacking. The programmed cell death-1/programmed cell death ligand-1 pathway has been implicated in several T-cell-mediated diseases. Manipulation of this pathway with antagonists or agonists is an attractive therapeutic option. The role of soluble programmed cell death-1 (sPD-1) and soluble programmed cell death ligand-1 (sPD-L1) in regulation of this pathway is debated. This study aimed to investigate the involvement of sPD-1 and sPD-L1 in the pathogenesis of TED, focusing on their utility as novel biomarkers to evaluate disease severity and treatment response. METHODS Thirty patients diagnosed with moderate-to-severe TED associated with Graves' disease were included. Blood samples were collected from patients before and 12 weeks after initiation of intravenous glucocorticosteroid (IVGC) treatment. Disease severity was assessed using the Clinical Activity Score (CAS) before and after IVGC treatment. Thyroid-stimulating hormone, free thyroxine, free triiodothyronine, thyroid-stimulating immunoglobulin, interleukin-6, sPD-1, and sPD-L1 levels were measured. Correlations between sPD-1, sPD-L1, and CAS before and after IVGC treatment were investigated. Serum concentrations of sPD-1 and sPD-L1 before and after IVGC treatment in patients with TED were compared with those in healthy controls (HCs). The changes in the tested protein concentrations upon IVGC treatment and their associations with clinical characteristics were investigated. Enzyme-linked immunosorbent assays were used to measure sPD-1 and sPD-L1 concentrations in peripheral blood serum. RESULTS There was a positive correlation of moderate Spearman's rank strength between sPD-L1 and CAS before and after treatment, and a positive correlation between sPD-1 and sPD-L1. However, no correlation was observed between sPD-1 and CAS. Baseline serum levels of sPD-1 and sPD-L1 did not significantly differ between patients with TED and HCs. There were no correlations between changes in the levels of the tested molecules upon IVGC treatment and the analyzed clinical features. The decreases of sPD-1 and sPD-L1 levels after 12 weeks of IVGC treatment were not significant. CONCLUSION The positive correlation of moderate Spearman's rank strength between sPD-L1 and CAS before and after 12 weeks of treatment indicates that sPD-L1 is involved in the pathogenesis of TED. sPD-L1 may become an additional immunological biomarker to assess the disease activity and monitor the respond to treatment. Although sPD-1 is reported in the literature to have an activating effect on lymphocytes, our study shows that sPD-1 may not play a significant role in the pathogenesis of TED, as its level does not differ significantly between the TED and HC groups and does not correlate with disease activity. Understanding the clinical value of sPD-1 and sPD-L1 is of great practical importance.
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Affiliation(s)
| | - Emilia Niedziela
- Collegium Medicum, Jan Kochanowski University in Kielce, 25-317 Kielce, Poland; Department of Endocrinology, Holy Cross Cancer Center, 25-734 Kielce, Poland
| | | | - Anna Słuszniak
- Department of Tumor Markers, Holy Cross Cancer Center, 25-734 Kielce, Poland
| | - Magdalena Chrapek
- Department of Mathematics, Faculty of Natural Sciences, Jan Kochanowski University, Kielce 25-406, Poland
| | - Iwona Pałyga
- Collegium Medicum, Jan Kochanowski University in Kielce, 25-317 Kielce, Poland; Department of Endocrinology, Holy Cross Cancer Center, 25-734 Kielce, Poland
| | - Aldona Kowalska
- Collegium Medicum, Jan Kochanowski University in Kielce, 25-317 Kielce, Poland; Department of Endocrinology, Holy Cross Cancer Center, 25-734 Kielce, Poland
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Tönshoff B, Patry C, Fichtner A, Höcker B, Böhmig GA. New Immunosuppressants in Pediatric Kidney Transplantation: What's in the Pipeline for Kids? Pediatr Transplant 2025; 29:e70008. [PMID: 39711054 DOI: 10.1111/petr.70008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 11/05/2024] [Accepted: 12/08/2024] [Indexed: 12/24/2024]
Abstract
The 1- and 5-year patient and graft survival rates of pediatric kidney transplant recipients have improved considerably in recent years. Regardless of early success, kidney transplantation is challenged by suboptimal long-term allograft and patient survival. Many kidney transplants are lost due to immune (rejection) and nonimmune allograft injuries, and patient survival is limited from cardiovascular disease, infection, and malignancy. Many of these co-morbidities are due to side effects of the currently available immunosuppressive drugs, especially calcineurin inhibitors and glucocorticoids, which are associated with long-term toxicity. Hence, there is an urgent need to develop new, more specific and less toxic immunosuppressive drugs. Unfortunately, there have also been no new drug approvals for adult kidney transplant recipients since belatacept in 2012, leaving the immunosuppressive drug armamentarium unchanged for more than 20 years. As a consequence of the lack of innovation in adult kidney transplant recipients, the pipeline of novel immunosuppressive agents for pediatric solid organ transplant recipients is also limited. The most promising agent in the near future, at least for adolescent patients, appears to be belatacept, despite its many limitations. In this review article, we report on three areas that appear to be the most relevant topics at this time: (i) extended-release tacrolimus, (ii) costimulation blockade with belatacept, and (iii) treatment of antibody-mediated rejection. Improved synergies between the pharmaceutical industry and the transplant community are needed to achieve the ultimate goal of improving long-term outcomes in pediatric kidney transplantation.
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Affiliation(s)
- Burkhard Tönshoff
- Department of Pediatrics I, Medical Faculty, University Children's Hospital Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Christian Patry
- Department of Pediatrics I, Medical Faculty, University Children's Hospital Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Alexander Fichtner
- Department of Pediatrics I, Medical Faculty, University Children's Hospital Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Britta Höcker
- Department of Pediatrics I, Medical Faculty, University Children's Hospital Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Georg A Böhmig
- Department of Medicine III, Medical University of Vienna, Vienna, Austria
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Zhang W, Yu Q, Gao X, Chen H, Su J, Chen Y, Li Y, Zhang N, Fu Z, Cui M. Myeloid-Derived Suppressor Cells Induce Exhaustion-Like CD8 + T Cells during JEV Infection. Int J Biol Sci 2024; 20:5959-5978. [PMID: 39664572 PMCID: PMC11628328 DOI: 10.7150/ijbs.102372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 10/18/2024] [Indexed: 12/13/2024] Open
Abstract
Japanese encephalitis (JE), caused by Japanese encephalitis virus (JEV), is a mosquito-borne zoonotic disease and a leading cause of viral encephalitis worldwide. While JEV has the ability to traverse the blood-brain barrier (BBB), the precise mechanisms by which it inhibits the immune response prior to penetrating the BBB remain unclear, presenting obstacles in the development of efficacious therapeutic interventions. This study investigated the impact of JEV on CD8+ T cell responses, with a particular focus on the dysfunction of CD8+ T cells during JEV infection. Our results demonstrated that JEV infection significantly elevated the expression of PD-1 and TIM-3 on CD8+ T cells, which are markers of T cell exhaustion, leading to inhibited function and impaired differentiation, resulting in a poorer prognosis in mice. Compared with nondiseased mice, symptomatic mice presented a greater proportion of exhaustion-like CD8+ T cells. In vitro experiments further demonstrated that MDSCs induced an exhaustion-like state in CD8+ T cells, characterized by significant upregulation of PD-1 and TIM-3 expression. Notably, blocking TIM-3 or depleting MDSCs restored CD8+ T cell functionality by rescuing the expression of IFN-γ and TNF-α. Furthermore, the depletion of MDSCs not only alleviated T cell exhaustion-like phenotypes but also improved survival rates in JEV-infected mice. These findings suggest that JEV promotes immune evasion through MDSC-induced CD8+ T cell exhaustion-like states and identify TIM-3 as a promising therapeutic target for JE treatment.
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Affiliation(s)
- Weijia Zhang
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Centre for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture of the People's Republic of China, Wuhan, China
- International Research Centre for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, China
| | - Qing Yu
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Centre for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture of the People's Republic of China, Wuhan, China
- International Research Centre for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, China
| | - Xiaochen Gao
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Centre for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture of the People's Republic of China, Wuhan, China
- International Research Centre for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, China
| | - Haowei Chen
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Centre for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture of the People's Republic of China, Wuhan, China
- International Research Centre for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, China
| | - Jie Su
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Centre for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture of the People's Republic of China, Wuhan, China
- International Research Centre for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, China
| | - Yanru Chen
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Centre for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture of the People's Republic of China, Wuhan, China
- International Research Centre for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, China
| | - Yanling Li
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Centre for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture of the People's Republic of China, Wuhan, China
- International Research Centre for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, China
| | - Nan Zhang
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Centre for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture of the People's Republic of China, Wuhan, China
- International Research Centre for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, China
| | - Zhenfang Fu
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Centre for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture of the People's Republic of China, Wuhan, China
- International Research Centre for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, China
| | - Min Cui
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Centre for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture of the People's Republic of China, Wuhan, China
- International Research Centre for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, China
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Su X, Yu H, Lei Q, Chen X, Tong Y, Zhang Z, Yang W, Guo Y, Lin L. Systemic lupus erythematosus: pathogenesis and targeted therapy. MOLECULAR BIOMEDICINE 2024; 5:54. [PMID: 39472388 PMCID: PMC11522254 DOI: 10.1186/s43556-024-00217-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Accepted: 10/16/2024] [Indexed: 11/02/2024] Open
Abstract
Systemic lupus erythematosus (SLE) is a multifaceted autoimmune disorder characterized by dysregulated immune responses and autoantibody production, which affects multiple organs and varies in clinical presentation and disease severity. The development of SLE is intricate, encompassing dysregulation within the immune system, a collapse of immunological tolerance, genetic susceptibilities to the disease, and a variety of environmental factors that can act as triggers. This review provides a comprehensive discussion of the pathogenesis and treatment strategies of SLE and focuses on the progress and status of traditional and emerging treatment strategies for SLE. Traditional treatment strategies for SLE have mainly employed non-specific approaches, including cytotoxic and immunosuppressive drugs, antimalarials, glucocorticoids, and NSAIDs. These strategies are effective in mitigating the effects of the disease, but they are not a complete cure and are often accompanied by adverse reactions. Emerging targeted therapeutic drugs, on the other hand, aim to control and treat SLE by targeting B and T cells, inhibiting their activation and function, as well as the abnormal activation of the immune system. A deeper understanding of the pathogenesis of SLE and the exploration of new targeted treatment strategies are essential to advance the treatment of this complex autoimmune disease.
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Affiliation(s)
- Xu Su
- Medical Research Center, College of Medicine, The Third People's Hospital of Chengdu (Affiliated Hospital of Southwest Jiaotong University, Southwest Jiaotong University, Chengdu, 610031, Sichuan, China
| | - Hui Yu
- Department of Urology, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, 610014, China
| | - Qingqiang Lei
- Center of Bone Metabolism and Repair, Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, 400000, China
| | - Xuerui Chen
- Medical Research Center, College of Medicine, The Third People's Hospital of Chengdu (Affiliated Hospital of Southwest Jiaotong University, Southwest Jiaotong University, Chengdu, 610031, Sichuan, China
| | - Yanli Tong
- Université Paris Cité, INSERM U1151, CNRS UMR8253, Institut Necker Enfants Malades, Paris, F-75015, France
| | - Zhongyang Zhang
- Department of Health Technology, The Danish National Research Foundation and Villum Foundation's Center IDUN, Technical University of Denmark, Kgs. Lyngby, Denmark
| | - Wenyong Yang
- Medical Research Center, College of Medicine, The Third People's Hospital of Chengdu (Affiliated Hospital of Southwest Jiaotong University, Southwest Jiaotong University, Chengdu, 610031, Sichuan, China.
- Department of Neurosurgery, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, 610014, China.
| | - Yuanbiao Guo
- Medical Research Center, College of Medicine, The Third People's Hospital of Chengdu (Affiliated Hospital of Southwest Jiaotong University, Southwest Jiaotong University, Chengdu, 610031, Sichuan, China.
| | - Liangbin Lin
- Medical Research Center, College of Medicine, The Third People's Hospital of Chengdu (Affiliated Hospital of Southwest Jiaotong University, Southwest Jiaotong University, Chengdu, 610031, Sichuan, China.
- Obesity and Metabolism Medicine-Engineering Integration Laboratory, Department of General Surgery, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, 610031, China.
- The Center of Gastrointestinal and Minimally Invasive Surgery, Department of General Surgery, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, 610031, China.
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Zhao F, Yu JS. Overview of dendritic cells and related pathways in autoimmune uveitis. Open Life Sci 2024; 19:20220887. [PMID: 39290500 PMCID: PMC11406227 DOI: 10.1515/biol-2022-0887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 05/08/2024] [Accepted: 05/09/2024] [Indexed: 09/19/2024] Open
Abstract
Dendritic cells (DCs) play a crucial role in bridging innate and adaptive immune responses. They are widely distributed in various tissues and organs, including the eyes. In the ocular context, permanent DCs are present at the peripheral edge of the retina and the peripapillary area in an immature state. However, during the inflammatory process, DCs become activated and contribute to the development of uveitis. This review focuses on introducing the characteristics and status of DC-induced uveitis, exploring factors that can influence the status of DCs, and discussing feasible methods for treating DCs in both experimental autoimmune uveitis animal models and humans. It emphasizes the importance of further research on molecular pathways and signaling pathways that regulate the function of DCs. For example, investigating molecules such as cytotoxic T-lymphocyte-associated protein 4, which inhibits the B7-CD28 co-stimulatory interaction, can help improve immune homeostasis. The aim is to identify new therapeutic targets and develop targeted strategies for DCs, such as DC vaccine therapy or the use of immune modulators. These approaches can be tailored to the immune characteristics and disease manifestations of individual patients, enabling personalized treatment strategies. This may include the personalized design and precise medication of DC therapy, with the ultimate goal of improving treatment efficacy while minimizing adverse reactions.
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Affiliation(s)
- Fan Zhao
- Graduate School of Hunan University of Traditional Chinese Medicine, Changsha, 410000, Hunan, China
| | - Jing-Sheng Yu
- Ophthalmology, The First Affiliated Hospital of Hunan University of Traditional Chinese Medicine, Pharmaceutical University, Changsha, 410007, Hunan, China
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Iglesias M, Bibicheff D, Komin A, Chicco M, Guinn S, Foley B, Raimondi G. T cell responsiveness to IL-10 defines the immunomodulatory effect of costimulation blockade via anti-CD154 and impacts transplant survival. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.12.598652. [PMID: 38915537 PMCID: PMC11195256 DOI: 10.1101/2024.06.12.598652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/26/2024]
Abstract
Costimulation blockade (CoB)-based immunotherapy is a promising alternative to immunosuppression for transplant recipients; however, the current limited understanding of the factors that impact its efficacy restrains its clinical applicability. In this context, pro- and anti-inflammatory cytokines are being recognized as having an impact on T cell activation beyond effector differentiation. This study aims at elucidating the impact of direct IL-10 signaling in T cells on CoB outcomes. We used a full-mismatch skin transplantation model where recipients had a T cell-restricted expression of a dominant negative IL-10 receptor (10R-DN), alongside anti-CD154 as CoB therapy. Unlike wild-type recipients, 10R-DN mice failed to benefit from CoB. This accelerated graft rejection correlated with increased accumulation of T cells producing TNF-α, IFN-γ, and IL-17. In vitro experiments indicated that while lack of IL-10 signaling did not change the ability of anti-CD154 to modulate alloreactive T cell proliferation, the absence of this pathway heightened TH1 effector cell differentiation. Furthermore, deficiency of IL-10 signaling in T cells impaired Treg induction, a hallmark of anti-CD154 therapy. Overall, these findings unveil an important and novel role of IL-10 signaling in T cells that defines the success of CoB therapies and identifies a target pathway for obtaining robust immunoregulation.
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Affiliation(s)
- Marcos Iglesias
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Darrel Bibicheff
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Alexander Komin
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Maria Chicco
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Samantha Guinn
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Brendan Foley
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Giorgio Raimondi
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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10
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Grosu-Bularda A, Hodea FV, Zamfirescu D, Stoian A, Teodoreanu RN, Lascăr I, Hariga CS. Exploring Costimulatory Blockade-Based Immunologic Strategies in Transplantation: Are They a Promising Immunomodulatory Approach for Organ and Vascularized Composite Allotransplantation? J Pers Med 2024; 14:322. [PMID: 38541064 PMCID: PMC10971463 DOI: 10.3390/jpm14030322] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Revised: 03/12/2024] [Accepted: 03/18/2024] [Indexed: 11/12/2024] Open
Abstract
The field of transplantation, including the specialized area of vascularized composite allotransplantation (VCA), has been transformed since the first hand transplant in 1998. The major challenge in VCA comes from the need for life-long immunosuppressive therapy due to its non-vital nature and a high rate of systemic complications. Ongoing research is focused on immunosuppressive therapeutic strategies to avoid toxicity and promote donor-specific tolerance. This includes studying the balance between tolerance and effector mechanisms in immune modulation, particularly the role of costimulatory signals in T lymphocyte activation. Costimulatory signals during T cell activation can have either stimulatory or inhibitory effects. Interfering with T cell activation through costimulation blockade strategies shows potential in avoiding rejection and prolonging the survival of transplanted organs. This review paper aims to summarize current data on the immunologic role of costimulatory blockade in the field of transplantation. It focuses on strategies that can be applied in vascularized composite allotransplantation, offering insights into novel methods for enhancing the success and safety of these procedures.
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Affiliation(s)
- Andreea Grosu-Bularda
- Department 11, Discipline Plastic and Reconstructive Surgery, Bucharest Clinical Emergency Hospital, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (R.N.T.); (I.L.); (C.S.H.)
- Clinic of Plastic Surgery, Aesthetic and Reconstructive Microsurgery, Emergency Clinical Hospital Bucharest, 050474 Bucharest, Romania
| | - Florin-Vlad Hodea
- Department 11, Discipline Plastic and Reconstructive Surgery, Bucharest Clinical Emergency Hospital, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (R.N.T.); (I.L.); (C.S.H.)
- Clinic of Plastic Surgery, Aesthetic and Reconstructive Microsurgery, Emergency Clinical Hospital Bucharest, 050474 Bucharest, Romania
| | | | | | - Răzvan Nicolae Teodoreanu
- Department 11, Discipline Plastic and Reconstructive Surgery, Bucharest Clinical Emergency Hospital, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (R.N.T.); (I.L.); (C.S.H.)
- Clinic of Plastic Surgery, Aesthetic and Reconstructive Microsurgery, Emergency Clinical Hospital Bucharest, 050474 Bucharest, Romania
| | - Ioan Lascăr
- Department 11, Discipline Plastic and Reconstructive Surgery, Bucharest Clinical Emergency Hospital, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (R.N.T.); (I.L.); (C.S.H.)
- Clinic of Plastic Surgery, Aesthetic and Reconstructive Microsurgery, Emergency Clinical Hospital Bucharest, 050474 Bucharest, Romania
| | - Cristian Sorin Hariga
- Department 11, Discipline Plastic and Reconstructive Surgery, Bucharest Clinical Emergency Hospital, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (R.N.T.); (I.L.); (C.S.H.)
- Clinic of Plastic Surgery, Aesthetic and Reconstructive Microsurgery, Emergency Clinical Hospital Bucharest, 050474 Bucharest, Romania
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11
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Cieplińska K, Niedziela E, Kowalska A. Immunological Processes in the Orbit and Indications for Current and Potential Drug Targets. J Clin Med 2023; 13:72. [PMID: 38202079 PMCID: PMC10780108 DOI: 10.3390/jcm13010072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Revised: 12/17/2023] [Accepted: 12/20/2023] [Indexed: 01/12/2024] Open
Abstract
Thyroid eye disease (TED) is an extrathyroidal manifestation of Graves' disease (GD). Similar to GD, TED is caused by an autoimmune response. TED is an autoimmune inflammatory disorder of the orbit and periorbital tissues, characterized by upper eyelid retraction, swelling, redness, conjunctivitis, and bulging eyes. The pathophysiology of TED is complex, with the infiltration of activated T lymphocytes and activation of orbital fibroblasts (OFs) and autoantibodies against the common autoantigen of thyroid and orbital tissues. Better understanding of the multifactorial pathogenesis of TED contributes to the development of more effective therapies. In this review, we present current and potential drug targets. The ideal treatment should slow progression of the disease with as little interference with patient immunity as possible. In the future, TED treatment will target the immune mechanism involved in the disease and will be based on a strategy of restoring tolerance to autoantigens.
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Affiliation(s)
| | - Emilia Niedziela
- Collegium Medicum, Jan Kochanowski University in Kielce, 25-317 Kielce, Poland; (E.N.); (A.K.)
- Department of Endocrinology, Holy Cross Cancer Center, 25-734 Kielce, Poland
| | - Aldona Kowalska
- Collegium Medicum, Jan Kochanowski University in Kielce, 25-317 Kielce, Poland; (E.N.); (A.K.)
- Department of Endocrinology, Holy Cross Cancer Center, 25-734 Kielce, Poland
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12
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Kitchens WH, Larsen CP, Badell IR. Costimulatory Blockade and Solid Organ Transplantation: The Past, Present, and Future. Kidney Int Rep 2023; 8:2529-2545. [PMID: 38106575 PMCID: PMC10719580 DOI: 10.1016/j.ekir.2023.08.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 08/01/2023] [Accepted: 08/28/2023] [Indexed: 12/19/2023] Open
Abstract
Belatacept is the first costimulatory blockade agent clinically approved for transplant immunosuppression. Although more than 10 years of study have demonstrated that belatacept offers superior long-term renal allograft and patient survival compared to conventional calcineurin inhibitor (CNI)-based immunosuppression regimens, the clinical adoption of belatacept has continued to lag because of concerns of an early risk of acute cellular rejection (ACR) and various logistical barriers to its administration. In this review, the history of the clinical development of belatacept is examined, along with the findings of the seminal BENEFIT and BENEFIT-EXT trials culminating in the clinical approval of belatacept. Recent efforts to incorporate belatacept into novel CNI-free immunosuppression regimens are reviewed, as well as the experience of the Emory Transplant Center in using a tapered course of low-dose tacrolimus in belatacept-treated renal allograft patients to garner the long-term outcome benefits of belatacept without the short-term increased risks of ACR. Potential avenues to increase the clinical adoption of belatacept in the future are explored, including surmounting the logistical barriers of belatacept administration through subcutaneous administration or more infrequent belatacept dosing. In addition, belatacept conversion strategies and potential expanded clinical indications of belatacept are discussed for pediatric transplant recipients, extrarenal transplant recipients, treatment of antibody-mediated rejection (AMR), and in patients with failed renal allografts. Finally, we discuss the novel immunosuppressive drugs currently in the development pipeline that may aid in the expansion of costimulation blockade utilization.
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Affiliation(s)
- William H. Kitchens
- Division of Transplantation, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Christian P. Larsen
- Division of Transplantation, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
| | - I. Raul Badell
- Division of Transplantation, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
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13
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Martin TM, Burke SJ, Wasserfall CH, Collier JJ. Islet beta-cells and intercellular adhesion molecule-1 (ICAM-1): Integrating immune responses that influence autoimmunity and graft rejection. Autoimmun Rev 2023; 22:103414. [PMID: 37619906 PMCID: PMC10543623 DOI: 10.1016/j.autrev.2023.103414] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Revised: 08/16/2023] [Accepted: 08/20/2023] [Indexed: 08/26/2023]
Abstract
Type 1 diabetes (T1D) develops due to autoimmune targeting of the pancreatic islet β-cells. Clinical symptoms arise from reduced insulin in circulation. The molecular events and interactions between discrete immune cell populations, infiltration of such leukocytes into pancreatic and islet tissue, and selective targeting of the islet β-cells during autoimmunity and graft rejection are not entirely understood. One protein central to antigen presentation, priming of immune cells, trafficking of leukocytes, and vital for leukocyte effector function is the intercellular adhesion molecule-1 (ICAM-1). The gene encoding ICAM-1 is transcriptionally regulated and rapidly responsive (i.e., within hours) to pro-inflammatory cytokines. ICAM-1 is a transmembrane protein that can be glycosylated; its presence on the cell surface provides co-stimulatory functions for immune cell activation and stabilization of cell-cell contacts. ICAM-1 interacts with the β2-integrins, CD11a/CD18 (LFA-1) and CD11b/CD18 (Mac-1), which are present on discrete immune cell populations. A whole-body ICAM-1 deletion protects NOD mice from diabetes onset, strongly implicating this protein in autoimmune responses. Since several different cell types express ICAM-1, its biology is fundamentally essential for various physiological and pathological outcomes. Herein, we review the role of ICAM-1 during both autoimmunity and islet graft rejection to understand the mechanism(s) leading to islet β-cell death and dysfunction that results in insufficient circulating quantities of insulin to control glucose homeostasis.
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Affiliation(s)
- Thomas M Martin
- Laboratory of Islet Biology and Inflammation, Pennington Biomedical Research Center, Baton Rouge, LA 70808, United States of America; Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 70803, United States of America
| | - Susan J Burke
- Laboratory of Immunogenetics, Pennington Biomedical Research Center, Baton Rouge, LA 70808, United States of America
| | - Clive H Wasserfall
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, United States of America
| | - J Jason Collier
- Laboratory of Islet Biology and Inflammation, Pennington Biomedical Research Center, Baton Rouge, LA 70808, United States of America; Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 70803, United States of America.
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14
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Miura S, Habibabady ZA, Pollok F, Ma M, Rosales IA, Kinoshita K, Pratts S, McGrath G, Chaban R, Fogarty S, Meibohm B, Daugherty B, Lederman S, Pierson RN. TNX-1500, a crystallizable fragment-modified anti-CD154 antibody, prolongs nonhuman primate cardiac allograft survival. Am J Transplant 2023; 23:1182-1193. [PMID: 37030662 PMCID: PMC10524282 DOI: 10.1016/j.ajt.2023.03.025] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 03/16/2023] [Accepted: 03/29/2023] [Indexed: 04/10/2023]
Abstract
Blockade of the CD40/CD154 T cell costimulation pathway is a promising approach to supplement or replace current clinical immunosuppression in solid organ transplantation. We evaluated the tolerability and activity of a novel humanized anti-CD154 monoclonal antibody, TNX-1500 (TNX), in a nonhuman primate heterotopic cardiac allogeneic (allo) transplant model. TNX-1500 contains a rupluzimab fragment antigen-binding region and an immunoglobin G4 crystallizable fragment region engineered to reduce binding to the crystallizable fragment gamma receptor IIa and associated risks of thrombosis. Recipients were treated for 6 months with standard-dose TNX (sTNX) monotherapy, low-dose TNX monotherapy (loTNX), or loTNX with mycophenolate mofetil (MMF) (loTNX + MMF). Results were compared with historical data using chimeric humanized 5c8 monotherapy dosed as for loTNX but discontinued at 3 months. Median survival time was similar for humanized 5c8 and both loTNX groups, but significantly longer with sTNX (>265 days) than with loTNX (99 days) or loTNX + MMF (88 days) (P < 0.05 for both comparisons against sTNX). Standard-dose TNX prevented antidonor alloantibody elaboration, inhibited chronic rejection, and was associated with a significantly reduced effector T cells/regulatory T cells ratio relative to loTNX with MMF. No thrombotic complications were observed. This study demonstrated that TNX was well tolerated, prolongs allograft survival, and prevents alloantibody production and cardiac allograft vasculopathy in a stringent preclinical nonhuman primate heart allotransplant model.
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Affiliation(s)
- Shuhei Miura
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA; Department of Cardiovascular Surgery, Sapporo Medical University, Sapporo, Japan; Department of Cardiovascular Surgery, Teine Keijinkai Hospital, Sapporo, Japan.
| | - Zahra A Habibabady
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Franziska Pollok
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA; Department of Anesthesiology, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - Madelyn Ma
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Ivy A Rosales
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Kohei Kinoshita
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Shannon Pratts
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Gannon McGrath
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Ryan Chaban
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | | | - Bernd Meibohm
- College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | | | | | - Richard N Pierson
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA.
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15
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Kivitz A, Wang L, Alevizos I, Gunsior M, Falloon J, Illei G, St Clair EW. The MIDORA trial: a phase II, randomised, double-blind, placebo-controlled, mechanistic insight and dosage optimisation study of the efficacy and safety of dazodalibep in patients with rheumatoid arthritis. RMD Open 2023; 9:e003317. [PMID: 37541743 PMCID: PMC10407378 DOI: 10.1136/rmdopen-2023-003317] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Accepted: 07/14/2023] [Indexed: 08/06/2023] Open
Abstract
OBJECTIVES To evaluate the safety, efficacy and response duration of four different dosing regimens of dazodalibep (DAZ), a non-antibody biological antagonist of CD40L, in patients with rheumatoid arthritis (RA). METHODS This double-blind study included adult patients with moderate-to-severe active RA with a positive test for serum rheumatoid factor and/or anticitrullinated protein antibodies, an inadequate response to methotrexate, other conventional disease-modifying antirheumatic drugs or tumour necrosis factor-α inhibitors, and no prior treatment with B-cell depleting agents. Eligible participants were randomised equally to five groups receiving intravenous infusions of DAZ or placebo. The primary endpoint was the change from baseline in the Disease Activity Score-28 with C reactive protein (DAS28-CRP) at day 113. Participants were followed through day 309. RESULTS The study randomised 78 eligible participants. The change from baseline in DAS28-CRP (least squares means±SE) at day 113 was significantly greater for all DAZ groups (-1.83±0.28 to -1.90±0.27; p<0.05) relative to PBO (-1.06±0.26); significant reductions in DAS28-CRP were also observed for all DAZ groups at day 309. The distribution of adverse events was generally balanced among DAZ and PBO groups (74% and 63%, respectively). There were four serious adverse events deemed by investigators to be unrelated to study medication. CONCLUSIONS DAZ treatment for all dosage regimens significantly reduced DAS28-CRP at day 113 relative to PBO. The safety data suggest an acceptable safety and tolerability profile. Treatment effects at day 113 and the prolonged duration of responses after DAZ cessation support the use of longer dosing intervals. TRIAL REGISTRATION NUMBER NCT04163991.
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Affiliation(s)
- Alan Kivitz
- Department of Rheumatology, Altoona Center for Clinical Research, Altoona, Pennsylvania, USA
| | | | | | | | | | - Gabor Illei
- Horizon Therapeutics plc, Rockville, Maryland, USA
- IRD Biomedical Consulting, LLC, Rockville, Maryland, USA
| | - E William St Clair
- Division of Rheumatology and Immunology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA
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16
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Chebotareva N, Cao V, Vinogradov A, Alentov I, Sergeeva N, Kononikhin A, Moiseev S. Preliminary study of anti-CD40 and ubiquitin proteasome antibodies in primary podocytopaties. Front Med (Lausanne) 2023; 10:1189017. [PMID: 37409273 PMCID: PMC10319126 DOI: 10.3389/fmed.2023.1189017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Accepted: 06/05/2023] [Indexed: 07/07/2023] Open
Abstract
Background Minimal change disease and focal segmental glomerulosclerosis are primary podocytopathies that are clinically presented in adults presenting with severe nephrotic syndrome. The pathogenesis of these diseases is not clear and many questions remain to be answered. A new concept about the role of changes in the antigenic determinant of podocytes and the production of anti-podocyte antibodies that cause podocyte damage is being developed. The aim of the study is to evaluate the levels of anti-CD40 and anti-ubiquitin carboxyl-terminal hydrolase L1 (anti-UCH-L1) antibodies in patients with podocytopathies in comparison with other glomerulopathies. Methods One hundred and six patients with glomerulopathy and 11 healthy subjects took part in the study. A histological study revealed primary FSGS in 35 patients (genetic cases of FSGS and secondary FSGS in the absence of NS were excluded), 15 had MCD, 21 - MN, 13 - MPGN, 22 patients - IgA nephropathy. The effect of steroid therapy was evaluated in patients with podocytopathies (FSGS and MCD). The serum levels of anti-UCH-L1 and anti-CD40 antibodies were measured by ELISA before steroid treatment. Results The levels of anti-UCH-L1 antibodies were significantly higher in MCD patients and anti-CD40 antibodies were higher in MCD and FSGS than in the control group and other groups of glomerulopathies. In addition, the level of anti-UCH-L1 antibodies was higher in patients with steroid-sensitive FSGS and MCD, and anti-CD40 antibodies were lower than in patients with steroid-resistant FSGS. An increase in anti-UCH-L1 antibody levels above 6.44 ng/mL may be a prognostic factor of steroid-sensitivity. The ROC curve (AUC = 0.875 [95% CI 0.718-0.999]) for response to therapy showed a sensitivity of 75% and specificity of 87.5%. Conclusion An increase in the level of anti-UCH-L1 antibodies is specific for steroid-sensitive FSGS and MCD, while an increase in anti-CD40 antibodies - for steroid-resistant FSGS, compared with other glomerulopathies. It suggests that these antibodies could be a potential factor for differential diagnosis and treatment prognosis.
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Affiliation(s)
- Natalia Chebotareva
- Sechenov First Moscow State Medical University, Tareev Clinic of Internal Diseases, Moscow, Russia
| | - Venzsin Cao
- Sechenov First Moscow State Medical University, Tareev Clinic of Internal Diseases, Moscow, Russia
| | | | - Igor Alentov
- Hertsen Moscow Oncology Research Institute, Department of Prediction of Conservative Treatment Efficiency, Moscow, Russia
| | - Natalia Sergeeva
- Hertsen Moscow Oncology Research Institute, Department of Prediction of Conservative Treatment Efficiency, Moscow, Russia
| | | | - Sergey Moiseev
- Sechenov First Moscow State Medical University, Tareev Clinic of Internal Diseases, Moscow, Russia
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17
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Tan X, Qi C, Zhao X, Sun L, Wu M, Sun W, Gu L, Wang F, Feng H, Huang X, Xie B, Shi Z, Xie P, Wu M, Zhang Y, Chen G. ERK Inhibition Promotes Engraftment of Allografts by Reprogramming T-Cell Metabolism. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2206768. [PMID: 37013935 DOI: 10.1002/advs.202206768] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 02/15/2023] [Indexed: 06/04/2023]
Abstract
Extracellular regulated protein kinases (ERK) signaling is a master regulator of cell behavior, life, and fate. Although ERK pathway is shown to be involved in T-cell activation, little is known about its role in the development of allograft rejection. Here, it is reported that ERK signaling pathway is activated in allograft-infiltrating T cells. On the basis of surface plasmon resonance technology, lycorine is identified as an ERK-specific inhibitor. ERK inhibition by lycorine significantly prolongs allograft survival in a stringent mouse cardiac allotransplant model. As compared to untreated mice, lycorine-treated mice show a decrease in the number and activation of allograft-infiltrated T cells. It is further confirmed that lycorine-treated mouse and human T cells are less responsive to stimulation in vitro, as indicated by their low proliferative rates and decreased cytokine production. Mechanistic studies reveal that T cells treated with lycorine exhibit mitochondrial dysfunction, resulting in metabolic reprogramming upon stimulation. Transcriptome analysis of lycorine-treated T cells reveals an enrichment in a series of downregulated terms related to immune response, the mitogen-activated protein kinase cascade, and metabolic processes. These findings offer new insights into the development of immunosuppressive agents by targeting the ERK pathway involved in T-cell activation and allograft rejection.
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Affiliation(s)
- Xiaosheng Tan
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei Province, 430030, P. R. China
- Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences, Wuhan, Hubei Province, 430030, P. R. China
- NHC Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei Province, 430030, P. R. China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei Province, 430030, P. R. China
| | - Changxing Qi
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, P. R. China
| | - Xiangli Zhao
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei Province, 430030, P. R. China
- Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences, Wuhan, Hubei Province, 430030, P. R. China
- NHC Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei Province, 430030, P. R. China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei Province, 430030, P. R. China
| | - Lingjuan Sun
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei Province, 430030, P. R. China
- Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences, Wuhan, Hubei Province, 430030, P. R. China
- NHC Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei Province, 430030, P. R. China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei Province, 430030, P. R. China
| | - Mi Wu
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, P. R. China
| | - Weiguang Sun
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, P. R. China
| | - Lianghu Gu
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, P. R. China
| | - Fengqing Wang
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, P. R. China
| | - Hao Feng
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei Province, 430030, P. R. China
- Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences, Wuhan, Hubei Province, 430030, P. R. China
- NHC Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei Province, 430030, P. R. China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei Province, 430030, P. R. China
| | - Xia Huang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei Province, 430030, P. R. China
- Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences, Wuhan, Hubei Province, 430030, P. R. China
- NHC Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei Province, 430030, P. R. China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei Province, 430030, P. R. China
| | - Bin Xie
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei Province, 430030, P. R. China
- Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences, Wuhan, Hubei Province, 430030, P. R. China
- NHC Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei Province, 430030, P. R. China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei Province, 430030, P. R. China
| | - Zhengyi Shi
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, P. R. China
| | - Peiling Xie
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei Province, 430030, P. R. China
- Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences, Wuhan, Hubei Province, 430030, P. R. China
- NHC Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei Province, 430030, P. R. China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei Province, 430030, P. R. China
| | - Meng Wu
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei Province, 430030, P. R. China
- Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences, Wuhan, Hubei Province, 430030, P. R. China
- NHC Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei Province, 430030, P. R. China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei Province, 430030, P. R. China
| | - Yonghui Zhang
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, P. R. China
| | - Gang Chen
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei Province, 430030, P. R. China
- Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences, Wuhan, Hubei Province, 430030, P. R. China
- NHC Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei Province, 430030, P. R. China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei Province, 430030, P. R. China
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Lovasik BP, Kim SC, Higginbotham L, Wakwe W, Mathews DV, Breeden C, Farris AB, Larsen CP, Ford ML, Nadler S, Adams AB. CD28-Selective Inhibition Prolongs Non-Human Primate Kidney Transplant Survival. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.03.539333. [PMID: 37205571 PMCID: PMC10187313 DOI: 10.1101/2023.05.03.539333] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
Costimulation blockade using belatacept results in improved renal function after kidney transplant as well as decreased likelihood of death/graft loss and reduced cardiovascular risk; however, higher rates and grades of acute rejection have prevented its widespread clinical adoption. Treatment with belatacept blocks both positive (CD28) and negative (CTLA-4) T cell signaling. CD28-selective therapies may offer improved potency by blocking CD28-mediated costimulation while leaving CTLA-4 mediated coinhibitory signals intact. Here we test a novel domain antibody directed at CD28 (anti-CD28 dAb (BMS-931699)) in a non-human primate kidney transplant model. Sixteen macaques underwent native nephrectomy and received life-sustaining renal allotransplantation from an MHC-mismatched donor. Animals were treated with belatacept alone, anti-CD28 dAb alone, or anti-CD28 dAb plus clinically relevant maintenance (MMF, Steroids) and induction therapy with either anti-IL-2R or T cell depletion. Treatment with anti-CD28 dAb extended survival compared to belatacept monotherapy (MST 187 vs. 29 days, p=0.07). The combination of anti-CD28 dAb and conventional immunosuppression further prolonged survival to MST ∼270 days. Animals maintained protective immunity with no significant infectious issues. These data demonstrate CD28-directed therapy is a safe and effective next-generation costimulatory blockade strategy with a demonstrated survival benefit and presumed advantage over belatacept by maintaining intact CTLA-4 coinhibitory signaling.
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Liu Y, Jiang J. A novel cuproptosis-related lncRNA signature predicts the prognosis and immunotherapy for hepatocellular carcinoma. Cancer Biomark 2023; 37:13-26. [PMID: 37005878 DOI: 10.3233/cbm-220259] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/04/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most serious malignant tumors with a poor prognosis worldwide. Cuproptosis is a novel copper-dependent cell death form, involving mitochondrial respiration and lipoylated components of the tricarboxylic acid (TCA) cycle. Long non-coding RNAs (lncRNAs) have been demonstrated to affect the tumorigenesis, growth, and metastasis of HCC. OBJECTIVE We explored the potential roles of cuproptosis-related lncRNAs in predicting the prognosis for HCC. METHODS The RNA-seq transcriptome data, mutation data, and clinical information data of HCC patients were downloaded from The Cancer Genome Atlas (TCGA) database. The least absolute shrinkage and selection operator (LASSO) algorithm and Cox regression analyses were performed to identify a prognostic cuproptosis-related lncRNA signature. The receiver operating characteristic (ROC) analysis was used to evaluate the predictive value of the lncRNA signature for HCC. The enrichment pathways, immune functions, immune cell infiltration, tumor mutation burden, and drug sensitivity were also analyzed. RESULTS We constructed a prognostic model consisting of 8 cuproptosis-related lncRNAs for HCC. The patients were divided into high-risk group and low-risk group according to the riskscore calculated using the model. Kaplan-Meier analysis revealed that the high-risk lncRNA signature was correlated with poor overall survival [hazard ratio (HR) =1.009, 95% confidence interval (CI) = 1.002-1.015; p= 0.010)] of HCC. A prognostic nomogram incorporated the lncRNA signature and clinicopathological features were constructed and showed favorable performance for predicting prognosis of HCC patients. In addition, the most immune-related functions were significantly different between the high-risk and low-risk groups. Tumor mutation burden (TMB) and immune checkpoints were also expressed differently between the two risk groups. Finally, HCC patients with low-risk score were more sensitive to several chemotherapy drugs. CONCLUSIONS The novel cuproptosis-related lncRNA signature could be used to predict prognosis and evaluate the effect of chemotherapy for HCC.
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Affiliation(s)
- Yanqing Liu
- Department of Laboratory Medicine, Ningbo First Hospital, Ningbo, Zhejiang, China
| | - Jianshuai Jiang
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo First Hospital, Ningbo, Zhejiang, China
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20
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Buondonno I, Sassi F, Cattaneo F, D’Amelio P. Association between Immunosenescence, Mitochondrial Dysfunction and Frailty Syndrome in Older Adults. Cells 2022; 12:cells12010044. [PMID: 36611837 PMCID: PMC9818926 DOI: 10.3390/cells12010044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 12/19/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022] Open
Abstract
Aging is associated with changes in the immune system, increased inflammation and mitochondrial dysfunction. The relationship between these phenomena and the clinical phenotype of frailty is unclear. Here, we evaluated the immune phenotypes, T cell functions and mitochondrial functions of immune cells in frail and robust older subjects. We enrolled 20 frail subjects age- and gender-matched with 20 robust controls, and T cell phenotype, response to immune stimulation, cytokine production and immune cell mitochondrial function were assessed. Our results showed that numbers of CD4+ and CD8+ T cells were decreased in frail subjects, without impairment to their ratios. Memory and naïve T cells were not significantly affected by frailty, whereas the expression of CD28 but not that of ICOS was decreased in T cells from frail subjects. T cells from robust subjects produced more IL-17 after CD28 stimulation. Levels of serum cytokines were similar in frail subjects and controls. Mitochondrial bioenergetics and ATP levels were significantly lower in immune cells from frail subjects. In conclusion, we suggest that changes in T cell profiles are associated with aging rather than with frailty syndrome; however, changes in T cell response to immune stimuli and reduced mitochondrial activity in immune cells may be considered hallmarks of frailty.
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Affiliation(s)
- Ilaria Buondonno
- Geriatric and Bone Disease Unit, Department of Medical Science, University of Torino, 10126 Torino, Italy
| | - Francesca Sassi
- Geriatric and Bone Disease Unit, Department of Medical Science, University of Torino, 10126 Torino, Italy
| | - Francesco Cattaneo
- Department of Public Health Sciences and Pediatrics, University of Torino, 10126 Torino, Italy
| | - Patrizia D’Amelio
- Geriatric and Bone Disease Unit, Department of Medical Science, University of Torino, 10126 Torino, Italy
- Department of Medicine, Service of Geriatric Medicine & Geriatric Rehabilitation, University of Lausanne Hospital (CHUV), 1011 Lausanne, Switzerland
- Correspondence: ; Tel.: +41-213143712
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21
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Fairchild RL. Fibroblastic reticular cells orchestrate long-term graft survival following recipient treatment with CD40 ligand-targeted costimulatory blockade. J Clin Invest 2022; 132:e165174. [PMID: 36519546 PMCID: PMC9753987 DOI: 10.1172/jci165174] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Fibroblastic reticular cells (FRCs) maintain the architecture of secondary lymphoid organs, which optimize interactions between antigen-presenting dendritic cells and reactive naive T cells. In this issue of the JCI, Zhao, Jung, and colleagues investigated CD4+FoxP3+ regulatory T cell development and long-term heart allograft survival in recipients treated with peritransplant costimulatory blockade to inhibit CD40/CD40 ligand (CD40L) signaling. Treatment with an anti-CD40L monoclonal antibody (mAb) increased the lymph node (LN) population of Madcam1+ FRCs and altered their transcription profile to express immunoregulatory mediators. Administration of nanoparticles, containing the anti-CD40L mAb and a targeting antibody against high endothelial venules, delivered the treatment into LNs of allograft recipients. Direct LN delivery of the costimulatory blockade allowed decreased dosing and increased the efficacy in extending graft survival. The results provide insights into mechanisms by which FRCs can promote donor-reactive tolerance, and establish a strategy for administering costimulation-blocking reagents that circumvent systemic effects and improve allograft outcomes.
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22
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Looking beyond the Skin: Pathophysiology of Cardiovascular Comorbidity in Psoriasis and the Protective Role of Biologics. Pharmaceuticals (Basel) 2022; 15:ph15091101. [PMID: 36145322 PMCID: PMC9503011 DOI: 10.3390/ph15091101] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 08/23/2022] [Accepted: 08/25/2022] [Indexed: 11/16/2022] Open
Abstract
Psoriasis is a chronic systemic inflammatory disease associated with a higher incidence of cardiovascular disease, especially in patients with moderate to severe psoriasis. It has been estimated that severe psoriasis confers a 25% increase in relative risk of cardiovascular disease, regardless of traditional risk factors. Although the underlying pathogenic mechanisms relating psoriasis to increased cardiovascular risk are not clear, atherosclerosis is emerging as a possible link between skin and vascular affection. The hypothesis that the inflammatory cascade activated in psoriasis contributes to the atherosclerotic process provides the underlying basis to suggest that an anti-inflammatory therapy that improved atherosclerosis would also reduce the risk of MACEs. In this sense, the introduction of biological drugs which specifically target cytokines implicated in the inflammatory cascade have increased the expectations of control over the cardiovascular comorbidity present in psoriasis patients, however, their role in vascular damage processes remains controversial. The aim of this paper is to review the mechanistic link between psoriasis and cardiovascular disease development, as well as analyzing which of the biological treatments could also reduce the cardiovascular risk in these patients, fueling a growing debate on the modification of the general algorithm of treatment.
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23
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Iglesias M, Brennan DC, Larsen CP, Raimondi G. Targeting inflammation and immune activation to improve CTLA4-Ig-based modulation of transplant rejection. Front Immunol 2022; 13:926648. [PMID: 36119093 PMCID: PMC9478663 DOI: 10.3389/fimmu.2022.926648] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 08/09/2022] [Indexed: 11/16/2022] Open
Abstract
For the last few decades, Calcineurin inhibitors (CNI)-based therapy has been the pillar of immunosuppression for prevention of organ transplant rejection. However, despite exerting effective control of acute rejection in the first year post-transplant, prolonged CNI use is associated with significant side effects and is not well suited for long term allograft survival. The implementation of Costimulation Blockade (CoB) therapies, based on the interruption of T cell costimulatory signals as strategy to control allo-responses, has proven potential for better management of transplant recipients compared to CNI-based therapies. The use of the biologic cytotoxic T-lymphocyte associated protein 4 (CTLA4)-Ig is the most successful approach to date in this arena. Following evaluation of the BENEFIT trials, Belatacept, a high-affinity version of CTLA4-Ig, has been FDA approved for use in kidney transplant recipients. Despite its benefits, the use of CTLA4-Ig as a monotherapy has proved to be insufficient to induce long-term allograft acceptance in several settings. Multiple studies have demonstrated that events that induce an acute inflammatory response with the consequent release of proinflammatory cytokines, and an abundance of allograft-reactive memory cells in the recipient, can prevent the induction of or break established immunomodulation induced with CoB regimens. This review highlights advances in our understanding of the factors and mechanisms that limit CoB regimens efficacy. We also discuss recent successes in experimentally designing complementary therapies that favor CTLA4-Ig effect, affording a better control of transplant rejection and supporting their clinical applicability.
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Affiliation(s)
- Marcos Iglesias
- Vascularized and Composite Allotransplantation (VCA) Laboratory, Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- *Correspondence: Giorgio Raimondi, ; Marcos Iglesias,
| | - Daniel C. Brennan
- Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Christian P. Larsen
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, United States
| | - Giorgio Raimondi
- Vascularized and Composite Allotransplantation (VCA) Laboratory, Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- *Correspondence: Giorgio Raimondi, ; Marcos Iglesias,
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24
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Li Y, Sun Y, Liu Y, Wang B, Li J, Wang H, Zhang H, Wang X, Han X, Lin Q, Zhou Y, Hu L, Song Y, Bao J, Gong L, Sun M, Yuan X, Zhang X, Lian M, Xiao X, Miao Q, Wang Q, Li KK, Du S, Ma A, Li Y, Xu J, Tang S, Shi J, Xu Y, Yang L, Zhang J, Huang Z, Zhou L, Cui Y, Seldin MF, Gershwin ME, Yan H, Zou Z, Zuo X, Tang R, Ma X. Genome-wide meta-analysis identifies susceptibility loci for autoimmune hepatitis type 1. Hepatology 2022; 76:564-575. [PMID: 35184318 DOI: 10.1002/hep.32417] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 02/10/2022] [Accepted: 02/16/2022] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIMS Autoimmune hepatitis (AIH) is a rare and chronic autoimmune liver disease. While genetic factors are believed to play a crucial role in the etiopathogenesis of AIH, our understanding of these genetic risk factors is still limited. In this study, we aimed to identify susceptibility loci to further understand the pathogenesis of this disease. APPROACH AND RESULTS We conducted a case-control association study of 1,622 Chinese patients with AIH type 1 and 10,466 population controls from two independent cohorts. A meta-analysis was performed to ascertain variants associated with AIH type 1. A single-nucleotide polymorphism within the human leukocyte antigen (HLA) region showed the strongest association with AIH (rs6932730: OR = 2.32; p = 9.21 × 10-73 ). The meta-analysis also identified two non-HLA loci significantly associated with AIH: CD28/CTLA4/ICOS on 2q33.3 (rs72929257: OR = 1.31; p = 2.92 × 10-9 ) and SYNPR on 3p14.2 (rs6809477: OR = 1.25; p = 5.48 × 10-9 ). In silico annotation, reporter gene assays, and CRISPR activation experiments identified a distal enhancer at 2q33.3 that regulated expression of CTLA4. In addition, variants near STAT1/STAT4 (rs11889341: OR = 1.24; p = 1.34 × 10-7 ), LINC00392 (rs9564997: OR = 0.81; p = 2.53 × 10-7 ), IRF8 (rs11117432: OR = 0.72; p = 6.10 × 10-6 ), and LILRA4/LILRA5 (rs11084330: OR = 0.65; p = 5.19 × 10-6 ) had suggestive association signals with AIH. CONCLUSIONS Our study identifies two novel loci (CD28/CTLA4/ICOS and SYNPR) exceeding genome-wide significance and suggests four loci as potential risk factors. These findings highlight the importance of costimulatory signaling and neuro-immune interaction in the pathogenesis of AIH.
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Affiliation(s)
- You Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, Shanghai, China
| | - Ying Sun
- Department of Liver Disease, Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Yanmin Liu
- Clinical Laboratory Center and Clinical Research Center for Autoimmune Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Jia Li
- Tianjin Second People's Hospital, Tianjin Institute of Hepatology, Tianjin, China
| | - Hanxiao Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, Shanghai, China
| | - Haiping Zhang
- Clinical Laboratory Center and Clinical Research Center for Autoimmune Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Xiaoyi Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Xu Han
- Tianjin Second People's Hospital, Tianjin Institute of Hepatology, Tianjin, China
| | - Qiuxiang Lin
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Yang Zhou
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Lilin Hu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuhu Song
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jie Bao
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ling Gong
- Department of Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Mengying Sun
- Department of Gastroenterology, The General Hospital of Western Theater Command, Chengdu, China
| | - Xiaoling Yuan
- Department of Infectious Disease, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xinhe Zhang
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, ShenYang, China
| | - Min Lian
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, Shanghai, China
| | - Xiao Xiao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, Shanghai, China
| | - Qi Miao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, Shanghai, China
| | - Qixia Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, Shanghai, China
| | - Ke-Ke Li
- Department of Dermatology, China-Japan Friendship Hospital, Beijing, China
- Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Shiyu Du
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing, China
| | - Anlin Ma
- Department of infection disease, China-Japan Friendship Hospital, Beijing, China
| | - Yiling Li
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, ShenYang, China
| | - Jie Xu
- Department of Infectious Disease, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shanhong Tang
- Department of Gastroenterology, The General Hospital of Western Theater Command, Chengdu, China
| | - Junping Shi
- Department of Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Yun Xu
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ling Yang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiming Zhang
- Department of Infectious Diseases, Huashan Hospital and Key Laboratory of Medical Molecular Virology (MOH & MOE), Shanghai Medical College, Fudan University, Shanghai, China
| | - Zuxiong Huang
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Lu Zhou
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Yong Cui
- Department of Dermatology, China-Japan Friendship Hospital, Beijing, China
- Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Michael F Seldin
- Division of Rheumatology, Department of Medicine, Allergy and Clinical Immunology, University of California at Davis, Davis, California, USA
- Department of Biochemistry and Molecular Medicine, University of California at Davis, Davis, California, USA
| | - M Eric Gershwin
- Division of Rheumatology, Department of Medicine, Allergy and Clinical Immunology, University of California at Davis, Davis, California, USA
| | - Huiping Yan
- Clinical Laboratory Center and Clinical Research Center for Autoimmune Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Zhengsheng Zou
- Department of Liver Disease, Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Xianbo Zuo
- Department of Dermatology, China-Japan Friendship Hospital, Beijing, China
- Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, Anhui, China
- Department of Pharmacy, China-Japan Friendship Hospital, Beijing, China
| | - Ruqi Tang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, Shanghai, China
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, Shanghai, China
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25
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Alharbi N, Skwarczynski M, Toth I. The influence of component structural arrangement on peptide vaccine immunogenicity. Biotechnol Adv 2022; 60:108029. [PMID: 36028180 DOI: 10.1016/j.biotechadv.2022.108029] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 08/19/2022] [Indexed: 11/02/2022]
Abstract
Peptide-based subunit vaccines utilise minimal immunogenic components (i.e. peptides) to generate highly specific immune responses, without triggering adverse reactions. However, strong adjuvants and/or effective delivery systems must be incorporated into such vaccines, as peptide antigens cannot induce substantial immune responses on their own. Unfortunately, many adjuvants are too weak or too toxic to be used in combination with peptide antigens. These shortcomings have been addressed by the conjugation of peptide antigens with lipidic/ hydrophobic adjuvanting moieties. The conjugates have shown promising safety profiles and improved immunogenicity without the help of traditional adjuvants and have been efficient in inducing desired immune responses following various routes of administration, including subcutaneous, oral and intranasal. However, not only conjugation per se, but also component arrangement influences vaccine efficacy. This review highlights the importance of influence of the vaccine chemical structure modification on the immune responses generated. It discusses a variety of factors that affect the immunogenicity of peptide conjugates, including: i) self-adjuvanting moiety length and number; ii) the orientation of epitopes and self-adjuvanting moieties in the conjugate; iii) the presence of spacers between conjugated components; iv) multiepitopic arrangement; and v) the effect of chirality on vaccine efficacy.
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Affiliation(s)
- Nedaa Alharbi
- School of Chemistry & Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia; University of Jeddah, College of Science and Arts, Department of Chemistry, Jeddah, Saudi Arabia
| | - Mariusz Skwarczynski
- School of Chemistry & Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia.
| | - Istvan Toth
- School of Chemistry & Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia; School of Pharmacy, The University of Queensland, Brisbane, QLD, 4102, Australia.
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26
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Huang HJ, Schechtman K, Askar M, Bernadt C, Mittler B, Dore P, Witt C, Byers D, Vazquez-Guillamet R, Halverson L, Nava R, Puri V, Gelman A, Kreisel D, Hachem RR. A pilot randomized controlled trial of de novo belatacept-based immunosuppression following anti-thymocyte globulin induction in lung transplantation. Am J Transplant 2022; 22:1884-1892. [PMID: 35286760 PMCID: PMC9262777 DOI: 10.1111/ajt.17028] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 03/01/2022] [Accepted: 03/02/2022] [Indexed: 01/25/2023]
Abstract
The development of donor-specific antibodies (DSA) after lung transplantation is common and results in adverse outcomes. In kidney transplantation, Belatacept has been associated with a lower incidence of DSA, but experience with Belatacept in lung transplantation is limited. We conducted a two-center pilot randomized controlled trial of de novo immunosuppression with Belatacept after lung transplantation to assess the feasibility of conducting a pivotal trial. Twenty-seven participants were randomized to Control (Tacrolimus, Mycophenolate Mofetil, and prednisone, n = 14) or Belatacept-based immunosuppression (Tacrolimus, Belatacept, and prednisone until day 89 followed by Belatacept, Mycophenolate Mofetil, and prednisone, n = 13). All participants were treated with rabbit anti-thymocyte globulin for induction immunosuppression. We permanently stopped randomization and treatment with Belatacept after three participants in the Belatacept arm died compared to none in the Control arm. Subsequently, two additional participants in the Belatacept arm died for a total of five deaths compared to none in the Control arm (log rank p = .016). We did not detect a significant difference in DSA development, acute cellular rejection, or infection between the two groups. We conclude that the investigational regimen used in this study is associated with increased mortality after lung transplantation.
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Affiliation(s)
| | | | - Medhat Askar
- Department of Pathology and Laboratory Medicine, Texas A & M College of Medicine
| | - Cory Bernadt
- Department of Pathology and Immunology, Washington University in St. Louis
| | - Brigitte Mittler
- Division of Pulmonary and Critical Care, Washington University in St. Louis
| | - Peter Dore
- Division of Biostatistics, Washington University in St. Louis
| | - Chad Witt
- Division of Pulmonary and Critical Care, Washington University in St. Louis
| | - Derek Byers
- Division of Pulmonary and Critical Care, Washington University in St. Louis
| | | | - Laura Halverson
- Division of Pulmonary and Critical Care, Washington University in St. Louis
| | - Ruben Nava
- Division of Cardiothoracic Surgery, Washington University in St. Louis
| | - Varun Puri
- Division of Cardiothoracic Surgery, Washington University in St. Louis
| | - Andrew Gelman
- Division of Cardiothoracic Surgery, Washington University in St. Louis
| | - Daniel Kreisel
- Division of Cardiothoracic Surgery, Washington University in St. Louis
| | - Ramsey R. Hachem
- Division of Pulmonary and Critical Care, Washington University in St. Louis
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27
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Muire PJ, Thompson MA, Christy RJ, Natesan S. Advances in Immunomodulation and Immune Engineering Approaches to Improve Healing of Extremity Wounds. Int J Mol Sci 2022; 23:4074. [PMID: 35456892 PMCID: PMC9032453 DOI: 10.3390/ijms23084074] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/01/2022] [Accepted: 04/03/2022] [Indexed: 12/04/2022] Open
Abstract
Delayed healing of traumatic wounds often stems from a dysregulated immune response initiated or exacerbated by existing comorbidities, multiple tissue injury or wound contamination. Over decades, approaches towards alleviating wound inflammation have been centered on interventions capable of a collective dampening of various inflammatory factors and/or cells. However, a progressive understanding of immune physiology has rendered deeper knowledge on the dynamic interplay of secreted factors and effector cells following an acute injury. There is a wide body of literature, both in vitro and in vivo, abstracted on the immunomodulatory approaches to control inflammation. Recently, targeted modulation of the immune response via biotechnological approaches and biomaterials has gained attention as a means to restore the pro-healing phenotype and promote tissue regeneration. In order to fully realize the potential of these approaches in traumatic wounds, a critical and nuanced understanding of the relationships between immune dysregulation and healing outcomes is needed. This review provides an insight on paradigm shift towards interventional approaches to control exacerbated immune response following a traumatic injury from an agonistic to a targeted path. We address such a need by (1) providing a targeted discussion of the wound healing processes to assist in the identification of novel therapeutic targets and (2) highlighting emerging technologies and interventions that utilize an immunoengineering-based approach. In addition, we have underscored the importance of immune engineering as an emerging tool to provide precision medicine as an option to modulate acute immune response following a traumatic injury. Finally, an overview is provided on how an intervention can follow through a successful clinical application and regulatory pathway following laboratory and animal model evaluation.
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Affiliation(s)
- Preeti J. Muire
- Combat Wound Care Research Department, US Army Institute of Surgical Research, JBSA Ft Sam Houston, San Antonio, TX 78234, USA; (M.A.T.); (R.J.C.)
| | | | | | - Shanmugasundaram Natesan
- Combat Wound Care Research Department, US Army Institute of Surgical Research, JBSA Ft Sam Houston, San Antonio, TX 78234, USA; (M.A.T.); (R.J.C.)
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Alexander M, Luo Y, Raimondi G, O’Shea JJ, Gadina M. Jakinibs of All Trades: Inhibiting Cytokine Signaling in Immune-Mediated Pathologies. Pharmaceuticals (Basel) 2021; 15:48. [PMID: 35056105 PMCID: PMC8779366 DOI: 10.3390/ph15010048] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/14/2021] [Accepted: 12/20/2021] [Indexed: 12/11/2022] Open
Abstract
Over the last 25 years, inhibition of Janus kinases (JAKs) has been pursued as a modality for treating various immune and inflammatory disorders. While the clinical development of JAK inhibitors (jakinibs) began with the investigation of their use in allogeneic transplantation, their widest successful application came in autoimmune and allergic diseases. Multiple molecules have now been approved for diseases ranging from rheumatoid and juvenile arthritis to ulcerative colitis, atopic dermatitis, graft-versus-host-disease (GVHD) and other inflammatory pathologies in 80 countries around the world. Moreover, two jakinibs have also shown surprising efficacy in the treatment of hospitalized coronavirus disease-19 (COVID-19) patients, indicating additional roles for jakinibs in infectious diseases, cytokine storms and other hyperinflammatory syndromes. Jakinibs, as a class of pharmaceutics, continue to expand in clinical applications and with the development of more selective JAK-targeting and organ-selective delivery. Importantly, jakinib safety and pharmacokinetics have been investigated alongside clinical development, further cementing the potential benefits and limits of jakinib use. This review covers jakinibs that are approved or are under late phase investigation, focusing on clinical applications, pharmacokinetic and safety profiles, and future opportunities and challenges.
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Affiliation(s)
- Madison Alexander
- Translational Immunology Section, National Institute of Arthritis, Musculoskeletal, and Skin Diseases, National Institutes of Health, 10 Center Drive, Building 10 Room 10C211, Bethesda, MD 20892, USA;
| | - Yiming Luo
- Vasculitis Translational Research Program, Systemic Autoimmunity Branch, National Institute of Arthritis, Musculoskeletal, and Skin Diseases, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA;
| | - Giorgio Raimondi
- Vascularized Composite Allotransplantation Laboratory, Department of Plastic and Reconstructive Surgery, Johns Hopkins School of Medicine, 720 Rutland Ave., Ross Research Building, Suite 755A, Baltimore, MD 21205, USA;
| | - John J. O’Shea
- Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal, and Skin Diseases, National Institutes of Health, 10 Center Drive, Building 10 Room 13C103C, Bethesda, MD 20892, USA;
| | - Massimo Gadina
- Translational Immunology Section, National Institute of Arthritis, Musculoskeletal, and Skin Diseases, National Institutes of Health, 10 Center Drive, Building 10 Room 10C211, Bethesda, MD 20892, USA;
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Valencia JC, Erwin-Cohen RA, Clavijo PE, Allen C, Sanford ME, Day CP, Hess MM, Johnson M, Yin J, Fenimore JM, Bettencourt IA, Tsuneyama K, Romero ME, Klarmann KD, Jiang P, Bae HR, McVicar DW, Merlino G, Edmondson EF, Anandasabapathy N, Young HA. Myeloid-Derived Suppressive Cell Expansion Promotes Melanoma Growth and Autoimmunity by Inhibiting CD40/IL27 Regulation in Macrophages. Cancer Res 2021; 81:5977-5990. [PMID: 34642183 PMCID: PMC8639618 DOI: 10.1158/0008-5472.can-21-1148] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 08/18/2021] [Accepted: 10/07/2021] [Indexed: 11/16/2022]
Abstract
The relationship between cancer and autoimmunity is complex. However, the incidence of solid tumors such as melanoma has increased significantly among patients with previous or newly diagnosed systemic autoimmune disease (AID). At the same time, immune checkpoint blockade (ICB) therapy of cancer induces de novo autoinflammation and exacerbates underlying AID, even without evident antitumor responses. Recently, systemic lupus erythematosus (SLE) activity was found to drive myeloid-derived suppressor cell (MDSC) formation in patients, a known barrier to healthy immune surveillance and successful cancer immunotherapy. Cross-talk between MDSCs and macrophages generally drives immune suppressive activity in the tumor microenvironment. However, it remains unclear how peripheral pregenerated MDSC under chronic inflammatory conditions modulates global macrophage immune functions and the impact it could have on existing tumors and underlying lupus nephritis. Here we show that pathogenic expansion of SLE-generated MDSCs by melanoma drives global macrophage polarization and simultaneously impacts the severity of lupus nephritis and tumor progression in SLE-prone mice. Molecular and functional data showed that MDSCs interact with autoimmune macrophages and inhibit cell surface expression of CD40 and the production of IL27. Moreover, low CD40/IL27 signaling in tumors correlated with high tumor-associated macrophage infiltration and ICB therapy resistance both in murine and human melanoma exhibiting active IFNγ signatures. These results suggest that preventing global macrophage reprogramming induced by MDSC-mediated inhibition of CD40/IL27 signaling provides a precision melanoma immunotherapy strategy, supporting an original and advantageous approach to treat solid tumors within established autoimmune landscapes. SIGNIFICANCE: Myeloid-derived suppressor cells induce macrophage reprogramming by suppressing CD40/IL27 signaling to drive melanoma progression, simultaneously affecting underlying autoimmune disease and facilitating resistance to immunotherapy within preexisting autoimmune landscapes.
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Affiliation(s)
- Julio C Valencia
- Laboratory of Cancer Immunometabolism, CCR, NCI, Frederick Maryland.
| | | | - Paul E Clavijo
- Head and Neck Surgery Branch, National Institute on Deafness and other Communication Disorders, Bethesda, Maryland
| | - Clint Allen
- Head and Neck Surgery Branch, National Institute on Deafness and other Communication Disorders, Bethesda, Maryland
| | | | - Chi-Ping Day
- Laboratory of Cancer Biology and Genetics, CCR, NCI, Bethesda, Maryland
| | - Megan M Hess
- Laboratory of Cancer Immunometabolism, CCR, NCI, Frederick Maryland
| | - Morgan Johnson
- Laboratory of Cancer Immunometabolism, CCR, NCI, Frederick Maryland
| | - Jie Yin
- Laboratory of Cancer Immunometabolism, CCR, NCI, Frederick Maryland
| | - John M Fenimore
- Laboratory of Cancer Immunometabolism, CCR, NCI, Frederick Maryland
| | | | | | | | | | - Peng Jiang
- Cancer Data Science laboratory, CCR, NCI, Bethesda, Maryland
| | - Heekyong R Bae
- Laboratory of Cancer Immunometabolism, CCR, NCI, Frederick Maryland
| | - Daniel W McVicar
- Laboratory of Cancer Immunometabolism, CCR, NCI, Frederick Maryland
| | - Glenn Merlino
- Laboratory of Cancer Biology and Genetics, CCR, NCI, Bethesda, Maryland
| | | | | | - Howard A Young
- Laboratory of Cancer Immunometabolism, CCR, NCI, Frederick Maryland
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Wu HH, Ralph KL, Sepuldeva E, Hansen G, Li H, Huang ZF, Liu D, Dziegelewski M, Ahlberg J, Frego L, Fogal S, van Tongeren S, Grimaldi C, Litzenberger T, Presky D, Singh S, Brodeur S, Kroe-Barrett R. An optimally designed anti-human CD40 antibody with potent B cell suppression for the treatment of autoimmune diseases. Int J Pharm 2021; 609:121162. [PMID: 34624444 DOI: 10.1016/j.ijpharm.2021.121162] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Revised: 09/30/2021] [Accepted: 10/03/2021] [Indexed: 12/13/2022]
Abstract
Antibodies targeting the CD40-CD40L pathway have great potential for treating autoimmune diseases like rheumatoid arthritis, systemic lupus erythematosus (SLE), lupus nephritis (LN), and inflammatory bowel diseases (IBD). However, in addition to the known difficulty in generating a purely antagonistic CD40 antibody, the presence of CD40 and CD40L on platelets creates additional unique challenges for the safety, target coverage, and clearance of antibodies targeting this pathway. Previously described therapeutic antibodies targeting this pathway have various shortcomings, and the full therapeutic potential of this axis has yet to be realized. Herein, we describe the generation and characterization of BI 655064, a novel, purely antagonistic anti-CD40 antibody that potently neutralizes CD40-CD40L-dependent B-cell stimulation without evidence of impacting platelet functions. This uniquely optimized antibody targeting a highly challenging pathway was obtained by applying stringent functional and biophysical criteria during the lead selection process. BI 655064 has favorable target-mediated drug disposition (TMDD)-saturation pharmacokinetics, consistent with that of a high-quality therapeutic monoclonal antibody.
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Affiliation(s)
- Helen Haixia Wu
- Boehringer Ingelheim Pharmaceuticals, Inc. Biotherapeutics Molecule Discovery, Ridgefield, CT, USA.
| | - Kerry-Leigh Ralph
- Boehringer Ingelheim Pharmaceuticals, Inc. Cancer Immunology & Immune Modulation, Ridgefield, CT, USA
| | - Eliud Sepuldeva
- Boehringer Ingelheim Pharmaceuticals, Inc. Biotherapeutics Molecule Discovery, Ridgefield, CT, USA
| | - Gale Hansen
- Boehringer Ingelheim Pharmaceuticals, Inc. Biotherapeutics Molecule Discovery, Ridgefield, CT, USA
| | - Hua Li
- Boehringer Ingelheim Pharmaceuticals, Inc. Biotherapeutics Molecule Discovery, Ridgefield, CT, USA
| | - Zhong-Fu Huang
- Boehringer Ingelheim Pharmaceuticals, Inc. Biotherapeutics Molecule Discovery, Ridgefield, CT, USA
| | - Dongmei Liu
- Boehringer Ingelheim Pharmaceuticals, Inc. Biotherapeutics Molecule Discovery, Ridgefield, CT, USA
| | - Michael Dziegelewski
- Boehringer Ingelheim Pharmaceuticals, Inc. Biotherapeutics Molecule Discovery, Ridgefield, CT, USA
| | - Jennifer Ahlberg
- Boehringer Ingelheim Pharmaceuticals, Inc. Biotherapeutics Molecule Discovery, Ridgefield, CT, USA
| | - Lee Frego
- Boehringer Ingelheim Pharmaceuticals, Inc. Biotherapeutics Molecule Discovery, Ridgefield, CT, USA
| | - Steve Fogal
- Boehringer Ingelheim Pharmaceuticals, Inc. Immunology & Respiratory, Ridgefield, CT, USA
| | - Susan van Tongeren
- Boehringer Ingelheim Pharmaceuticals, Inc. Nonclinical Drug Safety, Ridgefield, CT, USA
| | - Christine Grimaldi
- Boehringer Ingelheim Pharmaceuticals, Inc. Drug Metabolism and Pharmacokinetics, Ridgefield, CT, USA
| | - Tobias Litzenberger
- Boehringer Ingelheim Pharmaceuticals, Inc. Translational Medicine & Clinical Pharmacology, Biberach, B-W, Germany
| | | | - Sanjaya Singh
- Janssen Biotherapeutics at Johnson & Johnson. Spring House, PA, USA
| | - Scott Brodeur
- Janssen Pharmaceutical Companies at Johnson & Johnson. New Jersey, PA, USA
| | - Rachel Kroe-Barrett
- Boehringer Ingelheim Pharmaceuticals, Inc. Biotherapeutics Molecule Discovery, Ridgefield, CT, USA
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Iglesias M, Khalifian S, Oh BC, Zhang Y, Miller D, Beck S, Brandacher G, Raimondi G. A short course of tofacitinib sustains the immunoregulatory effect of CTLA4-Ig in the presence of inflammatory cytokines and promotes long-term survival of murine cardiac allografts. Am J Transplant 2021; 21:2675-2687. [PMID: 33331121 DOI: 10.1111/ajt.16456] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 12/07/2020] [Accepted: 12/11/2020] [Indexed: 01/25/2023]
Abstract
Costimulation blockade-based regimens are a promising strategy for management of transplant recipients. However, maintenance immunosuppression via CTLA4-Ig monotherapy is characterized by high frequency of rejection episodes. Recent evidence suggests that inflammatory cytokines contribute to alloreactive T cell activation in a CD28-independent manner, a reasonable contributor to the limited efficacy of CTLA4-Ig. In this study, we investigated the possible synergism of a combined short-term inhibition of cytokine signaling and CD28 engagement on the modulation of rejection. Our results demonstrate that the JAK/STAT inhibitor tofacitinib restored the immunomodulatory effect of CTLA4-Ig on mouse alloreactive T cells in the presence of inflammatory cytokines. Tofacitinib exposure conferred dendritic cells with a tolerogenic phenotype reducing their cytokine secretion and costimulatory molecules expression. JAK inhibition also directly affected T cell activation. In vivo, the combination of CTLA4-Ig and tofacitinib induced long-term survival of heart allografts and, importantly, it was equally effective when using grafts subjected to prolonged ischemia. Transplant survival correlated with a reduction in effector T cells and intragraft accumulation of regulatory T cells. Collectively, our studies demonstrate a powerful synergism between CTLA4-Ig and tofacitinib and suggest their combined use is a promising strategy for improved management of transplanted patients.
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Affiliation(s)
- Marcos Iglesias
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Saami Khalifian
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Byoung C Oh
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Yichuan Zhang
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Devin Miller
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Sarah Beck
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Gerald Brandacher
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Giorgio Raimondi
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Egwuagu CE, Alhakeem SA, Mbanefo EC. Uveitis: Molecular Pathogenesis and Emerging Therapies. Front Immunol 2021; 12:623725. [PMID: 33995347 PMCID: PMC8119754 DOI: 10.3389/fimmu.2021.623725] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 03/30/2021] [Indexed: 12/28/2022] Open
Abstract
The profound impact that vision loss has on human activities and quality of life necessitates understanding the etiology of potentially blinding diseases and their clinical management. The unique anatomic features of the eye and its sequestration from peripheral immune system also provides a framework for studying other diseases in immune privileged sites and validating basic immunological principles. Thus, early studies of intraocular inflammatory diseases (uveitis) were at the forefront of research on organ transplantation. These studies laid the groundwork for foundational discoveries on how immune system distinguishes self from non-self and established current concepts of acquired immune tolerance and autoimmunity. Our charge in this review is to examine how advances in molecular cell biology and immunology over the past 3 decades have contributed to the understanding of mechanisms that underlie immunopathogenesis of uveitis. Particular emphasis is on how advances in biotechnology have been leveraged in developing biologics and cell-based immunotherapies for uveitis and other neuroinflammatory diseases.
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Affiliation(s)
- Charles E Egwuagu
- Molecular Immunology Section, Laboratory of Immunology, National Eye Institute (NEI), National Institutes of Health, Bethesda, MD, United States
| | - Sahar A Alhakeem
- Molecular Immunology Section, Laboratory of Immunology, National Eye Institute (NEI), National Institutes of Health, Bethesda, MD, United States.,Department of Biomedical Sciences, College of Health Sciences, University of Wisconsin-Milwaukee, Milwaukee, WI, United States
| | - Evaristus C Mbanefo
- Molecular Immunology Section, Laboratory of Immunology, National Eye Institute (NEI), National Institutes of Health, Bethesda, MD, United States
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Lone SN, Bhat AA, Wani NA, Karedath T, Hashem S, Nisar S, Singh M, Bagga P, Das BC, Bedognetti D, Reddy R, Frenneaux MP, El-Rifai W, Siddiqi MA, Haris M, Macha MA. miRNAs as novel immunoregulators in cancer. Semin Cell Dev Biol 2021; 124:3-14. [PMID: 33926791 DOI: 10.1016/j.semcdb.2021.04.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 04/07/2021] [Accepted: 04/13/2021] [Indexed: 02/06/2023]
Abstract
The immune system is a well-known vital regulator of tumor growth, and one of the main hallmarks of cancer is evading the immune system. Immune system deregulation can lead to immune surveillance evasion, sustained cancer growth, proliferation, and metastasis. Tumor-mediated disruption of the immune system is accomplished by different mechanisms that involve extensive crosstalk with the immediate microenvironment, which includes endothelial cells, immune cells, and stromal cells, to create a favorable tumor niche that facilitates the development of cancer. The essential role of non-coding RNAs such as microRNAs (miRNAs) in the mechanism of cancer cell immune evasion has been highlighted in recent studies. miRNAs are small non-coding RNAs that regulate a wide range of post-transcriptional gene expression in a cell. Recent studies have focused on the function that miRNAs play in controlling the expression of target proteins linked to immune modulation. Studies show that miRNAs modulate the immune response in cancers by regulating the expression of different immune-modulatory molecules associated with immune effector cells, such as macrophages, dendritic cells, B-cells, and natural killer cells, as well as those present in tumor cells and the tumor microenvironment. This review explores the relationship between miRNAs, their altered patterns of expression in tumors, immune modulation, and the functional control of a wide range of immune cells, thereby offering detailed insights on the crosstalk of tumor-immune cells and their use as prognostic markers or therapeutic agents.
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Affiliation(s)
- Saife N Lone
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, Jammu & Kashmir, India
| | - Ajaz A Bhat
- Molecular and Metabolic Imaging Laboratory, Cancer Research Department, Sidra Medicine, Doha, Qatar
| | - Nissar A Wani
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, Jammu & Kashmir, India
| | | | - Sheema Hashem
- Molecular and Metabolic Imaging Laboratory, Cancer Research Department, Sidra Medicine, Doha, Qatar
| | - Sabah Nisar
- Molecular and Metabolic Imaging Laboratory, Cancer Research Department, Sidra Medicine, Doha, Qatar
| | - Mayank Singh
- Dr. B. R. Ambedkar Institute Rotary Cancer Hospital (BRAIRCH), AIIMS, New Delhi, India
| | - Puneet Bagga
- Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Bhudev Chandra Das
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Uttar Pradesh, India
| | - Davide Bedognetti
- Laboratory of Cancer Immunogenomics, Cancer Research Department, Sidra Medicine, Doha, Qatar; Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy; College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
| | - Ravinder Reddy
- Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA
| | | | - Wael El-Rifai
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Mushtaq A Siddiqi
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology, India
| | - Mohammad Haris
- Molecular and Metabolic Imaging Laboratory, Cancer Research Department, Sidra Medicine, Doha, Qatar; Laboratory Animal Research Center, Qatar University, Doha, Qatar.
| | - Muzafar A Macha
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology, India.
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Zhai Y, Moosavi R, Chen M. Immune Checkpoints, a Novel Class of Therapeutic Targets for Autoimmune Diseases. Front Immunol 2021; 12:645699. [PMID: 33968036 PMCID: PMC8097144 DOI: 10.3389/fimmu.2021.645699] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 03/02/2021] [Indexed: 12/14/2022] Open
Abstract
Autoimmune diseases, such as multiple sclerosis and type-1 diabetes, are the outcomes of a failure of immune tolerance. Immune tolerance is sustained through interplays between two inter-dependent clusters of immune activities: immune stimulation and immune regulation. The mechanisms of immune regulation are exploited as therapeutic targets for the treatment of autoimmune diseases. One of these mechanisms is immune checkpoints (ICPs). The roles of ICPs in maintaining immune tolerance and hence suppressing autoimmunity were revealed in animal models and validated by the clinical successes of ICP-targeted therapeutics for autoimmune diseases. Recently, these roles were highlighted by the clinical discovery that the blockade of ICPs causes autoimmune disorders. Given the crucial roles of ICPs in immune tolerance, it is plausible to leverage ICPs as a group of therapeutic targets to restore immune tolerance and treat autoimmune diseases. In this review, we first summarize working mechanisms of ICPs, particularly those that have been utilized for therapeutic development. Then, we recount the agents and approaches that were developed to target ICPs and treat autoimmune disorders. These agents take forms of fusion proteins, antibodies, nucleic acids, and cells. We also review and discuss safety information for these therapeutics. We wrap up this review by providing prospects for the development of ICP-targeting therapeutics. In summary, the ever-increasing studies and results of ICP-targeting of therapeutics underscore their tremendous potential to become a powerful class of medicine for autoimmune diseases.
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Affiliation(s)
- Yujia Zhai
- Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, United States
| | - Reza Moosavi
- Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, United States
| | - Mingnan Chen
- Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, United States
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Kim MY, Brennan DC. Therapies for Chronic Allograft Rejection. Front Pharmacol 2021; 12:651222. [PMID: 33935762 PMCID: PMC8082459 DOI: 10.3389/fphar.2021.651222] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 03/10/2021] [Indexed: 12/14/2022] Open
Abstract
Remarkable advances have been made in the pathophysiology, diagnosis, and treatment of antibody-mediated rejection (ABMR) over the past decades, leading to improved graft outcomes. However, long-term failure is still high and effective treatment for chronic ABMR, an important cause of graft failure, has not yet been identified. Chronic ABMR has a relatively different phenotype from active ABMR and is a slowly progressive disease in which graft injury is mainly caused by de novo donor specific antibodies (DSA). Since most trials of current immunosuppressive therapies for rejection have focused on active ABMR, treatment strategies based on those data might be less effective in chronic ABMR. A better understanding of chronic ABMR may serve as a bridge in establishing treatment strategies to improve graft outcomes. In this in-depth review, we focus on the pathophysiology and characteristics of chronic ABMR along with the newly revised Banff criteria in 2017. In addition, in terms of chronic ABMR, we identify the reasons for the resistance of current immunosuppressive therapies and look at ongoing research that could play a role in setting better treatment strategies in the future. Finally, we review non-invasive biomarkers as tools to monitor for rejection.
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Affiliation(s)
| | - Daniel C. Brennan
- Department of Internal Medicine, Johns Hopkins School of Medicine, Baltimore, MD, United States
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Kumar J, Reccia I, Virdis F, Podda M, Sharma AK, Halawa A. Belatacept in renal transplantation in comparison to tacrolimus and molecular understanding of resistance pattern: Meta-analysis and systematic review. World J Transplant 2021; 11:70-86. [PMID: 33816147 PMCID: PMC8009058 DOI: 10.5500/wjt.v11.i3.70] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 12/23/2020] [Accepted: 02/12/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The T-cell costimulation blocking agent belatacept has been identified as a possible substitute for calcineurin inhibitors, however, no consensus has been established against its use over the standard care agent Tacrolimus. AIM To evaluate the effectiveness of belatacept based maintenance immuno-suppressive regimens in comparison to tacrolimus in renal transplantion. METHODS We did extensive search of all the available literature comparing the role of belatacept to tacrolimus in renal transplant recipients by searching the PubMed, Embase, Cochrane, Crossref, Scopus, clinical trials registry on October 5, 2020. RESULTS The literature search identified four randomized controlled trials (n = 173 participants) comparing belatacept with tacrolimus. There was no significant difference in estimated renal function at 12 mo [mean difference 4.12 mL/min/1.73 m2, confidence interval (CI): -2.18 to 10.42, P = 0.20]. Further, belatacept group was associated with significant increase in biopsy proven acute rejection [relative risk (RR) = 3.27, CI: 0.88 to 12.11, P = 0.08] and worse 12 mo allograft survival (RR = 4.51, CI: 1.23 to 16.58, P = 0.02). However, incidence of new onset diabetes mellitus was lower with belatacept at 12 mo (RR = 0.26, CI: 0.07 to 0.99, P = 0.05). CONCLUSION The evidence reviewed in this meta-analysis suggested that belatacept-based maintenance immunosuppression regimens were associated with an increased risk allograft loss in renal transplant recipients with equivalent renal functioning against standard tacrolimus; however, observed significantly reduced new onset diabetes mellitus after transplantation incidence and lower serum low density lipid profile levels in belatacept group. In addition, the adaptation of belatacept in renal transplantation has been forestalled by increased rates of rejection and resistance owing to development of various effector memory T cells through, parallel differentiation and immunological plasticity.
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Affiliation(s)
- Jayant Kumar
- Department of Cancer and Surgery, Imperial College, London W12 0HS, United Kingdom
| | - Isabella Reccia
- Department of Cancer and Surgery, Imperial College, London W12 0HS, United Kingdom
| | - Francesco Virdis
- Department of Emergency General Surgery, Royal Free Hospital, London NW3 2QG, United Kingdom
| | - Mauro Podda
- Department of Surgery, General, Emergency and Robotic Surgical Unit, San Francesco Hospital, Nuoro 08100, Italy
| | - Ajay Kumar Sharma
- Department of Transplantation, Royal Liverpool University Hospital, Liverpool L7 8XP, United Kingdom
| | - Ahmed Halawa
- Department of Surgery, Sheffield Teaching Hospitals, Sheffield S10 2JF, United Kingdom
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La Muraglia GM, Zeng S, Crichton ES, Wagener ME, Ford ML, Badell IR. Superior inhibition of alloantibody responses with selective CD28 blockade is CTLA-4 dependent and T follicular helper cell specific. Am J Transplant 2021; 21:73-86. [PMID: 32406182 PMCID: PMC7665991 DOI: 10.1111/ajt.16004] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 04/15/2020] [Accepted: 05/07/2020] [Indexed: 01/25/2023]
Abstract
Anti-donor antibodies cause immunologic injury in transplantation. CD28 blockade with CTLA-4-Ig has the ability to reduce the incidence of these donor-specific antibodies (DSA), but its mechanism is suboptimal for the inhibition of alloimmunity in that CTLA-4-Ig blocks both CD28 costimulation and CTLA-4 coinhibition. Thus selective CD28 blockade that spares CTLA-4 has potential to result in improved inhibition of humoral alloimmunity. To test this possibility, we utilized a full allogeneic mismatch murine transplant model and T follicular helper (Tfh):B cell co-culture system. We observed that selective blockade with an anti-CD28 domain antibody (dAb) compared to CTLA-4-Ig led to superior inhibition of Tfh cell, germinal center, and DSA responses in vivo and better control of B cell responses in vitro. CTLA-4 blockade enhanced the humoral alloresponse and, in combination with anti-CD28 dAb, abrogated the effects of selective blockade. This CTLA-4-dependent inhibition was Tfh cell specific in that CTLA-4 expression by Tfh cells was necessary and sufficient for the improved humoral inhibition observed with selective CD28 blockade. As CD28 blockade attracts interest for control of alloantibodies in the clinic, these data support selective CD28 blockade as a superior strategy to address DSA via the sparing of CTLA-4 and more potent targeting of Tfh cells.
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Affiliation(s)
| | - Susan Zeng
- Emory Transplant Center, Atlanta, GA, USA
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Nagai K. Co-inhibitory Receptor Signaling in T-Cell-Mediated Autoimmune Glomerulonephritis. Front Med (Lausanne) 2020; 7:584382. [PMID: 33251233 PMCID: PMC7672203 DOI: 10.3389/fmed.2020.584382] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 09/22/2020] [Indexed: 12/12/2022] Open
Abstract
Autoimmune glomerulonephritis occurs as a consequence of autoantibodies and T-cell effector functions that target autoantigens. Co-signaling through cell surface receptors profoundly influences the optimal activation of T cells. The scope of this review is signaling mechanisms and the functional roles of representative T-cell co-inhibitory receptors in the regulation of autoimmune glomerulonephritis, along with current therapeutic challenges mainly on preclinical trials. Co-inhibitory receptors utilize both shared and unique signaling pathway, suggesting specialized functions that provide the rationale behind therapies for autoimmune glomerulonephritis by targeting these inhibitory receptors. These receptors largely suppress Th1 immunity, modify Th17 and Th2 immune response, and enhance Treg function. Anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) immunoglobulin (Ig), which is able to block both activating CD28 and inhibitory CTLA4 signaling, has been shown in preclinical and clinical investigations to have effects on glomerular disease. Other inhibitory receptors for treating glomerulonephritis have not been clinically tested, and efficacy of manipulating these pathways requires further preclinical investigation. While immune checkpoint inhibition using anti-CTLA4 antibodies and anti-programmed cell death 1 (PD-1)/PD-L1 antibodies has been approved for the treatment of several cancers, blockade of CTLA4 and PD-1/PD-L1 is associated with adverse effects that resemble autoimmune disorders, including systemic vasculitis. A renal autoimmune vasculitis model features an initial Th17 dominancy followed later by a Th1-dominant outcome and Treg cells that attenuate autoreactive T-cell function. Toward the development of effective therapies for T-cell-mediated autoimmune glomerulonephritis, it would be preferable to pay attention to the impact of the inhibitory pathways in immunological renal disease settings.
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Affiliation(s)
- Kei Nagai
- Department of Nephrology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
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Induction of Allograft Tolerance While Maintaining Immunity Against Microbial Pathogens: Does Coronin 1 Hold a Key? Transplantation 2020; 104:1350-1357. [PMID: 31895336 DOI: 10.1097/tp.0000000000003101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Selective suppression of graft rejection while maintaining anti-pathogen responses has been elusive. Thus far, the most successful strategies to induce suppression of graft rejection relies on inhibition of T-cell activation. However, the very same mechanisms that induce allograft-specific T-cell suppression are also important for immunity against microbial pathogens as well as oncogenically transformed cells, resulting in significant immunosuppression-associated comorbidities. Therefore, defining the pathways that differentially regulate anti-graft versus antimicrobial T-cell responses may allow the development of regimen to induce allograft-specific tolerance. Recent work has defined a molecular pathway driven by the immunoregulatory protein coronin 1 that regulates the phosphodiesterase/cyclic adenosine monophosphate pathway and modulates T cell responses. Interestingly, disruption of coronin 1 promotes allograft tolerance while immunity towards a range of pathogenic microbes is maintained. Here, we briefly review the work leading up to these findings as well as their possible implications for transplantation medicine.
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Yasmeen F, Seo H, Javaid N, Kim MS, Choi S. Therapeutic Interventions into Innate Immune Diseases by Means of Aptamers. Pharmaceutics 2020; 12:pharmaceutics12100955. [PMID: 33050544 PMCID: PMC7600108 DOI: 10.3390/pharmaceutics12100955] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 10/03/2020] [Accepted: 10/04/2020] [Indexed: 12/25/2022] Open
Abstract
The immune system plays a crucial role in the body's defense system against various pathogens, such as bacteria, viruses, and parasites, as well as recognizes non-self- and self-molecules. The innate immune system is composed of special receptors known as pattern recognition receptors, which play a crucial role in the identification of pathogen-associated molecular patterns from diverse microorganisms. Any disequilibrium in the activation of a particular pattern recognition receptor leads to various inflammatory, autoimmune, or immunodeficiency diseases. Aptamers are short single-stranded deoxyribonucleic acid or ribonucleic acid molecules, also termed "chemical antibodies," which have tremendous specificity and affinity for their target molecules. Their features, such as stability, low immunogenicity, ease of manufacturing, and facile screening against a target, make them preferable as therapeutics. Immune-system-targeting aptamers have a great potential as a targeted therapeutic strategy against immune diseases. This review summarizes components of the innate immune system, aptamer production, pharmacokinetic characteristics of aptamers, and aptamers related to innate-immune-system diseases.
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Schroder PM, Schmitz R, Fitch ZW, Ezekian B, Yoon J, Choi AY, Manook M, Barbas A, Leopardi F, Song M, Farris AB, Collins B, Kwun J, Knechtle SJ. Preoperative carfilzomib and lulizumab based desensitization prolongs graft survival in a sensitized non-human primate model. Kidney Int 2020; 99:161-172. [PMID: 32898569 DOI: 10.1016/j.kint.2020.08.020] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 07/23/2020] [Accepted: 08/20/2020] [Indexed: 12/22/2022]
Abstract
Sensitized patients are difficult to transplant due to pre-formed anti-donor immunity. We have previously reported successful desensitization using carfilzomib and belatacept in a non-human primate (NHP) model. Here we evaluated selective blockade of the co-stimulatory signal (CD28-B7) with Lulizumab, which preserves the co-inhibitory signal (CTLA4-B7). Five maximally MHC-mismatched pairs of NHPs were sensitized to each other with two sequential skin transplants. Individuals from each pair were randomized to either desensitization with once-weekly Carfilzomib (27mg/m2 IV) and Lulizumab (12.5mg/kg SC) over four weeks, or no desensitization (Control). NHPs then underwent life-sustaining kidney transplantation from their previous skin donor. Rhesus-specific anti-thymocyte globulin was used as induction therapy and immunosuppression maintained with tacrolimus, mycophenolate, and methylprednisolone. Desensitized subjects demonstrated a significant reduction in donor-specific antibody, follicular helper T cells (CD4+PD-1+ICOS+), and proliferating B cells (CD20+Ki67+) in the lymph nodes. Interestingly, regulatory T cell (CD4+CD25+CD127lo) frequency was maintained after desensitization in addition to increased frequency of naïve CD4 T cells (CCR7+CD45RA+) and naïve B cells (IgD+CD27-CD20+) in circulation. This was associated with significant prolongation in graft survival (MST = 5.8 ± 4.0 vs. 64.8 ± 36.3; p<0.05) and lower antibody-mediated rejection scores compared to control animals. However, all desensitized animals eventually developed AMR and graft failure. Desensitization with CFZ and Lulizumab improves allograft survival in allosensitized NHPs, by transient control of the germinal center and shifting of the immune system to a more naive phenotype. This regimen may translate into clinical practice to improve outcomes of highly sensitized transplant patients.
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Affiliation(s)
- Paul M Schroder
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA
| | - Robin Schmitz
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA
| | - Zachary W Fitch
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA
| | - Brian Ezekian
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA
| | - Janghoon Yoon
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA
| | - Ashley Y Choi
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA
| | - Miriam Manook
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA
| | - Andrew Barbas
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA
| | - Frank Leopardi
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA
| | - Mingqing Song
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA
| | - Alton B Farris
- Department of Pathology, Emory School of Medicine, Atlanta, Georgia, USA
| | - Bradley Collins
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA
| | - Jean Kwun
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.
| | - Stuart J Knechtle
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.
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Cardiovascular risk in patients with plaque psoriasis and psoriatic arthritis without a clinically overt cardiovascular disease: the role of endothelial progenitor cells. Postepy Dermatol Alergol 2020; 37:299-305. [PMID: 32774211 PMCID: PMC7394160 DOI: 10.5114/ada.2020.96085] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 02/20/2019] [Indexed: 11/26/2022] Open
Abstract
Psoriasis is an autoimmune, chronic disease determined by environmental and genetic factors. The occurrence of psoriasis is accompanied by metabolic diseases, cardiovascular diseases (CVD) and depression, disturbances on interpersonal interactions and a tendency towards social isolation. Regardless of the form of psoriasis and the severity of the disease, early arterial lesions are recorded in arterial vessels of patients. Nevertheless, the chance of CVD is higher in the population of patients with severe psoriasis than in patients with mild to moderate psoriasis. The correlation between the presence of atherosclerotic plaque and psoriatic plaque is partially explained by: (1) a similar inflammatory pathway – via the T helper cells, (2) impaired angiogenesis, and (3) endothelial dysfunction. In the considered tests, the diagnostic tools used showed a reduced level of endothelial progenitor cells in the circulation of patients with psoriasis. Endogenous angiopoietin stimulation in patients with psoriasis leads to deterioration of endothelial regeneration, atherosclerosis which secondarily contributes to the progression of heart failure. Clinical and experimental data confirm the potential of immunomodulatory methods to combat both autoimmune and cardiovascular diseases through the use of immunosuppressive drugs. Full understanding of the way in which CVD develops in patients with autoimmune diseases would enable the implementation of targeted cell therapy allowing the quality and life expectancy of patients to be improved. Modern cellular diagnostic tools allow the use of highly specific biomarkers, which in the near future will enable a reduction in morbidity and mortality due to CVD.
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Huang G, Zhang Y, Wei X, Yu Z, Lai J, Shen Q, Chen X, Tan G, Chen C, Luo W, Li Y, Zhou M, Li Y, Li B. CD8+GITR+ T cells may negatively regulate T cell overactivation in aplastic anemia. Immunol Invest 2020; 50:406-415. [PMID: 32462957 DOI: 10.1080/08820139.2020.1770785] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Affiliation(s)
- Guixuan Huang
- Institute of Hematology, School of Medicine, Jinan University, Guangzhou, China
| | - Yuping Zhang
- Department of Hematology, Guangzhou First People’s Hospital, the Second Affiliated Hospital of South China University of Technology, Guangzhou, China
| | - Xiaolei Wei
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhi Yu
- Department of Hematology, First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Jing Lai
- Department of Hematology, First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Qi Shen
- Department of Hematology, Second Clinical Medical College of Jinan University (Shenzhen People’s Hospital), Shengzhen, China
| | - Xiaohui Chen
- Institute of Hematology, School of Medicine, Jinan University, Guangzhou, China
| | - Guangxiao Tan
- Institute of Hematology, School of Medicine, Jinan University, Guangzhou, China
| | - Cunte Chen
- Institute of Hematology, School of Medicine, Jinan University, Guangzhou, China
| | | | - Yumiao Li
- Department of Hematology, Guangzhou First People’s Hospital, the Second Affiliated Hospital of South China University of Technology, Guangzhou, China
| | - Ming Zhou
- Department of Hematology, Guangzhou First People’s Hospital, the Second Affiliated Hospital of South China University of Technology, Guangzhou, China
| | - Yangqiu Li
- Institute of Hematology, School of Medicine, Jinan University, Guangzhou, China
| | - Bo Li
- Institute of Hematology, School of Medicine, Jinan University, Guangzhou, China
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Giffoni de Carvalho JT, Henao Agudelo JS, Baldivia DDS, Carollo CA, Silva DB, de Picoli Souza K, Saraiva Câmara NO, Dos Santos EL. Hydroethanolic stem bark extracts of Stryphnodendron adstringens impair M1 macrophages and promote M2 polarization. JOURNAL OF ETHNOPHARMACOLOGY 2020; 254:112684. [PMID: 32105746 DOI: 10.1016/j.jep.2020.112684] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 02/18/2020] [Accepted: 02/19/2020] [Indexed: 06/10/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Stryphnodendron adstringens has been used by indigenous Brazilian people to treat wound, infections, inflammation and other conditions. AIM OF THE STUDY This study aims to investigate the effect of S. adstringens on macrophage polarization. METHODS To prepare the hydroethanolic extract of Stryphnodendron adstringens (HESA), fresh bark was exposed to maceration, filtered and subsequently lyophilized. The extract HESA were analyzed by LC-DAD-MS to identify their constituents. Bone marrow cells were obtained from male C57BL/6 mice. Then, the cells were polarized into M1 or M2 subsets in the presence or absence of HESA. The membrane expression of TLR2, CD206, CCR7, class II MHC, and CD86, the intracellular expression of iNOS and IL-6 and the supernatant expression of IL-6 were determined by flow cytometry. RESULTS By LC-DAD-MS, twenty-four compounds could be detected from HESA and proanthocyanidins, flavan-3-ols, and chromones were identified. NO and iNOS were reduced in the HESA-treated cells. There was a reduction in IL6 in HESA-treated cells. The membrane expression of TLR2, CD206, CCR7, CD86, and class II MHC was reduced in HESA-treated cells. The densities of CD206 and IL-10 were found to be significantly increased in HESA-treated cells. CONCLUSION This work is the first to demonstrate that S. adstringens can modulate the functional polarization of macrophages into the M2 profile and suppress costimulatory molecules in M1 macrophages. These results corroborate with the ethnopharmacology use of S. adstringens, contributing to its pharmacological validation in wound treatment and expanding the knowledge about immunoregulatory action of this specie.
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Affiliation(s)
| | | | - Débora Da Silva Baldivia
- Research Group on Biotechnology and Bioprospecting Applied to Metabolism, Federal University of Grande Dourados, Dourados, Brazil
| | - Carlos Alexandre Carollo
- Laboratory of Natural Products and Mass Spectrometry, Federal University of Mato Grosso do Sul, Campo Grande, MS, Brazil
| | - Denise Brentan Silva
- Laboratory of Natural Products and Mass Spectrometry, Federal University of Mato Grosso do Sul, Campo Grande, MS, Brazil
| | - Kely de Picoli Souza
- Research Group on Biotechnology and Bioprospecting Applied to Metabolism, Federal University of Grande Dourados, Dourados, Brazil
| | - Niels Olsen Saraiva Câmara
- Laboratorio de Imunologia Clínica e Experimental, Disciplina de Nefrologia. Universidade Federal de São Paulo - UNIFESP, Brazil; Laboratório de Imunobiologia de Transplantes, Departamento de Imunologia. Universidade de São Paulo - USP, Brazil
| | - Edson Lucas Dos Santos
- Research Group on Biotechnology and Bioprospecting Applied to Metabolism, Federal University of Grande Dourados, Dourados, Brazil
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Cheng CH, Lee CF, Oh BC, Furtmüller GJ, Patel CH, Brandacher G, Powell JD. Targeting Metabolism as a Platform for Inducing Allograft Tolerance in the Absence of Long-Term Immunosuppression. Front Immunol 2020; 11:572. [PMID: 32328063 PMCID: PMC7161684 DOI: 10.3389/fimmu.2020.00572] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2019] [Accepted: 03/12/2020] [Indexed: 12/14/2022] Open
Abstract
Transplant tolerance in the absence of long-term immunosuppression has been an elusive goal for solid organ transplantation. Recently, it has become clear that metabolic reprogramming plays a critical role in promoting T cell activation, differentiation, and function. Targeting metabolism can preferentially inhibit T cell effector generation while simultaneously promoting the generation of T regulatory cells. We hypothesized that costimulatory blockade with CTLA4Ig in combination with targeting T cell metabolism might provide a novel platform to promote the induction of transplant tolerance.
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Affiliation(s)
- Chih-Hsien Cheng
- Sidney∼Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.,Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, United States.,Department of Liver and Transplantation Surgery, Chang-Gung Memorial Hospital, Chang-Gung Transplantation Institute, Chang-Gung University College of Medicine, Taoyuan, Taiwan
| | - Chen-Fang Lee
- Sidney∼Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.,Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, United States.,Department of Liver and Transplantation Surgery, Chang-Gung Memorial Hospital, Chang-Gung Transplantation Institute, Chang-Gung University College of Medicine, Taoyuan, Taiwan
| | - Byoung Chol Oh
- Vascularized Composite Allotransplantation Laboratory, Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Georg J Furtmüller
- Vascularized Composite Allotransplantation Laboratory, Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Chirag H Patel
- Sidney∼Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.,Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Gerald Brandacher
- Vascularized Composite Allotransplantation Laboratory, Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Jonathan D Powell
- Sidney∼Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.,Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, United States
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Carballido JM, Regairaz C, Rauld C, Raad L, Picard D, Kammüller M. The Emerging Jamboree of Transformative Therapies for Autoimmune Diseases. Front Immunol 2020; 11:472. [PMID: 32296421 PMCID: PMC7137386 DOI: 10.3389/fimmu.2020.00472] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Accepted: 02/28/2020] [Indexed: 12/12/2022] Open
Abstract
Standard treatments for autoimmune and autoinflammatory disorders rely mainly on immunosuppression. These are predominantly symptomatic remedies that do not affect the root cause of the disease and are associated with multiple side effects. Immunotherapies are being developed during the last decades as more specific and safer alternatives to small molecules with broad immunosuppressive activity, but they still do not distinguish between disease-causing and protective cell targets and thus, they still have considerable risks of increasing susceptibility to infections and/or malignancy. Antigen-specific approaches inducing immune tolerance represent an emerging trend carrying the potential to be curative without inducing broad immunosuppression. These therapies are based on antigenic epitopes derived from the same proteins that are targeted by the autoreactive T and B cells, and which are administered to patients together with precise instructions to induce regulatory responses capable to restore homeostasis. They are not personalized medicines, and they do not need to be. They are precision therapies exquisitely targeting the disease-causing cells that drive pathology in defined patient populations. Immune tolerance approaches are truly transformative options for people suffering from autoimmune diseases.
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Affiliation(s)
- José M. Carballido
- Translational Medicine, Novartis Institutes for Biomedical Research, Basel, Switzerland
- Autoimmunity Transplantation and Inflammation, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Camille Regairaz
- Autoimmunity Transplantation and Inflammation, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Celine Rauld
- Autoimmunity Transplantation and Inflammation, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Layla Raad
- Autoimmunity Transplantation and Inflammation, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Damien Picard
- Translational Medicine, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Michael Kammüller
- Translational Medicine, Novartis Institutes for Biomedical Research, Basel, Switzerland
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Chen R, Ganesan A, Okoye I, Arutyunova E, Elahi S, Lemieux MJ, Barakat K. Targeting B7‐1 in immunotherapy. Med Res Rev 2020; 40:654-682. [DOI: 10.1002/med.21632] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2019] [Revised: 07/30/2019] [Accepted: 08/07/2019] [Indexed: 12/14/2022]
Affiliation(s)
- Rui Chen
- Faculty of Pharmacy and Pharmaceutical SciencesUniversity of AlbertaEdmonton Alberta Canada
| | - Aravindhan Ganesan
- Faculty of Pharmacy and Pharmaceutical SciencesUniversity of AlbertaEdmonton Alberta Canada
| | - Isobel Okoye
- Department of Dentistry, Faculty of Medicine and DentistryUniversity of AlbertaEdmonton Alberta Canada
| | - Elena Arutyunova
- Department of Biochemistry, Faculty of Medicine and DentistryUniversity of AlbertaEdmonton Alberta Canada
| | - Shokrollah Elahi
- Department of Dentistry, Faculty of Medicine and DentistryUniversity of AlbertaEdmonton Alberta Canada
- Li Ka Shing Institute of VirologyUniversity of AlbertaEdmonton Alberta Canada
- Department of Oncology, Faculty of Medicine and DentistryUniversity of AlbertaEdmonton Alberta Canada
- Department of Medical Microbiology and Immunology, Faculty of Medicine and DentistryUniversity of AlbertaEdmonton Alberta Canada
| | - M. Joanne Lemieux
- Department of Biochemistry, Faculty of Medicine and DentistryUniversity of AlbertaEdmonton Alberta Canada
| | - Khaled Barakat
- Faculty of Pharmacy and Pharmaceutical SciencesUniversity of AlbertaEdmonton Alberta Canada
- Li Ka Shing Institute of VirologyUniversity of AlbertaEdmonton Alberta Canada
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Preventive CTLA-4-Ig Treatment Reduces Hepatic Egg Load and Hepatic Fibrosis in Schistosoma mansoni-Infected Mice. BIOMED RESEARCH INTERNATIONAL 2019; 2019:1704238. [PMID: 31950032 PMCID: PMC6948272 DOI: 10.1155/2019/1704238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 10/02/2019] [Accepted: 11/12/2019] [Indexed: 11/21/2022]
Abstract
Background Hepatic fibrosis and granuloma formation as a consequence of tissue entrapped eggs produced by female schistosomes characterize the pathology of Schistosoma mansoni infection. We have previously shown that single-sex infection with female schistosomes mitigates hepatic fibrosis after secondary infection. This was associated with an increased expression of cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), known as a negative regulator of T cell activation. Based on these findings, we hypothesized that administration of agonistic CTLA-4-Ig (Belatacept) is capable to prevent and/or treat hepatic fibrosis during schistosomiasis. Methods Mice were infected with 50 S. mansoni cercariae and CTLA-4-Ig, or appropriated control-Ig was administered for 4 weeks. Preventive treatment started 4 weeks after infection, before onset of egg production, and therapeutic treatment started 8 weeks after infection when hepatic fibrosis was already established. Results When given early after infection, livers of CTLA-4-Ig-treated mice showed significantly reduced collagen deposition and decreased expression of profibrotic genes in comparison to controls. In addition, administration of CTLA-4-Ig suppressed the inflammatory T cell response in infected mice. If therapy was started at a later time point when fibrogenesis was initiated, CTLA-4-Ig had no impact on hepatic fibrosis. Conclusion We could demonstrate that an early preventive administration of CTLA-4-Ig suppresses effector T cell function and therefore ameliorates liver fibrosis. CTLA-4-Ig administration after onset of egg production fails to treat hepatic fibrosis.
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Wang J, Wang P, Wang S, Tan J. Donor-specific HLA Antibodies in Solid Organ Transplantation: Clinical Relevance and Debates. EXPLORATORY RESEARCH AND HYPOTHESIS IN MEDICINE 2019; 000:1-11. [DOI: 10.14218/erhm.2019.00012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
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50
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Parsons RF, Larsen CP, Pearson TC, Badell IR. Belatacept and CD28 Costimulation Blockade: Preventing and Reducing Alloantibodies over the Long Term. CURRENT TRANSPLANTATION REPORTS 2019; 6:277-284. [PMID: 32158639 PMCID: PMC7063534 DOI: 10.1007/s40472-019-00260-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Purpose of Review Highlight developments in T and B cell biology that are helping elucidate the mechanisms underlying CD28 pathway blockade-mediated inhibition of alloantibodies in transplantation, and discuss recent clinical observations on the impact of belatacept on de novo and established HLA antibodies. Recent Findings The identification of T follicular helper cells as the CD4+ T cell subset required for optimal humoral immunity, along with newly identified roles for CD28 and the B7 molecules on B cell lineage cells has begun to pave the way for improved understanding and discovery of the mechanisms of CD28 costimulation blockade-mediated antibody inhibition. There has been resurgent clinical interest in the ability of belatacept to attenuate alloantibody responses. New reports have continued to document its ability to prevent de novo antibody responses, and more recent studies have surfaced exploring its potential to control nascent or pre-existing HLA antibodies. Summary A growing understanding of the mechanisms of anti-CD28-mediated alloantibody inhibition and continued clinical successes will guide the clinical optimization of belatacept and next generation CD28 blockers to prevent and reduce alloantibodies over the long-term.
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