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Kanda M, Manzouri B. The evolving role of ciclosporin in the management of vernal keratoconjunctivitis. FRONTIERS IN OPHTHALMOLOGY 2025; 5:1525868. [PMID: 40352688 PMCID: PMC12062066 DOI: 10.3389/fopht.2025.1525868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Accepted: 03/19/2025] [Indexed: 05/14/2025]
Abstract
In the spectrum of allergic eye disease, vernal keratoconjunctivitis (VKC) is classed as one of the most severe disease entities and can have profound effects on visual development as well as on the emotional and psychological well-being of afflicted children. The traditional mainstay of treatment for the condition, to control the ocular inflammation, has been steroids but the use of these drugs has not been without side effects. Ciclosporin offers an alternative to steroids, providing symptom relief and control of the ocular inflammation, whilst averting the problems associated with raised intraocular pressure, cataract formation and reactivation of herpes simplex keratitis, all recognised side effects of topical steroids. However, the journey to the development of a formulation of an unpreserved ciclosporin for use in human eyes has been a protracted one; the aim of this article is to outline this journey and the role of ciclosporin in the modern management of this debilitating disease.
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Affiliation(s)
| | - Bita Manzouri
- Queen’s Hospital, Barking Havering and Redbridge University Hospitals NHS Trust, Romford, United Kingdom
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Wang Y, Zhang S, Kang N, Dong L, Ni H, Liu S, Chong S, Ji Z, Wan Z, Chen X, Wang F, Lu Y, Hou B, Tong P, Qi H, Xu MM, Liu W. Progressive polyadenylation and m6A modification of Ighg1 mRNA maintain IgG1 antibody homeostasis in antibody-secreting cells. Immunity 2024; 57:2547-2564.e12. [PMID: 39476842 DOI: 10.1016/j.immuni.2024.10.004] [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: 03/01/2024] [Revised: 07/16/2024] [Accepted: 10/08/2024] [Indexed: 11/15/2024]
Abstract
Antigen-specific antibodies are generated by antibody-secreting cells (ASCs). How RNA post-transcriptional modification affects antibody homeostasis remains unclear. Here, we found that mRNA polyadenylations and N6-methyladenosine (m6A) modifications maintain IgG1 antibody production in ASCs. IgG heavy-chain transcripts (Ighg) possessed a long 3' UTR with m6A sites, targeted by the m6A reader YTHDF1. B cell-specific deficiency of YTHDF1 impaired IgG production upon antigen immunization through reducing Ighg1 mRNA abundance in IgG1+ ASCs. Disrupting either the m6A modification of a nuclear-localized splicing intermediate Ighg1 or the nuclear localization of YTHDF1 reduced Ighg1 transcript stability. Single-cell RNA sequencing identified an ASC subset with excessive YTHDF1 expression in systemic lupus erythematosus patients, which was decreased upon therapy with immunosuppressive drugs. In a lupus mouse model, inhibiting YTHDF1-m6A interactions alleviated symptoms. Thus, we highlight a mechanism in ASCs to sustain the homeostasis of IgG antibody transcripts by integrating Ighg1 mRNA polyadenylation and m6A modification.
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Affiliation(s)
- Yu Wang
- State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua-Peking Center for Life Sciences, Institute for Immunology, Ministry of Education Key Laboratory of Protein Sciences, Tsinghua University, Beijing, China
| | - Shaocun Zhang
- State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua-Peking Center for Life Sciences, Institute for Immunology, Ministry of Education Key Laboratory of Protein Sciences, Tsinghua University, Beijing, China.
| | - Na Kang
- State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua-Peking Center for Life Sciences, Institute for Immunology, Ministry of Education Key Laboratory of Protein Sciences, Tsinghua University, Beijing, China; The First Affiliated Hospital of Anhui Medical University and Institute of Clinical Immunology, Anhui Medical University, Hefei, Anhui, China
| | - Lihui Dong
- Department of Basic Medical Sciences, School of Medicine, Tsinghua-Peking Center for Life Sciences, Institute for Immunology, Tsinghua University, Beijing 100084, China
| | - Haochen Ni
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, College of Future Technology, Sino-Danish College, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Sichen Liu
- State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua-Peking Center for Life Sciences, Institute for Immunology, Ministry of Education Key Laboratory of Protein Sciences, Tsinghua University, Beijing, China
| | - Siankang Chong
- State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua-Peking Center for Life Sciences, Institute for Immunology, Ministry of Education Key Laboratory of Protein Sciences, Tsinghua University, Beijing, China
| | - Zhenglin Ji
- State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua-Peking Center for Life Sciences, Institute for Immunology, Ministry of Education Key Laboratory of Protein Sciences, Tsinghua University, Beijing, China; The First Affiliated Hospital of Anhui Medical University and Institute of Clinical Immunology, Anhui Medical University, Hefei, Anhui, China
| | - Zhengpeng Wan
- State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua-Peking Center for Life Sciences, Institute for Immunology, Ministry of Education Key Laboratory of Protein Sciences, Tsinghua University, Beijing, China
| | - Xiangjun Chen
- Zhejiang Key Laboratory of Multi-Omics in Infection and Immunity, Center for Infectious Disease Research, School of Medicine, Westlake University, Hangzhou 310024, China; Research Center for Industries of the Future, Westlake University, Hangzhou 310024, China
| | - Fei Wang
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Yun Lu
- State Key Joint Laboratory of Environmental Simulation and Pollution Control, School of Environment, Tsinghua University, Beijing 100084, China
| | - Baidong Hou
- Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, College of life Sciences, University of Chinese Academy of Sciences, Beijing, P.R.China
| | - Pei Tong
- Key Laboratory of Immune Response and Immunotherapy, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China
| | - Hai Qi
- Department of Basic Medical Sciences, School of Medicine, Tsinghua-Peking Center for Life Sciences, Institute for Immunology, Tsinghua University, Beijing 100084, China
| | - Meng Michelle Xu
- Department of Basic Medical Sciences, School of Medicine, Tsinghua-Peking Center for Life Sciences, Institute for Immunology, Tsinghua University, Beijing 100084, China.
| | - Wanli Liu
- State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua-Peking Center for Life Sciences, Institute for Immunology, Ministry of Education Key Laboratory of Protein Sciences, Tsinghua University, Beijing, China.
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Tsunoda S, Harada T, Kikushige Y, Kishimoto T, Yoshizaki K. Immunology and targeted therapy in Castleman disease. Expert Rev Clin Immunol 2024; 20:1101-1112. [PMID: 38785062 DOI: 10.1080/1744666x.2024.2357689] [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: 03/01/2024] [Accepted: 05/16/2024] [Indexed: 05/25/2024]
Abstract
INTRODUCTION Castleman disease (CD) is a benign lymphoproliferative disease causing severe systemic inflammation. Interleukin-6 (IL-6) is a major pathogenesis of multicentric CD (MCD), but only 30-60% of patients respond to IL-6 inhibitors. Novel agents for IL-6 inhibitor-refractory cases are needed. Clinical data and samples are being collected on a large scale and the clinical, pathological, and pathogenetic aspects are being elucidated. AREAS COVERED The pathological and clinical classification of CD is outlined. Focusing on idiopathic MCD (iMCD), this review identifies therapeutic targets and summarizes currently recommended drugs and promising therapeutic candidates. EXPERT OPINION The pathogenesis of MCD has been implicated in the activation of the Janus kinase (JAK)-transcriptional signaling activator (STAT) 3 pathway and the phosphatidylinositol 3-kinase (PI3K)/Akt/mechanical target of rapamycin (mTOR) signaling pathway. iMCD-TAFRO (thrombocytopenia, anasarca, fever/elevated CRP, reticulin myelofibrosis/renal dysfunction, organ enlargement) is resistant to IL-6 inhibitors, and cyclosporine and mTOR inhibitors are sometimes effective. JAK inhibitors and mTOR inhibitors may be therapeutic agents for iMCD. Recently, we have shown that peripheral helper T (Tph) cell abnormalities are at the core of iMCD pathogenesis. Therapies targeting chemokine (C-X-C motif) ligand 13 (CXCL13) produced by Tph cells and blocking the Tph-CXCL13-B cell pathway may satisfy unmet need in refractory cases.
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Affiliation(s)
- Shinichiro Tsunoda
- Division of Clinical Immunology and Rheumatology, Department of Internal Medicine, Sumitomo Hospital, Osaka, Japan
| | - Takuya Harada
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medicine, Fukuoka, Japan
- Department of Hematology, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
| | - Yoshikane Kikushige
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medicine, Fukuoka, Japan
- Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Tadamitsu Kishimoto
- Laboratory of Immune Regulation, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Kazuyuki Yoshizaki
- The Institute of Scientific and Industrial Research, SANKEN, Osaka University, Osaka, Japan
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Wang S, Kang Y, He C, Jin H. The systemic treatments for drug reaction with eosinophilia and systemic symptoms (DRESS) beyond corticosteroids. World Allergy Organ J 2024; 17:100935. [PMID: 39156598 PMCID: PMC11325795 DOI: 10.1016/j.waojou.2024.100935] [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: 02/25/2024] [Revised: 05/26/2024] [Accepted: 06/29/2024] [Indexed: 08/20/2024] Open
Abstract
Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity syndrome (DiHS), is a severe type of cutaneous adverse reaction. The gold standard therapy for DRESS involves the discontinuation of the culprit drug, supportive therapies, and administration of corticosteroids. However, in cases of primary treatment failure or suboptimal response, there arises an urgent need for alternative interventions. This review focuses on exploring alternative systemic therapies for patients with steroid-resistant DRESS, steroid-dependent DRESS, or refractory DRESS, encompassing immunosuppressive agents, intravenous immunoglobulin, plasmapheresis, biologics, and small molecule drugs, with an emphasis on their clinical efficacy and the underlying mechanisms in the treatment of DRESS. Furthermore, this review provides a summary of potential management strategies and laboratory workup during the treatment of DRESS.
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Affiliation(s)
- Sifan Wang
- Department of Dermatology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, 100730, China
| | - Yuanbo Kang
- Peking Union Medical College, Chinese Academy of Medical Sciences, Dongdan Santiao 9#, Dongcheng District, Beijing, 100730, China
| | - Chunxia He
- Department of Dermatology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, 100730, China
| | - Hongzhong Jin
- Department of Dermatology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, 100730, China
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Santonocito S, Polizzi A, Matarese M, Caltabiano R, Isola G. Analysis of a Combination Therapy Protocol for the Treatment of Oral Mucous Membrane Pemphigoid: A Retrospective Case Series Study. Int J Dent 2024; 2024:5524514. [PMID: 38362240 PMCID: PMC10869199 DOI: 10.1155/2024/5524514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 01/05/2024] [Accepted: 01/30/2024] [Indexed: 02/17/2024] Open
Abstract
Mucous membrane pemphigoid (MMP) is an autoimmune-based bullous disease affecting the mucous membranes, mainly oral and ocular. One of the most common clinical manifestations is desquamative gingivitis (DG), characterized by intense symptoms and functional limitations. The dentist is among the first specialists to observe DG and, therefore, must be able to diagnose it. In this regard, the purpose of the present study was to evaluate the efficacy and safety of a clinical protocol for the topical management of patients with DG and MMP buccal lesions. Thirteen patients with clinical and histologic diagnoses of MMP-localized DG in the oral cavity were retrospectively enrolled. Each patient received topical treatment with clobetasol propionate oral gel 0.05%; nicotinamide; oral probiotic (contains Bifidobacterium lactis HN019, Kluyveromyces marxianus fragilis B0399, colostrum, and biotin); and doxycycline. Before and after 3 months of therapy, clinic records were collected for each patient. Seven patients (53.8%) had a complete response to treatment; four patients (30.8%) had a partial response to treatment; and, finally, two patients (15.4%) had no benefit from therapy. Dental management of patients presenting solely with oral manifestations of MMP may involve the use of topical corticosteroids, doxycycline, vitamin supplements, and probiotics and associating professional oral hygiene procedures.
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Affiliation(s)
- Simona Santonocito
- Department of General Surgery and Surgical-Medical Specialties, School of Dentistry, University of Catania, Via S. Sofia 78, Catania 95124, Italy
| | - Alessandro Polizzi
- Department of General Surgery and Surgical-Medical Specialties, School of Dentistry, University of Catania, Via S. Sofia 78, Catania 95124, Italy
| | - Marco Matarese
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Via Consolare Valeria 1, Messina 98123, Italy
| | - Rosario Caltabiano
- Department of General Surgery and Surgical-Medical Specialties, School of Dentistry, University of Catania, Via S. Sofia 78, Catania 95124, Italy
| | - Gaetano Isola
- Department of General Surgery and Surgical-Medical Specialties, School of Dentistry, University of Catania, Via S. Sofia 78, Catania 95124, Italy
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Jiang L, Wang H, Huang Y, Liang H, Wang X, Fan J. Reactivation of occult hepatitis B virus infection in a renal transplant recipient. Virol J 2022; 19:216. [PMID: 36522738 PMCID: PMC9753329 DOI: 10.1186/s12985-022-01946-4] [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: 07/24/2022] [Accepted: 12/04/2022] [Indexed: 12/23/2022] Open
Abstract
We report a case of hepatitis B virus (HBV) reactivation in a renal transplant recipient. Reactivation manifested as an occult infection with detectable HBV-DNA and negativity for hepatitis B surface antigen (HBsAg). The anti-HBs antibody titre was above the protective threshold and continued to rise, to 951.36 mIU/ml, after HBV reactivation. Sequencing revealed multiple vaccine- and diagnostic-escape mutations in the major hydrophilic region of HBsAg. This case demonstrates both reactivation of an HBV escape mutant in a vaccinated patient and host immunity after virus mutation.
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Affiliation(s)
- Lili Jiang
- grid.13402.340000 0004 1759 700XState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang China
| | - Huiqi Wang
- grid.13402.340000 0004 1759 700XState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang China
| | - Yaping Huang
- grid.13402.340000 0004 1759 700XState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang China
| | - Hanying Liang
- grid.13402.340000 0004 1759 700XState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang China
| | - Xiaodong Wang
- grid.13402.340000 0004 1759 700XState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang China
| | - Jun Fan
- grid.13402.340000 0004 1759 700XState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang China
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Motiee M, Zavaran Hosseini A, Soudi S. Evaluating the effects of Cyclosporine A immunosuppression on Mycobacterial infection by inhaling of Cyclosporine A administrated BALB/c mice with live Bacillus Calmette Guérin. Tuberculosis (Edinb) 2021; 132:102163. [PMID: 34999486 DOI: 10.1016/j.tube.2021.102163] [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: 06/11/2021] [Revised: 12/16/2021] [Accepted: 12/19/2021] [Indexed: 11/30/2022]
Abstract
Cyclosporine A (CsA) is an immunosuppressive drug used in organ transplantation and treatment of autoimmune diseases. Effects of CsA on determining the direction of the immune response and pathogenesis of infections by altering immune responses particulary T cells functions have always been questionable. We evaluated the effect of different doses of CsA on course of infection in BALB/c mice infected with live Bacillus Calmette Guérin (BCG) (as an example of Mycobacterial infections). Four groups of mice (n = 5) receiving 5, 25, 125, and 0 mg/kg of CsA, three times a week, were infected with BCG aerosolly. Before BCG inhalation and 40-/60- days post-infection, cell proliferation and CD4+CD25+ cell percentage were evaluated in splenocytes of mice after culture and stimulation with PHA or BCG lysate. The histopathological alterations and bacterial burden were assessed in lung tissue. Cells showed a dose-dependent decrease in proliferation and the percentage of CD4+ CD25+ cells. After BCG infection, in presence of dose 125 mg/kg, there were some exceptions. The number of bacteria and histopathological lesions and inflammation in lung tissues increased in a dose-dependent manner. CsA immunosuppressed BCG infected mice can be used as a safe model for studying Mycobacterium species pathogenesis and related cellular immune responses.
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Affiliation(s)
- Mahdieh Motiee
- Immunology Department, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Ahmad Zavaran Hosseini
- Immunology Department, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Sara Soudi
- Immunology Department, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
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Kumawat M, Singh R, Karuna I, Ahlawat N, Ahlawat S. Salmonella Typhimurium peptidyl-prolyl cis-trans isomerase C (PPIase C) plays a substantial role in protein folding to maintain the protein structure. World J Microbiol Biotechnol 2020; 36:168. [PMID: 33029674 DOI: 10.1007/s11274-020-02943-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 09/29/2020] [Indexed: 01/18/2023]
Abstract
Salmonella is a well-known food-borne pathogen causing disease in humans and animals worldwide. Peptidyl-prolyl isomerases (PPIases) catalyse the cis-trans isomerisation of prolyl bound, which is a slow and rate-limiting step of protein folding. Here, we present the biochemical and molecular characterisation of a novel multi-domain parvulin-type, PPIases-C from the pathogenic bacteria Salmonella Typhimurium, annotated as rPpiC. The recombinant plasmid PpiC_pET28c was used for protein induction using 1.5 mM concentration of isopropyl-β-D-thiogalactopyranoside at 30 °C. Subsequently, the protein was identified by using the LC-MS technique showing high match score and sequence coverage with available PPIases-C proteins database. Using the succinyl-ala-phe-pro-phe-p nitroanilide as a substrate, Vmax of the enzyme was found to be 0.8187 ± 0.1352 µmoles/min and Km = 1.6014 ± 0.8449 µM, respectively. With this, we conclude that rPpiC protein is an active form of protein from Salmonella Typhimurium and plays an important role in protein folding.
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Affiliation(s)
- Manoj Kumawat
- Department of Microbiology, ICMR- National Institute for Research in Environmental Health, Bhopal, 462030, India. .,Department of Biochemistry & Biochemical Engineering, SHUATS, Allahabad, 211007, India.
| | - Ranu Singh
- Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, 462066, India
| | - Irungbam Karuna
- Divisions of Biochemistry, Indian Veterinary Research Institute, Izatnagar, India
| | - Neeraj Ahlawat
- Department of Animal Husbandry and Dairying, SHUATS, Allahabad, 211007, India
| | - Sushma Ahlawat
- Department of Biochemistry & Biochemical Engineering, SHUATS, Allahabad, 211007, India.
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Park H, Christian LS, Kim MJ, Li QJ, Hong J. Synthesis and Biological Evaluation of Subglutinol Analogs for Immunomodulatory Agents. J Med Chem 2019; 63:283-294. [PMID: 31793781 DOI: 10.1021/acs.jmedchem.9b01579] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Autoimmune diseases are chronic inflammatory diseases associated with high morbidity and mortality. Treatment options for autoimmune diseases have increased over the past several decades, but they are, in general, limited in their clinical efficacy due to high toxicity and lack of selectivity. Thus, efforts must be made to identify new immunomodulatory agents that are effective through a novel mechanism to circumvent existing side effects. To define the structural requirements of subglutinols for immunomodulatory activity and to provide guiding principles on future therapeutic development, we prepared and evaluated several subglutinol analogs for their immunomodulatory activities. Our efforts identified a subglutinol analog with reduced structural complexity as a potential lead compound for future autoimmune drug development. Our study will provide an important framework for the design of potent and nontoxic immunomodulating agents derived from subglutinols.
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Affiliation(s)
- Hyeri Park
- Department of Chemistry , Duke University , Durham , North Carolina 27708 , United States
| | | | - Mi Jung Kim
- Department of Chemistry , Duke University , Durham , North Carolina 27708 , United States
| | | | - Jiyong Hong
- Department of Chemistry , Duke University , Durham , North Carolina 27708 , United States
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Randomized Sirolimus-based Early Calcineurin Inhibitor Reduction in Liver Transplantation: Impact on Renal Function. Transplantation 2019; 104:1003-1018. [PMID: 31577671 DOI: 10.1097/tp.0000000000002980] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
BACKGROUND The long-term use of calcineurin inhibitors (CNIs) after liver transplantation (LT) is associated with nephrotoxicity. METHODS Five-year follow-up data were retrieved from the randomized controlled multicenter SiLVER trial. Standard CNI-based mammalian target of rapamycin-free immunosuppression (group A, n = 264) was compared with a 50% reduction of CNI and introduction of the mammalian target of rapamycin inhibitor Sirolimus (SIR) within 4-6 weeks after LT (group B, n = 261). RESULTS Median MELD at LT was low with 10 (7-15) (group A) and 11 (8-15) (group B) in the intention-to-treat approach. CNI dose and CNI trough were reduced by 20% and 8% (group A) versus 55% and 56% (group B) at 3 months posttransplantation. Renal function was preserved at 3 months after LT in the SIR arm (estimated glomerular filtration rate 74 [57-95] versus 67 [55-85] mL/min/1.73m2 P = 0.004) but was similarly impaired thereafter compared with group A. The per protocol analysis identified LT recipients in group B with concomitant early CNI minimization and SIR treatment ≥ year 1 with significantly superior estimated glomerular filtration rate and lowest rate of chronic kidney disease (≥stage 3) from year 1 onwards until study end. Competing risk factors for renal disease (arterial hypertension, fat metabolism disorder, and hyperglycemia) were not associated with worse kidney function. CONCLUSIONS Prevention of CNI nephrotoxicity by SIR-based early CNI minimization protects renal function only short-term after LT in the intention-to-treat analysis of this low MELD cohort. Yet, selected LT recipients compliant with early CNI minimization and SIR maintenance achieved better long-term renal outcomes compared with real-world practice.
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11
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Iida T, Nojima M, Nakase H. Therapeutic Efficacy and Adverse Events of Tacrolimus in Patients with Crohn's Disease: Systematic Review and Meta-Analysis. Dig Dis Sci 2019; 64:2945-2954. [PMID: 30982208 DOI: 10.1007/s10620-019-05619-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 04/08/2019] [Indexed: 12/18/2022]
Abstract
BACKGROUND Only a few randomized controlled trials (RCTs) and some uncontrolled trials have reported the efficacy and adverse events (AEs) of tacrolimus (Tac) in patients with refractory Crohn's disease (CD). The aim of this study was to undertake a systematic review and meta-analysis of the therapeutic efficacy and AEs of Tac in patients with CD. METHODS We investigated studies reporting the therapeutic efficacy of Tac in patients with CD from 1950 until December 2017. Study subjects were categorized into three groups: systemic administration of Tac for patients with luminal CD (Group 1); systemic administration of Tac for patients with perianal CD (Group 2); and topical administration of Tac for patients with localized CD (Group 3). The primary endpoint of this study was the remission rate. Secondary endpoints were partial response rate, factors related to remission, and the incidence of AEs. RESULTS The remission rate of Group 1, 2, and 3 was 37.1, 32.0, and 22.7%, respectively. The partial response rate of those was 42.3, 42.9, and 44.3%, respectively. In addition, the incidence of AEs of those was 50.9, 65.5, and 40.0%, respectively. No life-threatening AEs were observed in any study. CONCLUSION This systematic review and meta-analysis demonstrated that Tac therapy was effective for subpopulation of CD patients and that the incidence of AEs was tolerable. Therefore, Tac therapy should be considered an option for patients with CD. However, there have been few well-designed RCTs on this subject and further studies are required.
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Affiliation(s)
- Tomoya Iida
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Minami 1-jo Nishi 16-chome, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Masanori Nojima
- Center for Translational Research, The Institute of Medical Science Hospital, The University of Tokyo, Tokyo, 108-8639, Japan
| | - Hiroshi Nakase
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Minami 1-jo Nishi 16-chome, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.
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12
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A systematic investigation on animal models of cyclosporine A combined with Escherichia coli to simulate the immunosuppressive status of sepsis patients before onset. Int Immunopharmacol 2018; 62:67-76. [DOI: 10.1016/j.intimp.2018.05.031] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Revised: 05/29/2018] [Accepted: 05/29/2018] [Indexed: 02/07/2023]
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13
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Buchholz BM, Lykoudis PM, Ravikumar R, Pollok JM, Fusai GK. Role of colectomy in preventing recurrent primary sclerosing cholangitis in liver transplant recipients. World J Gastroenterol 2018; 24:3171-3180. [PMID: 30065563 PMCID: PMC6064960 DOI: 10.3748/wjg.v24.i28.3171] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 07/08/2018] [Accepted: 07/16/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To study the published evidence on the impact of colectomy in preventing recurrent primary sclerosing cholangitis (rPSC).
METHODS An unrestricted systematic literature search in PubMed, EMBASE, Medline OvidSP, ISI Web of Science, Lista (EBSCO) and the Cochrane library was performed on clinical studies investigating colectomy in liver transplantation (LT) recipients with and without rPSC in the liver allograft. Study quality was evaluated according to a modification of the methodological index for non-randomized studies (MINORS) criteria. Primary endpoints were the impact of presence, timing and type of colectomy on rPSC. Overall presence of inflammatory bowel disease (IBD), time of IBD diagnosis, posttransplant IBD and immunosuppressive regimen were investigated as secondary outcome.
RESULTS The literature search yielded a total of 180 publications. No randomized controlled trial was identified. Six retrospective studies met the inclusion criteria of which 5 studies were graded as high quality articles. Reporting of IBD was heterogenous but in four publications, either inflammatory bowel disease, ulcerative colitis or in particular active colitis post-LT significantly increased the risk of rPSC. The presence of an intact (i.e., retained) colon at LT was identified as risk factor for rPSC in two of the high quality studies while four studies found no effect. Type of colectomy was not associated with rPSC but this endpoint was underreported (only in 33% of included studies). Neither tacrolimus nor cyclosporine A yielded a significant benefit in disease recurrence of primary sclerosing cholangitis (PSC).
CONCLUSION The data favours a protective role of pre-/peri-LT colectomy in rPSC but the current evidence is not strong enough to recommend routine colectomy for rPSC prevention.
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Affiliation(s)
- Bettina M Buchholz
- Department of HPB Surgery and Liver Transplantation, Royal Free Hospital London, London NW32QG, United Kingdom
| | - Panagis M Lykoudis
- Department of HPB Surgery and Liver Transplantation, Royal Free Hospital London, London NW32QG, United Kingdom
| | - Reena Ravikumar
- Department of HPB Surgery and Liver Transplantation, Royal Free Hospital London, London NW32QG, United Kingdom
| | - Joerg M Pollok
- Department of HPB Surgery and Liver Transplantation, Royal Free Hospital London, London NW32QG, United Kingdom
| | - Giuseppe K Fusai
- Department of HPB Surgery and Liver Transplantation, Royal Free Hospital London, London NW32QG, United Kingdom
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14
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Voitena J, Cunha O, Fukushima F, Carvalho G, Ramos L, Henriques V, Costa D. Eficácia dos colírios ciclosporina e tacrolimo no tratamento de ceratoconjuntivite seca em cães. ARQ BRAS MED VET ZOO 2018. [DOI: 10.1590/1678-4162-9849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
RESUMO O objetivo deste estudo foi avaliar os efeitos do tacrolimo e da ciclosporina na produção lacrimal de cães com ceratoconjuntivite seca (CCS) durante 90 dias. Para tanto, foram utilizados colírios de tacrolimo 0,02% (TcL) e ciclosporina 0,1% (CsA) em 14 cães com CCS. Os animais foram distribuídos em dois grupos e avaliados antes do início do tratamento (T0) e aos 15 (T1), 30 (T2), 45 (T3), 60 (T4), 75 (T5) e 90 (T6) dias após o início do tratamento. Na avaliação clínica, observou-se maior redução da secreção ocular, da opacidade e do edema corneano e da vascularização conjuntival. no grupo tacrolimo. No teste de Schirmer, verificou-se produção basal de 6(4,07 e 5,86(2,85mm/min no TcL e CsA, respectivamente, com aumento significativo da produção lacrimal em ambos os grupos, contudo houve aumento significativo da produção lacrimal a partir dos 15 dias de tratamento no grupo TcL (17,88(5,51mm/min), mas apenas a partir dos 45 dias no grupo CsA (11,86(4,74mm/min). Conclui-se que o uso do colírio tacrolimo aumentou em 68,83% a produção lacrimal em 90 dias de tratamento, comparado com a ciclosporina (56,82%), além de diminuir as manifestações clínicas inerentes à CCS, quando comparado à terapia com ciclosporina.
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Affiliation(s)
| | - O. Cunha
- Universidade Federal do Paraná, Brazil
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15
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Nassiri N, Rodriguez Torres Y, Meyer Z, Beyer MA, Vellaichamy G, Dhaliwal AS, Chungfat N, Hwang FS. Current and emerging therapy of dry eye disease. Part A: pharmacological modalities. EXPERT REVIEW OF OPHTHALMOLOGY 2017. [DOI: 10.1080/17469899.2017.1327350] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Affiliation(s)
- Nariman Nassiri
- Kresge Eye Institute - Department of Ophthalmology, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Yasaira Rodriguez Torres
- Kresge Eye Institute - Department of Ophthalmology, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Zachary Meyer
- Kresge Eye Institute - Department of Ophthalmology, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Michael A. Beyer
- Kresge Eye Institute - Department of Ophthalmology, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Gautham Vellaichamy
- Kresge Eye Institute - Department of Ophthalmology, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Amar S. Dhaliwal
- Kresge Eye Institute - Department of Ophthalmology, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Neil Chungfat
- Department of Ophthalmology, School of Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Frank S. Hwang
- Kresge Eye Institute - Department of Ophthalmology, School of Medicine, Wayne State University, Detroit, MI, USA
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16
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Mycophenolic acid potently inhibits rotavirus infection with a high barrier to resistance development. Antiviral Res 2016; 133:41-9. [PMID: 27468950 DOI: 10.1016/j.antiviral.2016.07.017] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Accepted: 07/24/2016] [Indexed: 12/13/2022]
Abstract
Rotavirus infection has emerged as an important cause of complications in organ transplantation recipients. Immunosuppressants used to prevent alloreactivity can also interfere with virus infection, but the direct effects of the specific type of immunosuppressants on rotavirus infection are still unclear. Here we profiled the effects of different immunosuppressants on rotavirus using a 2D culture model of Caco2 human intestinal cell line and a 3D model of human primary intestinal organoids inoculated with laboratory and patient-derived rotavirus strains. We found that the responsiveness of rotavirus to Cyclosporine A treatment was moderate and strictly regulated in an opposite direction by its cellular targets cyclophilin A and B. Treatment with mycophenolic acid (MPA) resulted in a 99% inhibition of viral RNA production at the clinically relevant concentration (10 μg/ml) in Caco2 cells. This effect was further confirmed in organoids. Importantly, continuous treatment with MPA for 30 passages did not attenuate its antiviral potency, indicating a high barrier to drug resistance development. Mechanistically, the antiviral effects of MPA act via inhibiting the IMPDH enzyme and resulting in guanosine nucleotide depletion. Thus for transplantation patients at risk for rotavirus infection, the choice of MPA as an immunosuppressive agent appears rational.
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17
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Levy O, Labbé A, Borderie V, Laroche L, Bouheraoua N. La ciclosporine topique en ophtalmologie : pharmacologie et indications thérapeutiques. J Fr Ophtalmol 2016; 39:292-307. [DOI: 10.1016/j.jfo.2015.11.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Revised: 11/21/2015] [Accepted: 11/27/2015] [Indexed: 01/12/2023]
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18
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Gire AI, Karakus S, Ingrodi SM, Akpek EK. Frequent Dosing of Topical Cyclosporine A for Severe Ocular Surface Disease. J Ocul Pharmacol Ther 2016; 32:150-4. [PMID: 26789928 DOI: 10.1089/jop.2015.0078] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
PURPOSE To study the systemic safety and patient tolerability of frequent dosing of cyclosporine A (CsA) 0.05% eyedrops in the treatment of ocular surface disease. This is a retrospective case series. Patients with significant ocular surface diseases who were treated using topical CsA higher than the usual twice daily dosing (3-8 times daily and over a treatment period of 1-70 months). The main outcome measures are plasma levels of CsA and local tolerability. METHODS Symptom assessment, corneal staining using fluorescein, conjunctival staining using lissamine green, tear film breakup time, and other signs according to the disease process were monitored. Discontinuation of treatment due to intolerability was recorded. CsA levels were measured in the plasma at a clinical laboratory. RESULTS Plasma levels of CsA were below the level of detection (7 ng/mL) in all the 41 patients included. All patients tolerated the treatment well with none discontinuing due to any treatment-related local adverse effects. CONCLUSIONS This study demonstrates that CsA 0.05% ophthalmic emulsion applied more frequently than the usual twice daily dosing was safe and well tolerated in patients with significant ocular surface diseases.
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Affiliation(s)
- Anisa I Gire
- Ocular Surface Diseases and Dry Eye Clinic, Wilmer Eye Institute, Johns Hopkins University School of Medicine , Baltimore, Maryland
| | - Sezen Karakus
- Ocular Surface Diseases and Dry Eye Clinic, Wilmer Eye Institute, Johns Hopkins University School of Medicine , Baltimore, Maryland
| | - Shanna M Ingrodi
- Ocular Surface Diseases and Dry Eye Clinic, Wilmer Eye Institute, Johns Hopkins University School of Medicine , Baltimore, Maryland
| | - Esen Karamursel Akpek
- Ocular Surface Diseases and Dry Eye Clinic, Wilmer Eye Institute, Johns Hopkins University School of Medicine , Baltimore, Maryland
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19
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Karakhanova S, Oweira H, Steinmeyer B, Sachsenmaier M, Jung G, Elhadedy H, Schmidt J, Hartwig W, Bazhin AV, Werner J. Interferon-γ, interleukin-10 and interferon-inducible protein 10 (CXCL10) as serum biomarkers for the early allograft dysfunction after liver transplantation. Transpl Immunol 2015; 34:14-24. [PMID: 26658573 DOI: 10.1016/j.trim.2015.12.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Revised: 11/14/2015] [Accepted: 12/02/2015] [Indexed: 01/29/2023]
Abstract
Orthotopic liver transplantation (LTP) is nowadays a standard procedure, and provides the chance of survival of patients with end-stage non-treatable chronic liver disease or acute liver failure. Despite long-term survival with a good quality of life in the majority of patients, about 20% develop early allograft dysfunction (EAD), which leads to death or the need for re-transplantation. Therefore, the early diagnosis of EAD and evaluation of its risk factors are very important. Many primary pathological processes leading to EAD are accompanied by the release of different mediators and by a change of biochemical parameters detectable in the peripheral blood. The aim of this study was to investigate cytokines as well as soluble mediators in the serum of patients with and without EAD from our LTP bank, and to evaluate their predictive and prognostic values for EAD. We demonstrated for the first time that the level of IFNγ during the nearest preoperative period may serve as a predictive parameter for EAD. We additionally found that IL-10 and CXCL10 (IP-10) levels in the early postoperative period can be prognostic for EAD. We believe our data expand the spectrum of predictive and prognostic parameters for EAD in LTP.
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Affiliation(s)
- Svetlana Karakhanova
- Department of General Surgery, University of Heidelberg, 69120 Heidelberg, Germany.
| | - Hani Oweira
- Department of General Surgery, University of Heidelberg, 69120 Heidelberg, Germany
| | - Beate Steinmeyer
- Department of General Surgery, University of Heidelberg, 69120 Heidelberg, Germany
| | - Milena Sachsenmaier
- Department of General Surgery, University of Heidelberg, 69120 Heidelberg, Germany
| | - Gregor Jung
- Department of General Surgery, University of Heidelberg, 69120 Heidelberg, Germany
| | - Hazem Elhadedy
- Department of General Surgery, University of Heidelberg, 69120 Heidelberg, Germany
| | - Jan Schmidt
- Department of General Surgery, University of Heidelberg, 69120 Heidelberg, Germany; General and Visceral Surgery Center, 8002 Zurich, Switzerland
| | - Werner Hartwig
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University, 81377 Munich, Germany
| | - Alexandr V Bazhin
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University, 81377 Munich, Germany
| | - Jens Werner
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University, 81377 Munich, Germany
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20
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Egorova GB, Mitichkina TS, Fedorov AA, Shamsudinova AR. [Topical cyclosporine for the treatment of ocular surface changes in contact lens wearers]. Vestn Oftalmol 2015; 131:36-42. [PMID: 25872385 DOI: 10.17116/oftalma2015131136-42] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
OBJECTIVE To assess opportunities for the use of cyclosporine emulsion 0.05% for the treatment of dry eye syndrome in long-term contact lens wearers. MATERIAL AND METHODS A total of 25 long-term contact lens wearers (50 eyes) with signs of dry eye syndrome and corneal epitheliopathy of different degree, unresponsive to conventional artificial tears therapy, were observed. All of them were prescribed cyclosporine emulsion 0.05% twice daily at 12-hour intervals 10 min before inserting contact lenses or after removing. Biomicroscopy with fluorescein eye stain test, determination of the tear film break-up time (Norn's test), optical coherence tomography of tear meniscus (OCT-meniscometry), Jones test, impression cytology, and corneal confocal microscopy (Confoscan-4, "Nidek", Japan) were used to evaluate the treatment effect. RESULTS The treatment resulted in better contact lens tolerance, significantly increased mean values of tear film break-up time (by 13.2% at 1 month, 62% at 3 months, and 37.3% at 6 months as compared with the baseline) and basal tear secretion (by 29%, 32%, and 82.4% at 1, 3, and 6 months correspondingly). Confocal microscopy revealed restitution of corneal superficial epithelial structure and cell density. Goblet cells were present in impression cytology specimens. CONCLUSION Topical use of cyclosporine emulsion 0.05% has a positive effect on morphofunctional parameters of ocular surface and promotes basal tear secretion and precorneal tear film stability.
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Affiliation(s)
- G B Egorova
- Research Institute of Eye Diseases, 11 A, B Rossolimo St., Moscow, Russian Federation, 119021
| | - T S Mitichkina
- Research Institute of Eye Diseases, 11 A, B Rossolimo St., Moscow, Russian Federation, 119021
| | - A A Fedorov
- Research Institute of Eye Diseases, 11 A, B Rossolimo St., Moscow, Russian Federation, 119021
| | - A R Shamsudinova
- Research Institute of Eye Diseases, 11 A, B Rossolimo St., Moscow, Russian Federation, 119021
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21
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Studebaker AW, Hutzen B, Pierson CR, Shaffer TA, Raffel C, Jackson EM. Oncolytic measles virus efficacy in murine xenograft models of atypical teratoid rhabdoid tumors. Neuro Oncol 2015; 17:1568-77. [PMID: 25838138 DOI: 10.1093/neuonc/nov058] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2014] [Accepted: 03/11/2015] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND Atypical teratoid rhabdoid tumor (AT/RT) is a rare, highly malignant pediatric tumor of the central nervous system that is usually refractory to available treatments. The aggressive growth, propensity to disseminate along the neuroaxis, and young age at diagnosis contribute to the poor prognosis. Previous studies have demonstrated the efficacy of using oncolytic measles virus (MV) against localized and disseminated models of medulloblastoma. The purpose of this study was to evaluate the oncolytic potential of MV in experimental models of AT/RT. METHODS Following confirmation of susceptibility to MV infection and killing of AT/RT cells in vitro, nude mice were injected with BT-12 and BT-16 AT/RT cells stereotactically into the caudate nucleus (primary tumor model) or lateral ventricle (disseminated tumor model). Recombinant MV was administered either intratumorally or intravenously. Survival was determined for treated and control animals. Necropsy was performed on animals showing signs of progressive disease. RESULTS All cell lines exhibited significant killing when infected with MV, all formed syncytia with infection, and all generated infectious virus after infection. Orthotopic xenografts displayed cells with rhabdoid-like cellular morphology, were negative for INI1 expression, and showed dissemination within the intracranial and spinal subarachnoid spaces. Intratumoral injection of live MV significantly prolonged the survival of animals with intracranial and metastatic tumors. CONCLUSION These data demonstrate that AT/RT is susceptible to MV killing and suggest that the virus may have a role in treating this tumor in the clinical setting.
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Affiliation(s)
- Adam W Studebaker
- Center for Childhood Cancer and Blood Diseases, Research Institute at Nationwide Children's Hospital, Columbus, Ohio (A.W.S., B.H.); Nationwide Children's Hospital Department of Pathology and Laboratory Medicine and Departments of Pathology and Anatomy, The Ohio State University College of Medicine, Columbus, Ohio (C.R.P.); Animal Resources Core, Research Institute at Nationwide Children's Hospital, Columbus, Ohio (T.A.S.); Department of Neurological Surgery and Pediatrics, University of California, San Francisco, California (C.R.); Department of Neurosurgery, Johns Hopkins University, Baltimore, Maryland (E.M.J.)
| | - Brian Hutzen
- Center for Childhood Cancer and Blood Diseases, Research Institute at Nationwide Children's Hospital, Columbus, Ohio (A.W.S., B.H.); Nationwide Children's Hospital Department of Pathology and Laboratory Medicine and Departments of Pathology and Anatomy, The Ohio State University College of Medicine, Columbus, Ohio (C.R.P.); Animal Resources Core, Research Institute at Nationwide Children's Hospital, Columbus, Ohio (T.A.S.); Department of Neurological Surgery and Pediatrics, University of California, San Francisco, California (C.R.); Department of Neurosurgery, Johns Hopkins University, Baltimore, Maryland (E.M.J.)
| | - Christopher R Pierson
- Center for Childhood Cancer and Blood Diseases, Research Institute at Nationwide Children's Hospital, Columbus, Ohio (A.W.S., B.H.); Nationwide Children's Hospital Department of Pathology and Laboratory Medicine and Departments of Pathology and Anatomy, The Ohio State University College of Medicine, Columbus, Ohio (C.R.P.); Animal Resources Core, Research Institute at Nationwide Children's Hospital, Columbus, Ohio (T.A.S.); Department of Neurological Surgery and Pediatrics, University of California, San Francisco, California (C.R.); Department of Neurosurgery, Johns Hopkins University, Baltimore, Maryland (E.M.J.)
| | - Terri A Shaffer
- Center for Childhood Cancer and Blood Diseases, Research Institute at Nationwide Children's Hospital, Columbus, Ohio (A.W.S., B.H.); Nationwide Children's Hospital Department of Pathology and Laboratory Medicine and Departments of Pathology and Anatomy, The Ohio State University College of Medicine, Columbus, Ohio (C.R.P.); Animal Resources Core, Research Institute at Nationwide Children's Hospital, Columbus, Ohio (T.A.S.); Department of Neurological Surgery and Pediatrics, University of California, San Francisco, California (C.R.); Department of Neurosurgery, Johns Hopkins University, Baltimore, Maryland (E.M.J.)
| | - Corey Raffel
- Center for Childhood Cancer and Blood Diseases, Research Institute at Nationwide Children's Hospital, Columbus, Ohio (A.W.S., B.H.); Nationwide Children's Hospital Department of Pathology and Laboratory Medicine and Departments of Pathology and Anatomy, The Ohio State University College of Medicine, Columbus, Ohio (C.R.P.); Animal Resources Core, Research Institute at Nationwide Children's Hospital, Columbus, Ohio (T.A.S.); Department of Neurological Surgery and Pediatrics, University of California, San Francisco, California (C.R.); Department of Neurosurgery, Johns Hopkins University, Baltimore, Maryland (E.M.J.)
| | - Eric M Jackson
- Center for Childhood Cancer and Blood Diseases, Research Institute at Nationwide Children's Hospital, Columbus, Ohio (A.W.S., B.H.); Nationwide Children's Hospital Department of Pathology and Laboratory Medicine and Departments of Pathology and Anatomy, The Ohio State University College of Medicine, Columbus, Ohio (C.R.P.); Animal Resources Core, Research Institute at Nationwide Children's Hospital, Columbus, Ohio (T.A.S.); Department of Neurological Surgery and Pediatrics, University of California, San Francisco, California (C.R.); Department of Neurosurgery, Johns Hopkins University, Baltimore, Maryland (E.M.J.)
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22
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Hope CM, Coates PTH, Carroll RP. Immune profiling and cancer post transplantation. World J Nephrol 2015; 4:41-56. [PMID: 25664246 PMCID: PMC4317627 DOI: 10.5527/wjn.v4.i1.41] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Revised: 11/03/2014] [Accepted: 11/07/2014] [Indexed: 02/06/2023] Open
Abstract
Half of all long-term (> 10 year) australian kidney transplant recipients (KTR) will develop squamous cell carcinoma (SCC) or solid organ cancer (SOC), making cancer the leading cause of death with a functioning graft. At least 30% of KTR with a history of SCC or SOC will develop a subsequent SCC or SOC lesion. Pharmacological immunosuppression is a major contributor of the increased risk of cancer for KTR, with the cancer lesions themselves further adding to systemic immunosuppression and could explain, in part, these phenomena. Immune profiling includes; measuring immunosuppressive drug levels and pharmacokinetics, enumerating leucocytes and leucocyte subsets as well as testing leucocyte function in either an antigen specific or non-specific manner. Outputs can vary from assay to assay according to methods used. In this review we define the rationale behind post-transplant immune monitoring assays and focus on assays that associate and/or have the ability to predict cancer and rejection in the KTR. We find that immune monitoring can identify those KTR of developing multiple SCC lesions and provide evidence they may benefit from pharmacological immunosuppressive drug dose reductions. In these KTR risk of rejection needs to be assessed to determine if reduction of immunosuppression will not harm the graft.
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23
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Mizokami D, Araki K, Tanaka N, Suzuki H, Tomifuji M, Yamashita T, Matsushita K, Shimada H, Shiotani A. Tacrolimus prevents laryngotracheal stenosis in an acute-injury rat model. Laryngoscope 2015; 125:E210-5. [PMID: 25647147 DOI: 10.1002/lary.25178] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Revised: 11/28/2014] [Accepted: 01/05/2015] [Indexed: 01/09/2023]
Abstract
OBJECTIVES/HYPOTHESIS Acquired laryngotracheal stenosis is a challenging problem for otolaryngologists. Several studies suggest tacrolimus may inhibit post-transplant airway stenosis that occurs with coronary drug-eluting stents. The objective of the present study was to determine whether tacrolimus modulates wound healing of the airway mucosa and prevents laryngotracheal stenosis in an acute injury animal model. STUDY DESIGN Basic science. METHODS The laryngotracheal mucosa of rats was scraped with a nylon brush through the tracheostoma. Tacrolimus (0.2 mg/kg or 1.0 mg/kg) was systemically administered intramuscularly for 5 days. Nine days after scraping, the pathological changes and the degree of stenosis were assessed by hematoxylin and eosin staining or by immunohistochemical staining for nuclear factor of activated T cell and interleukin 2. RESULTS Lumen stenosis resulted from hyperplasia of the airway epithelium and a thickened submucosal layer with extensive fibrosis, angiogenesis, and collagen deposition. There was a significant preventive effect on airway stenosis at the tracheal and cricoid levels in the low-dose (0.2 mg/kg) tacrolimus-treated animals, compared to the untreated animals (P < .05). This effect was insignificant with treatment by high-dose tacrolimus (1.0 mg/kg). Immunohistochemistry showed that, after tacrolimus treatment, the expressions of nuclear factor of activated T cell and interleukin 2 were downregulated in submucosal fibroblasts, neovascular cells, and glandular cells. CONCLUSIONS This study suggests that low-dose systemic tacrolimus has a preventive effect on laryngotracheal stenosis by inhibiting the activation of immune cells in the injured airway mucosa via the calcineurin/nuclear factor of activated T cell/interleukin 2 pathway. LEVEL OF EVIDENCE NA.
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Affiliation(s)
- Daisuke Mizokami
- Department of Otolaryngology-Head and Neck Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Koji Araki
- Department of Otolaryngology-Head and Neck Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Nobuaki Tanaka
- Department of Otolaryngology-Head and Neck Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Hiroshi Suzuki
- Department of Otolaryngology-Head and Neck Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan
| | | | - Taku Yamashita
- Department of Otolaryngology-Head and Neck Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Kazuyuki Matsushita
- Department of Molecular Diagnosis, Division of Clinical Genetics and Proteomics, Graduate School of Medicine, Chiba University, Chiba City, Chiba, Japan
| | - Hideaki Shimada
- Department of Surgery, Toho University School of Medicine, Ota-Ku, Tokyo, Japan
| | - Akihiro Shiotani
- Department of Otolaryngology-Head and Neck Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan
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24
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Millet P, Landel V, Virard I, Morello M, Féron F. Rôles bénéfiques de la vitamine D sur la neurodégénérescence et les troubles mentaux. CAHIERS DE NUTRITION ET DE DIETETIQUE 2014. [DOI: 10.1016/j.cnd.2014.03.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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25
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El-Gowelli HM, El-Mas MM. Central modulation of cyclosporine-induced hypertension. Naunyn Schmiedebergs Arch Pharmacol 2014; 388:351-61. [DOI: 10.1007/s00210-014-1074-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2014] [Accepted: 11/18/2014] [Indexed: 12/25/2022]
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26
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Moes AD, Hesselink DA, Zietse R, van Schaik RHN, van Gelder T, Hoorn EJ. Calcineurin inhibitors and hypertension: a role for pharmacogenetics? Pharmacogenomics 2014; 15:1243-51. [DOI: 10.2217/pgs.14.87] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Hypertension is a common side effect of calcineurin inhibitors (CNIs), which are drugs used to prevent rejection after transplantation. Hypertension after kidney transplantation has been associated with earlier graft failure and higher cardiovascular mortality in the recipient. Recent data indicate that enzymes and transporters involved in CNI pharmacokinetics and pharmacodynamics, including CYP3A5, ABCB1, WNK4 and SPAK, are also associated with salt-sensitive hypertension. These insights raise the question whether polymorphisms in the genes encoding these proteins increase the risk of CNI-induced hypertension. Predicting who is at risk for CNI-induced hypertension may be useful for when selecting specific interventions, including dietary salt restriction, thiazide diuretics or a CNI-free immunosuppressive regimen. This review aims to explore the pharmacogenetics of CNI-induced hypertension, highlighting the knowns and unknowns.
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Affiliation(s)
- Arthur D Moes
- Department of Internal Medicine, Nephrology & Transplantation, Erasmus Medical Center, PO Box 2040 – Room H-438, 3000 CA Rotterdam, The Netherlands
| | - Dennis A Hesselink
- Department of Internal Medicine, Nephrology & Transplantation, Erasmus Medical Center, PO Box 2040 – Room H-438, 3000 CA Rotterdam, The Netherlands
| | - Robert Zietse
- Department of Internal Medicine, Nephrology & Transplantation, Erasmus Medical Center, PO Box 2040 – Room H-438, 3000 CA Rotterdam, The Netherlands
| | - Ron HN van Schaik
- Department of Clinical Chemistry, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Teun van Gelder
- Department of Internal Medicine, Nephrology & Transplantation, Erasmus Medical Center, PO Box 2040 – Room H-438, 3000 CA Rotterdam, The Netherlands
- Department of Hospital Pharmacy, Clinical Pharmacology Unit, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Ewout J Hoorn
- Department of Internal Medicine, Nephrology & Transplantation, Erasmus Medical Center, PO Box 2040 – Room H-438, 3000 CA Rotterdam, The Netherlands
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Millet P, Landel V, Virard I, Morello M, Féron F. [Role of vitamin D in the physiopathology of neurodegenerative diseases]. Biol Aujourdhui 2014; 208:77-88. [PMID: 24948021 DOI: 10.1051/jbio/20140007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Indexed: 12/19/2022]
Abstract
The involvement of vitamin D in brain function has been discovered in the past 25 years by epidemiological and fundamental studies. Research on neurodegenerative diseases and their animal or cellular models unveiled converging lines of evidence indicating that hypovitaminosis D is not just an effect of the progression of neurodegenerative diseases, but truly an aggravating co-factor, sometimes very closely related to their physiopathology. Vitamin D is a steroid hormone capable of regulating the expression of hundreds of genes through both genetic and epigenetic mechanisms. This reflects the highly pleiotropic nature of its action in its conventional bone and phosphocalcic metabolism targets. Its role in the central nervous system and neurodegenerative diseases makes no exception to this rule. Here we focus on the identified role and mechanisms of vitamin D in multiple sclerosis, Alzheimer's disease and Parkinson's disease. The important prevalence of hypovitaminosis D under our latitudes in general and in at-risk groups in particular, its easy evaluation and correction, and the results of early clinical studies, suggest that vitamin D supplementation could usefully complement our therapeutic armory to fight these diseases.
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Affiliation(s)
- Pascal Millet
- Aix Marseille Université, CNRS, NICN UMR7259, 13916 Marseille, France
| | - Véréna Landel
- Aix Marseille Université, CNRS, NICN UMR7259, 13916 Marseille, France
| | - Isabelle Virard
- Aix Marseille Université, CNRS, NICN UMR7259, 13916 Marseille, France
| | - Maria Morello
- Aix Marseille Université, CNRS, NICN UMR7259, 13916 Marseille, France - Università degli Studi di Roma Tor Vergata, Facoltà di Medicina, Biochimica Clinica, Divisione di Nutrizione Umana, Scienza della Nutrizione, Viale Oxford 1, 00133 Rome, Italie
| | - François Féron
- Aix Marseille Université, CNRS, NICN UMR7259, 13916 Marseille, France
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Lin R, Kim H, Hong J, Li QJ. Biological evaluation of subglutinol a as a novel immunosuppressive agent for inflammation intervention. ACS Med Chem Lett 2014; 5:485-90. [PMID: 24900866 DOI: 10.1021/ml4004809] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Accepted: 03/10/2014] [Indexed: 12/31/2022] Open
Abstract
Subglutinol A (1) is an immunosuppressive natural product isolated from Fusarium subglutinans, an endophytic fungus from the vine Tripterygium wilfordii. We show that 1 exerts multimodal immune-suppressive effects on activated T cells in vitro: subglutinol A (1) effectively blocks T cell proliferation and survival while profoundly inhibiting pro-inflammatory IFNγ and IL-17 production by fully differentiated effector Th1 and Th17 cells. Our data further reveal that 1 may exert its anti-inflammatory effects by exacerbating mitochondrial damage in T cells. Additionally, we demonstrate that 1 significantly reduces lymphocytic infiltration into the footpad and ameliorates footpad swelling in the mouse model of Th1-driven delayed-type hypersensitivity. These results suggest the potential of 1 as a novel therapeutic for inflammatory diseases.
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Affiliation(s)
- Regina Lin
- Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710, United States
| | - Hyoungsu Kim
- Department
of Chemistry, Duke University, Durham, North Carolina 27708, United States
| | - Jiyong Hong
- Department
of Chemistry, Duke University, Durham, North Carolina 27708, United States
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, United States
| | - Qi-Jing Li
- Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710, United States
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29
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The medically immunocompromised adult traveler and pre-travel counseling: Status quo 2014. Travel Med Infect Dis 2014; 12:219-28. [DOI: 10.1016/j.tmaid.2014.04.009] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2014] [Revised: 04/16/2014] [Accepted: 04/24/2014] [Indexed: 12/11/2022]
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High-Throughput Proteomic Approaches to the Elucidation of Potential Biomarkers of Chronic Allograft Injury (CAI). Proteomes 2013; 1:159-179. [PMID: 28250402 PMCID: PMC5302743 DOI: 10.3390/proteomes1020159] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Revised: 09/06/2013] [Accepted: 09/09/2013] [Indexed: 12/12/2022] Open
Abstract
This review focuses on the role of OMICs technologies, concentrating in particular on proteomics, in biomarker discovery in chronic allograft injury (CAI). CAI is the second most prevalent cause of allograft dysfunction and loss in the first decade post-transplantation, after death with functioning graft (DWFG). The term CAI, sometimes referred to as chronic allograft nephropathy (CAN), describes the deterioration of renal allograft function and structure as a result of immunological processes (chronic antibody-mediated rejection), and other non-immunological factors such as calcineurin inhibitor (CNI) induced nephrotoxicity, hypertension and infection. Current methods for assessing allograft function are costly, insensitive and invasive; traditional kidney function measurements such as serum creatinine and glomerular filtration rate (GFR) display poor predictive abilities, while the current “gold-standard” involving histological diagnosis with a renal biopsy presents its own inherent risks to the overall health of the allograft. As early as two years post-transplantation, protocol biopsies have shown more than 50% of allograft recipients have mild CAN; ten years post-transplantation more than 50% of the allograft recipients have progressed to severe CAN which is associated with diminishing graft function. Thus, there is a growing medical requirement for minimally invasive biomarkers capable of identifying the early stages of the disease which would allow for timely intervention. Proteomics involves the study of the expression, localization, function and interaction of the proteome. Proteomic technologies may be powerful tools used to identify novel biomarkers which would predict CAI in susceptible individuals. In this paper we will review the use of proteomics in the elucidation of novel predictive biomarkers of CAI in clinical, animal and in vitro studies.
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Puigdemont A, Brazís P, Ordeix L, Dalmau A, Fuertes E, Olivar A, Pérez C, Ravera I. Efficacy of a new topical cyclosporine A formulation in the treatment of atopic dermatitis in dogs. Vet J 2013; 197:280-5. [DOI: 10.1016/j.tvjl.2013.02.018] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2012] [Revised: 02/18/2013] [Accepted: 02/21/2013] [Indexed: 11/30/2022]
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Dey M, Auffinger B, Lesniak MS, Ahmed AU. Antiglioma oncolytic virotherapy: unattainable goal or a success story in the making? Future Virol 2013; 8:675-693. [PMID: 24910708 DOI: 10.2217/fvl.13.47] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Initial observations from as early as the mid-1800s suggested that patients suffering from hematological malignancies would transiently go into remission upon naturally contracting viral infections laid the foundation for the oncolytic virotherapy research field. Since then, research focusing on anticancer oncolytic virotherapy has rapidly evolved. Today, oncolytic viral vectors have been engineered to stimulate and manipulate the host immune system, selectively targeting tumor tissues while sparing non-neoplastic cells. Glioblastoma multiforme, the most common adult primary brain tumor, has a disasterous history. It is one of the most deadly cancers known to humankind. Over the last century our understanding of this disease has grown exponentially. However, the median survival of patients suffering from this disease has only been extended by a few months. Even with the best, most aggressive modern therapeutic approaches available, malignant gliomas are still virtually 100% fatal. Motivated by the desperate need to find effective treatment strategies, more investments have been applied to oncolytic virotherapy preclinical and clinical studies. In this review we will discuss the antiglioma oncolytic virotherapy research field. We will survey its history and the principles laid down to serve as basis for preclinical works. We will also debate the variety of viral vectors used, their clinical applications, the lessons learned from clinical trials and possible future directions.
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Affiliation(s)
- Mahua Dey
- The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, 5841 South Maryland Avenue, MC 3026, Chicago, IL 60637, USA
| | - Brenda Auffinger
- The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, 5841 South Maryland Avenue, MC 3026, Chicago, IL 60637, USA
| | - Maciej S Lesniak
- The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, 5841 South Maryland Avenue, MC 3026, Chicago, IL 60637, USA
| | - Atique U Ahmed
- The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, 5841 South Maryland Avenue, MC 3026, Chicago, IL 60637, USA
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Beardsley RM, Suhler EB, Rosenbaum JT, Lin P. Pharmacotherapy of scleritis: current paradigms and future directions. Expert Opin Pharmacother 2013; 14:411-24. [PMID: 23425055 DOI: 10.1517/14656566.2013.772982] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Scleritis is an inflammatory condition affecting the eye wall that may be associated with a number of systemic inflammatory diseases. Because scleritis can be refractory to standard treatment, knowledge of the body of available and emerging therapies is paramount and is reviewed here. AREAS COVERED This review focuses on both traditional and emerging therapies for noninfectious scleritis. The authors cover the mechanisms of action and potential adverse effects of each of the treatment modalities. In addition, a summary of the significant MEDLINE indexed literature under the subject heading 'scleritis', 'treatment', 'immunomodulator' will be provided on each therapy, including commentary on appropriate use and relative contraindications. Novel treatments and potential drug candidates that are currently being evaluated in clinical trials with therapeutic potential will also be reviewed. EXPERT OPINION While oral nonsteroidal anti-inflammatory drugs and oral corticosteroids are widely used, effective, first-line agents for inflammatory scleritis, refractory cases require antimetabolites, T-cell inhibitors, or biologic response modifiers. In particular, there is emerging evidence for the use of targeted biologic response modifiers, and potentially, for local drug delivery.
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Affiliation(s)
- Robert M Beardsley
- Oregon Health & Science University, Casey Eye Institute, 3375 SW Terwilliger Blvd, Portland, OR 97239, USA
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34
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Dugas HL, Peters JI, Williams RO. Nebulization of mycophenolate mofetil inhalation suspension in rats: Comparison with oral and pulmonary administration of Cellcept®. Int J Pharm 2013; 441:19-29. [DOI: 10.1016/j.ijpharm.2012.12.016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2012] [Revised: 11/30/2012] [Accepted: 12/12/2012] [Indexed: 10/27/2022]
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Heo J, Sepah YJ, Yohannan J, Renner M, Akhtar A, Gregory A, Shulman M, Do DV, Nguyen QD. The role of biologic agents in the management of non-infectious uveitis. Expert Opin Biol Ther 2012; 12:995-1008. [PMID: 22780091 DOI: 10.1517/14712598.2012.688021] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Uveitis is an intriguing group of disorders characterized by inflammation of the uveal tract. Due to the potential grave consequences of the disease process, it is important to assess the various therapeutic options available for treating uveitis, and their outcomes. AREAS COVERED This review discusses the use of conventional agents in the management of uveitis, including discussion of the molecular and clinical properties of corticosteroids, antimetabolites, calcineurin inhibitors and alkylating agents and their side effects. In addition, it also discusses the molecular and clinical properties of novel biologic agents and their side effects. Moreover, recommendations as to when biologic agents should be employed are also discussed. EXPERT OPINION We recommend that in general (except in selected cases of Adamantiades-Behçet's disease) biologics should not be used as a first-line therapy for uveitis due to inconvenience, high cost, and potential immunosuppressive effects. However, many biologics are potent in inducing drug-free remission of uveitis and may be employed to manage recurrent diseases or diseases not responsive to conventional agents.
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Affiliation(s)
- Jangwon Heo
- Johns Hopkins University School of Medicine, Wilmer Eye Institute, Johns Hopkins Hospital, Retinal Imaging Research and Reading Center, 600 North Wolfe Street, Maumenee 745, Baltimore, MD 21287, USA
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Abstract
This article reviews the current understanding of the mechanisms of calcineurin inhibitor-induced hypertension. Already early after the introduction of cyclosporine in the 1980s, vasoconstriction, sympathetic excitation and sodium retention by the kidney had been shown to play a role in this form of hypertension. The vasoconstrictive effects of calcineurin inhibitors are related to interference with the balance of vasoactive substances, including endothelin and nitric oxide. Until recently, the renal site of the sodium-retaining effect of calcineurin inhibitors was unknown. We and others have shown that calcineurin inhibitors increase the activity of the thiazide-sensitive sodium chloride cotransporter through an effect on the kinases WNK and SPAK. Here, we review the pertinent literature on the hypertensinogenic effects of calcineurin inhibitors, including neural, vascular and renal effects, and we propose an integrated model of calcineurin inhibitor-induced hypertension.
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37
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Marsella R, Sousa CA, Gonzales AJ, Fadok VA. Current understanding of the pathophysiologic mechanisms of canine atopic dermatitis. J Am Vet Med Assoc 2012; 241:194-207. [DOI: 10.2460/javma.241.2.194] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Abstract
Oncolytic virotherapy is an emerging treatment modality that uses replication-competent viruses to destroy cancers. Recent advances include preclinical proof of feasibility for a single-shot virotherapy cure, identification of drugs that accelerate intratumoral virus propagation, strategies to maximize the immunotherapeutic action of oncolytic viruses and clinical confirmation of a critical viremic threshold for vascular delivery and intratumoral virus replication. The primary clinical milestone has been completion of accrual in a phase 3 trial of intratumoral herpes simplex virus therapy using talimogene laherparepvec for metastatic melanoma. Key challenges for the field are to select 'winners' from a burgeoning number of oncolytic platforms and engineered derivatives, to transiently suppress but then unleash the power of the immune system to maximize both virus spread and anticancer immunity, to develop more meaningful preclinical virotherapy models and to manufacture viruses with orders-of-magnitude higher yields than is currently possible.
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Rodriguez-Aller M, Kaufmann B, Guillarme D, Stella C, Furrer P, Rudaz S, El Zaoui I, Valamanesh F, Di Tommaso C, Behar-Cohen F, Veuthey JL, Gurny R. In vivo characterisation of a novel water-soluble Cyclosporine A prodrug for the treatment of dry eye disease. Eur J Pharm Biopharm 2012; 80:544-52. [DOI: 10.1016/j.ejpb.2011.11.017] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2011] [Revised: 11/21/2011] [Accepted: 11/28/2011] [Indexed: 01/13/2023]
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40
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Romagnani P, Crescioli C. CXCL10: a candidate biomarker in transplantation. Clin Chim Acta 2012; 413:1364-73. [PMID: 22366165 DOI: 10.1016/j.cca.2012.02.009] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2011] [Revised: 02/10/2012] [Accepted: 02/10/2012] [Indexed: 10/28/2022]
Abstract
Interferon (IFN) γ-induced protein 10 kDa (IP-10) or C-X-C motif chemokine 10 (CXCL10) is a small cytokine belonging to the CXC chemokine family. This family of signaling molecules is known to control several biological functions and to also play pivotal roles in disease initiation and progression. By binding to its specific cognate receptor CXCR3, CXCL10 critically regulates chemotaxis during several immune-inflammatory processes. In particular, this chemokine controls chemotaxis during the inflammatory response resulting from allograft rejection after transplantation. Interestingly, a strong association has been described between CXCL10 production, immune response and the fate of the graft following allotransplantation. Enhanced CXCL10 production has been observed in recipients of transplants of different organs. This enhanced production likely comes from either the graft or the immune cells and is correlated with an increase in the concentration of circulating CXCL10. Because CXCL10 can be easily measured in the serum and plasma from a patient, the detection and quantitation of circulating CXCL10 could be used to reveal a transplant recipient's immune status. The purpose of this review is to examine the critical role of CXCL10 in the pathogenesis of allograft rejection following organ transplantation. This important role highlights the potential utilization of CXCL10 not only as a therapeutic target but also as a biomarker to predict the severity of rejection, to monitor the inflammatory status of organ recipients and, hopefully, to fine-tune patient therapy in transplantation.
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Affiliation(s)
- Paola Romagnani
- Excellence Center for Research, Transfer and High Education (DENOthe), University of Florence, 50139 Florence, Italy
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42
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Lee SJ, Kim SJ, Lee JS. Effects of Low-Dose Cyclosporine on Human Corneal Epithelial Cells. JOURNAL OF THE KOREAN OPHTHALMOLOGICAL SOCIETY 2011. [DOI: 10.3341/jkos.2011.52.11.1344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Affiliation(s)
- Sang Jun Lee
- Department of Ophthalmology, Pusan National University School of Medicine, Busan, Korea
| | - Su Jin Kim
- Department of of Ophthalmology, Maryknoll Medical Center, Busan, Korea
| | - Jong Soo Lee
- Department of Ophthalmology, Pusan National University School of Medicine, Busan, Korea
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Amor KT, Ryan C, Menter A. The use of cyclosporine in dermatology: part I. J Am Acad Dermatol 2010; 63:925-46; quiz 947-8. [PMID: 21093659 DOI: 10.1016/j.jaad.2010.02.063] [Citation(s) in RCA: 106] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2009] [Revised: 12/15/2009] [Accepted: 02/01/2010] [Indexed: 11/19/2022]
Abstract
UNLABELLED Cyclosporine is a calcineurin inhibitor that acts selectively on T cells. It has been used in dermatology since 1997 for its US Food and Drug Administration indication of psoriasis and off-label for various other inflammatory skin conditions, including atopic dermatitis, blistering disorders, and connective tissue diseases. In the last decade, many dermatologists have hesitated to use this important drug in their clinical practices because of its toxicity profile. The purpose of this article is to review the mechanism of action of cyclosporine and its current uses and dosing schedules. It is our goal to create a framework in which dermatologists feel comfortable and safe incorporating cyclosporine into their prescribing regimens. LEARNING OBJECTIVES After completing this learning activity, participants should be able to describe the mechanism of action of cyclosporine, recognize the potential role of cyclosporine in dermatology and the evidence to support this role, and incorporate cyclosporine into his or her prescribing regimens.
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Affiliation(s)
- Karrie T Amor
- Department of Dermatology at the University of Texas, Houston, Texas, USA
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44
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Lerche CM, Wulf HC. Photocarcinogenicity of selected topically applied dermatological drugs: calcineurin inhibitors, corticosteroids, and vitamin D analogs. Dermatol Reports 2010; 2:e13. [PMID: 25386250 PMCID: PMC4211469 DOI: 10.4081/dr.2010.e13] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2010] [Accepted: 09/02/2010] [Indexed: 12/13/2022] Open
Abstract
Topical therapies constitute the mainstay of dermatological treatments for skin disorders, such as atopic dermatitis, contact dermatitis, psoriasis, or acne. Since some of these diseases are often chronic, treatment duration may last for years and may even last the patient's entire lifetime. Obviously, such long-term therapy may raise safety concerns, which also include the potential photocarcinogenic effect. Most patients are exposed to ultraviolet radiation (UVR) during leisure, work, vacations, or in tanning beds. Additionally, the patients may receive UVR via UVB phototherapy or psoralens plus UVA radiation (PUVA). The use of immunosuppressant's, such as corticosteroids and calcineurin inhibitors, has markedly increased. Patients with skin diseases have benefited from both systemic and topical treatment of both new and established drugs. The issue of a black box warning by the US Food and Drug Administration has increased concerns about photocarcinogenesis, which raises the question: "Are these drugs safe?" This review focuses on the mechanism of action and photocarcinogenic potential of commonly used topical treatments, such as corticosteroids, calcineurin inhibitors, and vitamin D analogs.
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Affiliation(s)
- Catharina M Lerche
- Department of Dermatology, Copenhagen University Hospital, Bispebjerg, Copenhagen, Denmark
| | - Hans Christian Wulf
- Department of Dermatology, Copenhagen University Hospital, Bispebjerg, Copenhagen, Denmark
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Fernandes de Abreu DA, Ibrahim EC, Boucraut J, Khrestchatisky M, Féron F. Severity of experimental autoimmune encephalomyelitis is unexpectedly reduced in mice born to vitamin D-deficient mothers. J Steroid Biochem Mol Biol 2010; 121:250-3. [PMID: 20214984 DOI: 10.1016/j.jsbmb.2010.03.006] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2009] [Revised: 02/02/2010] [Accepted: 03/01/2010] [Indexed: 11/23/2022]
Abstract
Accumulating data indicate that vitamin D, a sun-induced hormone, plays a key role in multiple sclerosis (MS) etiology. Notably, it has been shown that there is a remarkable season of birth effect in MS. We surmised that gestational vitamin D deficiency is a risk factor for MS. To test this hypothesis, a vitamin D deficiency was induced in C57BL/6 female mice 6 weeks prior to conception and prolonged until offspring birth. Contrary to our prediction, we show here that adult offspring exposed to developmental vitamin D deficiency (DVD) developed a striking milder and delayed experimental autoimmune encephalomyelitis (EAE), when compared to control offspring. Using reverse transcription and quantitative real-time PCR, we measured the expression level of 22 candidate transcripts in the spleen, the cerebrum and the spinal cord, at Day0 and Day30 post-immunization. We report here that, at Day30 post-immunization, TNF, osteopontin, H2-Eb were over-expressed and IFN was under-expressed in the spinal cord of control mice and not in DVD mice. Another discrepancy between nervous and immune systems was observed: expression of IL4 was dysregulated exclusively in the spleen. Reduced symptom severity in DVD mice can partially be explained by a nervous system-restricted over-expression of vitamin D receptor (VDR), two heat shock proteins (HSP90, HSPa8) and FK506 binding protein 1a (FKBP1a), at Day0. Our clinical test and molecular findings converge to indicate that maternal hypovitaminosis D imprints the foetus and alters the susceptibility of the offspring to EAE. We propose a new hypothesis to explain our unexpected observations.
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Obaculactone suppresses Th1 effector cell function through down-regulation of T-bet and prolongs skin graft survival in mice. Biochem Pharmacol 2010; 80:218-25. [DOI: 10.1016/j.bcp.2010.03.028] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2010] [Revised: 03/22/2010] [Accepted: 03/24/2010] [Indexed: 11/20/2022]
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Kaçmaz RO, Kempen JH, Newcomb C, Daniel E, Gangaputra S, Nussenblatt RB, Rosenbaum JT, Suhler EB, Thorne JE, Jabs DA, Levy-Clarke GA, Foster CS. Cyclosporine for ocular inflammatory diseases. Ophthalmology 2010; 117:576-84. [PMID: 20031223 DOI: 10.1016/j.ophtha.2009.08.010] [Citation(s) in RCA: 176] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2009] [Revised: 07/02/2009] [Accepted: 08/04/2009] [Indexed: 11/28/2022] Open
Abstract
PURPOSE To evaluate the clinical outcomes of cyclosporine treatment for noninfectious ocular inflammation. DESIGN Retrospective cohort study. PARTICIPANTS A total of 373 patients with noninfectious ocular inflammation managed at 4 tertiary ocular inflammation clinics in the United States observed to use cyclosporine as a single noncorticosteroid immunosuppressive agent to their treatment regimen, between 1979 and 2007 inclusive. METHODS Participants were identified from the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Demographic and clinical characteristics, including dosage of cyclosporine and main outcome measures, were obtained for every eye of every patient at every visit via medical record review by trained expert reviewers. MAIN OUTCOME MEASURES Control of inflammation, sustained control after reducing corticosteroid dosages, and discontinuation of therapy because of toxicity. RESULTS Of the 373 patients (681 eyes) initiating cyclosporine monotherapy, 33.4% by 6 months and 51.9% by 1 year gained sustained, complete control of inflammation over at least 2 visits spanning at least 28 days. Approximately 25% more improved to a level of slight inflammatory activity by each of these time points. Corticosteroid-sparing success (completely controlled inflammation for at least 28 days with prednisone < or = 10 mg/day) was achieved by 22.1% by 6 months and 36.1% within 1 year. Toxicity led to discontinuation of therapy within 1 year by 10.7% of the population. Patients aged more than 55 years were more than 3-fold more likely to discontinue therapy because of toxicity than patients aged 18 to 39 years. Doses of 151 to 250 mg/day tended to be more successful than lower doses and were not associated with a higher discontinuation for toxicity rate; higher doses did not seem to offer a therapeutic advantage. CONCLUSIONS Cyclosporine, with corticosteroid therapy as indicated, was modestly effective for controlling ocular inflammation. Our data support a preference for cyclosporine adult dosing between 151 and 250 mg/day. Although cyclosporine was tolerated by the majority of patients, toxicity was more frequent with increasing age; alternative agents may be preferred for patients aged more than 55 years.
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Affiliation(s)
- R Oktay Kaçmaz
- Department of Ophthalmology, The Mount Sinai School of Medicine, New York, New York, USA
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Vitamin D, a neuro-immunomodulator: implications for neurodegenerative and autoimmune diseases. Psychoneuroendocrinology 2009; 34 Suppl 1:S265-77. [PMID: 19545951 DOI: 10.1016/j.psyneuen.2009.05.023] [Citation(s) in RCA: 270] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2009] [Revised: 05/20/2009] [Accepted: 05/20/2009] [Indexed: 01/26/2023]
Abstract
It has been known for more than 20 years that vitamin D exerts marked effects on immune and neural cells. These non-classical actions of vitamin D have recently gained a renewed attention since it has been shown that diminished levels of vitamin D induce immune-mediated symptoms in animal models of autoimmune diseases and is a risk factor for various brain diseases. For example, it has been demonstrated that vitamin D (i) modulates the production of several neurotrophins, (ii) up-regulates Interleukin-4 and (iii) inhibits the differentiation and survival of dendritic cells, resulting in impaired allo-reactive T cell activation. Not surprisingly, vitamin D has been found to be a strong candidate risk-modifying factor for Multiple Sclerosis (MS), the most prevalent neurological and inflammatory disease in the young adult population. Vitamin D is a seco-steroid hormone, produced photochemically in the animal epidermis. The action of ultraviolet light (UVB) on 7-dehydrocholesterol results in the production of pre-vitamin D which, after thermo-conversion and two separate hydroxylations, gives rise to the active 1,25-dihydroxyvitamin D. Vitamin D acts through two types of receptors: (i) the vitamin D receptor (VDR), a member of the steroid/thyroid hormone superfamily of transcription factors, and (ii) the MARRS (membrane associated, rapid response steroid binding) receptor, also known as Erp57/Grp58. In this article, we review some of the mechanisms that may underlie the role of vitamin D in various brain diseases. We then assess how vitamin D imbalance may lay the foundation for a range of adult disorders, including brain pathologies (Parkinson's disease, epilepsy, depression) and immune-mediated disorders (rheumatoid arthritis, type I diabetes mellitus, systemic lupus erythematosus or inflammatory bowel diseases). Multidisciplinary scientific collaborations are now required to fully appreciate the complex role of vitamin D in mammal metabolism.
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Norman KG, Canter JA, Shi M, Milne GL, Morrow JD, Sligh JE. Cyclosporine A suppresses keratinocyte cell death through MPTP inhibition in a model for skin cancer in organ transplant recipients. Mitochondrion 2009; 10:94-101. [PMID: 19836469 DOI: 10.1016/j.mito.2009.10.001] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2009] [Revised: 09/25/2009] [Accepted: 10/13/2009] [Indexed: 01/16/2023]
Abstract
Transplant recipients have an elevated risk of skin cancer, with a 65- to 250-fold increase in squamous cell carcinoma. Usage of the immunosuppressant cyclosporine A (CsA) is associated with the development of skin cancer. We hypothesized that the increased incidence of skin cancer was due to the action of CsA within keratinocyte mitochondria where it can inhibit mitochondrial permeability transition pore (MPTP) opening. Normally, MPTP opening is induced by oxidative stress such as that caused by UV light and leads to cell death, thereby eliminating a cell that has been exposed to genotoxic insult. However, in the presence of CsA, damaged cells may survive and consequently form tumors. To test this hypothesis, we treated keratinocytes with levels of CsA used therapeutically in transplant patients and assessed their viability following UVA-irradiation. CsA prevented cell death by inhibiting MPTP opening, even though the levels of oxidative stress were increased markedly. Nim811, a non-immunosuppressive drug that can block the MPTP had a similar effect while the immunosuppressive drug tacrolimus that does not interact with the mitochondria had no effect. These findings suggest that CsA may promote skin cancer in transplant patients by allowing keratinocyte survival under conditions of increased genotoxic stress.
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Affiliation(s)
- Kimberly G Norman
- Department of Medicine, Division of Dermatology, VA Tennessee Valley Healthcare System and Vanderbilt University Medical Center, Nashville, TN, USA
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Fletcher AL, Lowen TE, Sakkal S, Reiseger JJ, Hammett MV, Seach N, Scott HS, Boyd RL, Chidgey AP. Ablation and regeneration of tolerance-inducing medullary thymic epithelial cells after cyclosporine, cyclophosphamide, and dexamethasone treatment. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2009; 183:823-31. [PMID: 19564346 DOI: 10.4049/jimmunol.0900225] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2023]
Abstract
Immunosuppressive drugs and cytotoxic chemotherapy agents are designed to kill or suppress autoreactive, alloaggressive, or hyperinflammatory T cells, or disseminated malignancies. However, they also cause severe immunological side effects ranging from interrupted thymopoiesis and general immunodeficiency to, paradoxically, autoimmunity. Consistent with the cross-talk between thymocytes and stromal cells, we now show that these common therapeutic agents have major effects on murine thymic epithelial cells (TEC), crucially required to rebuild immunity posttreatment. We show that the immunosuppressant cyclosporine A, which has been linked to a thymus-dependent autoimmune syndrome in some patients, causes extensive loss of autoimmune regulator (Aire(+)) tolerance-inducing MHC class II(high) medullary TEC (mTEC(high)). Post-cyclosporine A, Aire expression was restored within 7 days. Full recovery of the mTEC(high) subset occurred within 10 days and was linked to a decrease in a relatively resistant MHC class II(low) mTEC subset (mTEC(low)), consistent with a previously described precursor-product relationship. Cyclophosphamide and dexamethasone caused more extensive ablation of thymocytes and stromal cells but again severely depleted tolerance-inducing mTEC(high). Together, these data show that Aire(+) mTECs are highly sensitive to damage and that mTEC regeneration follows a conserved pattern regardless of the treatment regimen used.
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Affiliation(s)
- Anne L Fletcher
- Immune Regeneration Laboratory, Monash University, Clayton, Australia
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