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Lazarou C, Moysidou E, Christodoulou M, Lioulios G, Sampani E, Dimitriadis C, Fylaktou A, Stangou M. Non-Invasive Biomarkers for Early Diagnosis of Kidney Allograft Dysfunction: Current and Future Applications in the Era of Precision Medicine. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:262. [PMID: 40005378 PMCID: PMC11857372 DOI: 10.3390/medicina61020262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 01/22/2025] [Accepted: 01/24/2025] [Indexed: 02/27/2025]
Abstract
Kidney transplantation stands as the preferred treatment for end-stage kidney disease, significantly improving both the quality and longevity of life compared to dialysis. In recent years, the survival rates for patients and grafts have markedly increased thanks to innovative strategies in desensitization protocols for incompatible transplants and advancements in immunosuppressive therapies. For kidney transplant recipients, preventing allograft rejection is of paramount importance, necessitating the use of immunosuppressive medications. Regular follow-up appointments are essential, as monitoring the function of the kidney allograft is critical. Currently, established biomarkers such as serum creatinine, estimated Glomerular Filtration Rate (eGFR), proteinuria, and albuminuria are commonly employed to assess allograft function. However, these biomarkers have limitations, as elevated levels often indicate significant allograft damage only after it has occurred, thereby constraining treatment options and the potential for restoring graft function. Additionally, kidney biopsies, while considered the gold standard for diagnosing rejection, are invasive and carry associated risks. Consequently, the identification and development of new, sensitive, and specific biomarkers like dd-cfDNA, microRNAs (e.g., miR-21, miR-155), and sCD30 for allograft rejection are crucial. To tackle this challenge, intensive ongoing research employing cutting-edge technologies, including "omics" approaches, like genomic techniques, proteomics, or metabolomics, is uncovering a variety of promising new biomarkers.
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Affiliation(s)
- Christina Lazarou
- Department of Nephrology, Papageorgiou General Hospital, 56429 Thessaloniki, Greece;
| | - Eleni Moysidou
- School of Medicine, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece; (E.M.); (M.C.); (E.S.); (C.D.)
| | - Michalis Christodoulou
- School of Medicine, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece; (E.M.); (M.C.); (E.S.); (C.D.)
| | - Georgios Lioulios
- Department of Nephrology, 424 Military Hospital of Thessaloniki, 56429 Thessaloniki, Greece;
| | - Erasmia Sampani
- School of Medicine, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece; (E.M.); (M.C.); (E.S.); (C.D.)
| | - Chrysostomos Dimitriadis
- School of Medicine, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece; (E.M.); (M.C.); (E.S.); (C.D.)
| | - Asimina Fylaktou
- Department of Immunology, National Peripheral Histocompatibility Center, General Hospital Hippokration, 54642 Thessaloniki, Greece;
| | - Maria Stangou
- School of Medicine, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece; (E.M.); (M.C.); (E.S.); (C.D.)
- 1st Department of Nephrology, Hippokration Hospital, School of Medicine, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
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Ren SH, Shao B, Wang HD, Zhang JY, Qin H, Sun CL, Zhu YL, Wang ZB, Lan X, Gao YC, Wang H. Oxymatrine attenuates chronic allograft rejection by modulating immune responses and inhibiting fibrosis. Eur J Pharmacol 2024; 985:177082. [PMID: 39486768 DOI: 10.1016/j.ejphar.2024.177082] [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: 01/06/2024] [Revised: 10/28/2024] [Accepted: 10/29/2024] [Indexed: 11/04/2024]
Abstract
BACKGROUND Chronic rejection (CR) is a significant obstacle to long-term allograft survival. Oxymatrine (OMT) is a prominent bioactive compound widely utilized in traditional Chinese medicine for the management of inflammatory disorders and it has considerable potential as a therapeutic candidate for the treatment of CR. METHODS Well-established major histocompatibility complex (MHC) class II mismatched B6 mice. C-H-2bm12-to-C57BL/6 mouse transplantation was used as a CR model. Hematoxylin and eosin (H&E) staining, immunohistochemistry, and Masson's trichrome staining were used to assess pathological changes in the grafts, and the percentages of immune cells were determined by flow cytometry. The effects of OMT on the regulation of CD4+ T cell differentiation and cytokine secretion were verified in vitro. RESULTS OMT effectively alleviated pathological graft damage, characterized by chronic changes in intimal lesions, vasculopathy, and fibrosis and significantly prolonged cardiac allograft survival. OMT exerted its immunomodulatory effects by inhibiting T helper 1 (Th1) and T helper 17 (Th17) cell differentiation while promoting Treg differentiation both in vivo and in vitro. Further studies revealed that OMT inhibited the phosphorylation of mammalian target of rapamycin (mTOR), which is a potential mechanism underlying its immunosuppressive effects. OMT also inhibited the activation of B cells and the production of donor-specific antibody (DSA). In addition, OMT effectively alleviated chronic changes in fibrosis in cardiac allografts, and these changes may be related to the inhibition of the transforming growth factor-β (TGF-β)-Smad 2/3 pathway. CONCLUSIONS OMT attenuated CR by modulating the immune response and inhibiting graft fibrosis. Further in-depth investigations of OMT may provide valuable insights into the development of novel therapeutic strategies for CR inhibition.
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Affiliation(s)
- Shao-Hua Ren
- Department of General Surgery, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China; Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Bo Shao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Hong-da Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Jing-Yi Zhang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Hong Qin
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Cheng-Lu Sun
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Yang-Lin Zhu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Zhao-Bo Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Xu Lan
- Beijing University of Chinese Medicine Third Affiliated Hospital, Beijing, China
| | - Yong-Chang Gao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Hao Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China; Tianjin Key Laboratory of Precise Vascular Reconstruction and Organ Function Repair, Tianjin, China.
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Costaguta A, Costaguta G, Álvarez F. Autoimmune hepatitis: Towards a personalized treatment. World J Hepatol 2024; 16:1225-1242. [PMID: 39606175 PMCID: PMC11586748 DOI: 10.4254/wjh.v16.i11.1225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 09/02/2024] [Accepted: 10/11/2024] [Indexed: 11/06/2024] Open
Abstract
Autoimmune hepatitis is an uncommon condition that affects both adults and children and is characterized by chronic and recurrent inflammatory activity in the liver. This inflammation is accompanied by elevated IgG and autoantibody levels. Historically, treatment consists of steroids with the addition of azathioprine, which results in remission in approximately 80% of patients. Despite significant advancements in our understanding of the immune system over the past two decades, few modifications have been made to treatment algorithms, which have remained largely unchanged since they were first proposed more than 40 years ago. This review summarized the various treatment options currently available as well as our experiences using them. Although steroids are the standard treatment for induction therapy, other medications may be considered. Cyclosporin A, a calcineurin inhibitor that decreases T cell activation, has proven effective for induction of remission, but its long-term side effects limit its appeal for maintenance. Tacrolimus, a drug belonging to the same family, has been used in patients with refractory diseases with fewer side effects. Sirolimus and everolimus have interesting effects on regulatory T cell populations and may become viable options in the future. Mycophenolate mofetil is not effective for induction but is a valid alternative for patients who are intolerant to azathioprine. B cell-depleting drugs, such as rituximab and belimumab, have been successfully used in refractory cases and are useful in both the short and long term. Other promising treatments include anti-tumor necrosis factors, Janus kinases inhibitors, and chimeric antigen receptor T cell therapy. This growing armamentarium allows us to imagine a more tailored approach to the treatment of autoimmune hepatitis in the near future.
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Affiliation(s)
- Alejandro Costaguta
- Department of Hepatology and Liver Transplant Unit, Sanatorio de Niños de Rosario, Rosario 2000, Santa Fe, Argentina.
| | - Guillermo Costaguta
- Department of Gastroenterology, Hepatology, and Nutrition, CHU Sainte-Justine, Montreal H3T 1C5, Quebec, Canada
| | - Fernando Álvarez
- Department of Pediatrics, CHU Sainte-Justine, Montreal H3T 1C5, Quebec, Canada
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Karolin A, Escher G, Rudloff S, Sidler D. Nephrotoxicity of Calcineurin Inhibitors in Kidney Epithelial Cells is Independent of NFAT Signaling. Front Pharmacol 2022; 12:789080. [PMID: 35140605 PMCID: PMC8819135 DOI: 10.3389/fphar.2021.789080] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 12/29/2021] [Indexed: 01/01/2023] Open
Abstract
Background: Calcineurin inhibitors (CNIs) such as cyclosporine A and tacrolimus are commonly used after renal transplantation to suppress the immune system. In lymphoid cells, cyclosporine A acts via the calcineurin/nuclear factor of activated T-cell (NFAT) axis. In non-lymphoid cells, such as kidney epithelial cells, cyclosporine A induces calcineurin inhibitor toxicity. It is unknown via which off-targets cyclosporine A induces calcineurin inhibitor toxicity in kidney epithelial cells. Methods: To measure a compound’s potential to induce nephrotoxicity, the expression of the surrogate marker Fn14 was measured by flow cytometry. Compounds were tested for their potential to induce Fn14 either chemically or plasmid-mediated. Mice were injected with various compounds, and changes in nephrotoxic gene expression levels of the kidney epithelial cells were then analyzed. Results: Fn14 is specifically upregulated due to calcineurin inhibitor toxicity inducing agents. Inhibition of the NFAT axis showed no increase of the Fn14 expression on the surface of kidney cells. However, inhibition of p38 MAPK, phosphoinositide-3-kinase (PI3K)/Akt, protein kinase C (PKC), and inhibitor of nuclear factor-κB (IκB) kinase (IKK) showed clear induction of Fn14 and increased expressions of nephrotoxic, inflammatory, and fibrotic genes in vitro and in vivo. Conclusions: These findings show that cyclosporine A acts independently of NFAT on kidney epithelial cells. Moreover, inhibition of serine/threonine protein kinases mimics cyclosporine A’s activity on kidney epithelial cells. This mimicking effect indicates that these protein kinases are off-targets of cyclosporine A and damage structural renal cells when inhibited and therefore contributes likely to the development and progression of calcineurin inhibitor toxicity.
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Affiliation(s)
- Andrea Karolin
- Department for Nephrology and Hypertension, University Hospital Insel Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Geneviève Escher
- Department for Nephrology and Hypertension, University Hospital Insel Bern, Bern, Switzerland
| | - Stefan Rudloff
- Department for Nephrology and Hypertension, University Hospital Insel Bern, Bern, Switzerland
| | - Daniel Sidler
- Department for Nephrology and Hypertension, University Hospital Insel Bern, Bern, Switzerland
- *Correspondence: Daniel Sidler,
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Immunosuppressive calcineurin inhibitor cyclosporine A induces proapoptotic endoplasmic reticulum stress in renal tubular cells. J Biol Chem 2022; 298:101589. [PMID: 35033536 PMCID: PMC8857494 DOI: 10.1016/j.jbc.2022.101589] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 01/03/2022] [Accepted: 01/05/2022] [Indexed: 12/26/2022] Open
Abstract
Current immunosuppressive strategies in organ transplantation rely on calcineurin inhibitors cyclosporine A (CsA) or tacrolimus (Tac). Both drugs are nephrotoxic, but CsA has been associated with greater renal damage than Tac. CsA inhibits calcineurin by forming complexes with cyclophilins, whose chaperone function is essential for proteostasis. We hypothesized that stronger toxicity of CsA may be related to suppression of cyclophilins with ensuing endoplasmic reticulum (ER) stress and unfolded protein response (UPR) in kidney epithelia. Effects of CsA and Tac (10 µM for 6 h each) were compared in cultured human embryonic kidney 293 (HEK 293) cells, primary human renal proximal tubule (PT) cells, freshly isolated rat PTs, and knockout HEK 293 cell lines lacking the critical ER stress sensors, protein kinase RNA-like ER kinase or activating transcription factor 6 (ATF6). UPR was evaluated by detection of its key components. Compared with Tac treatment, CsA induced significantly stronger UPR in native cultured cells and isolated PTs. Evaluation of proapoptotic and antiapoptotic markers suggested an enhanced apoptotic rate in CsA-treated cells compared with Tac-treated cells as well. Similar to CsA treatment, knockdown of cyclophilin A or B by siRNA caused proapoptotic UPR, whereas application of the chemical chaperones tauroursodeoxycholic acid or 4-phenylbutyric acid alleviated CsA-induced UPR. Deletion of protein kinase RNA-like ER kinase or ATF6 blunted CsA-induced UPR as well. In summary, inhibition of cyclophilin chaperone function with ensuing ER stress and proapoptotic UPR aggravates CsA toxicity, whereas pharmacological modulation of UPR bears potential to alleviate renal side effects of CsA.
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Yan MT, Chao CT, Lin SH. Chronic Kidney Disease: Strategies to Retard Progression. Int J Mol Sci 2021; 22:ijms221810084. [PMID: 34576247 PMCID: PMC8470895 DOI: 10.3390/ijms221810084] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/12/2021] [Accepted: 09/13/2021] [Indexed: 12/11/2022] Open
Abstract
Chronic kidney disease (CKD), defined as the presence of irreversible structural or functional kidney damages, increases the risk of poor outcomes due to its association with multiple complications, including altered mineral metabolism, anemia, metabolic acidosis, and increased cardiovascular events. The mainstay of treatments for CKD lies in the prevention of the development and progression of CKD as well as its complications. Due to the heterogeneous origins and the uncertainty in the pathogenesis of CKD, efficacious therapies for CKD remain challenging. In this review, we focus on the following four themes: first, a summary of the known factors that contribute to CKD development and progression, with an emphasis on avoiding acute kidney injury (AKI); second, an etiology-based treatment strategy for retarding CKD, including the approaches for the common and under-recognized ones; and third, the recommended approaches for ameliorating CKD complications, and the final section discusses the novel agents for counteracting CKD progression.
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Affiliation(s)
- Ming-Tso Yan
- Department of Medicine, Division of Nephrology, Cathay General Hospital, School of Medicine, Fu-Jen Catholic University, Taipei 106, Taiwan;
- National Defense Medical Center, Graduate Institute of Medical Sciences, Taipei 114, Taiwan
| | - Chia-Ter Chao
- Department of Internal Medicine, Nephrology Division, National Taiwan University Hospital, Taipei 104, Taiwan;
- Graduate Institute of Toxicology, National Taiwan University College of Medicine, Taipei 104, Taiwan
- Department of Internal Medicine, Nephrology Division, National Taiwan University College of Medicine, Taipei 104, Taiwan
| | - Shih-Hua Lin
- National Defense Medical Center, Graduate Institute of Medical Sciences, Taipei 114, Taiwan
- Department of Internal Medicine, Nephrology Division, National Defense Medical Center, Taipei 104, Taiwan
- Correspondence: or
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Zhao L, Hu C, Han F, Chen D, Cheng J, Wu J, Peng W, Chen J. Induction therapy with mesenchymal stromal cells in kidney transplantation: a meta-analysis. Stem Cell Res Ther 2021; 12:158. [PMID: 33648596 PMCID: PMC7923637 DOI: 10.1186/s13287-021-02219-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 02/09/2021] [Indexed: 12/22/2022] Open
Abstract
Objective The aim of this meta-analysis was to evaluate the therapeutic effects of mesenchymal stromal cells (MSCs) versus traditional regimens for induction therapy in kidney transplantation (KT), especially the safety of MSC infusion, practicability of MSCs as induction therapy agents, and posttransplant complications. Methods PubMed, Embase, EBSCO, Ovid, and the Cochrane Library were searched for prospective clinical trials that compared MSCs with traditional regimens for induction therapy in KT. Results Four trials were included, including a total of 197 patients. The pooled results revealed that MSC therapy had a lower 1-year infection rate than did the traditional therapies (RR = 0.65, 95% CI: 0.46–0.9, P = 0.01). There were no significant differences between the two protocols regarding the 1-year acute rejection (AR) rate (RR = 0.77, 95% CI: 0.41–1.45, P = 0.42), 1-year graft survival rate (RR = 0.99, 95% CI: 0.95–1.03, P = 0.74), delayed graft function (DGF) rate (RR = 0.54, 95% CI: 0.21–1.38, P = 0.2) and renal graft function at 1 month (MD = −1.56, 95% CI: − 14.2–11.08, p = 0.81), 3 months (MD = 0.15, 95% CI: − 5.63–5.93, p = 0.96), 6 months (MD = − 1.95, 95% CI: − 9.87–5.97, p = 0.63), and 12 months (MD = − 1.13, 95% CI: − 7.16–4.89, p = 0.71) postsurgery. Subgroup analysis demonstrated that the 1-year AR rate, 1-year graft survival rate, DGF rate, and renal graft function at 12 months postsurgery did not significantly differ between the low-dose calcineurin inhibitor (CNI) group and the standard-dose CNI group, indicating the potential benefits of successful CNI sparing in combination with MSC treatment. Moreover, when MSCs were applied as an alternative therapy rather than an additional therapy or allogeneic MSCs were utilized instead of autologous MSCs, all of the outcomes mentioned above were comparable. Conclusion Induction therapy with MSCs is safe and has similar immune response modulation effects to those of traditional regimens in the short term in KT recipients. However, regarding the long-term effects, as suggested by the 1-year infection rate and the potential of CNI sparing, MSC therapy has significant advantages. However, these advantages should be further verified in more well-designed, multicenter randomized controlled trials (RCTs) with large sample sizes and long follow-up periods. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02219-7.
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Affiliation(s)
- Lingfei Zhao
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.,Institute of Nephrology, Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Chenxia Hu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Fei Han
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China
| | - Dajin Chen
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China
| | - Jun Cheng
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China
| | - Jianyong Wu
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China
| | - Wenhan Peng
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China
| | - Jianghua Chen
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
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Alshamsan A, Binkhathlan Z, Kalam MA, Qamar W, Kfouri H, Alghonaim M, Lavasanifar A. Mitigation of Tacrolimus-Associated Nephrotoxicity by PLGA Nanoparticulate Delivery Following Multiple Dosing to Mice while Maintaining its Immunosuppressive Activity. Sci Rep 2020; 10:6675. [PMID: 32317681 PMCID: PMC7174389 DOI: 10.1038/s41598-020-63767-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 04/06/2020] [Indexed: 12/13/2022] Open
Abstract
The aim of this study was to assess the ability of PLGA nanoparticles (NPs) to reduce the tacrolimus (TAC)-associated nephrotoxicity following multiple dose administration. The mean diameter of prepared NPs was in the range of 227 to 263 nm with an 8.32% drug loading (w/w). Moreover, in vitro release profile of TAC-loaded NPs showed a sustained release of the drug with only less than 30% release within 12 days. Flow cytometry as well as fluorescence microscopy results confirmed the uptake of FITC-labelled PLGA NPs by dendritic cells. The ex vivo study showed that TAC-loaded NPs caused a significant suppression of the proliferation of CD4+ and CD8+ cells, which was comparable to the control formulation (Prograf). In vivo immunosuppressive activity as well as the kidney function were assessed following drug administration to mice. The animals received TAC subcutaneously at a daily dose of 1 mg/kg for 30 days delivered as the control formulation (Prograf) or TAC-loaded NPs. The results revealed significantly lower drug-associated toxicity with an activity comparable to Prograf for TAC-loaded PLGA NPs. These findings show a potential for PLGA NPs in reducing the nephrotoxicity of TAC while preserving the immunosuppressive activity.
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Affiliation(s)
- Aws Alshamsan
- Nanobiotechnology Unit, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia. .,Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia.
| | - Ziyad Binkhathlan
- Nanobiotechnology Unit, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia.,Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia.,Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada
| | - Mohd Abul Kalam
- Nanobiotechnology Unit, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia.,Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia
| | - Wajhul Qamar
- Central Laboratory, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.,Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Hala Kfouri
- Department of Pathology, College of Medicine, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Mohammed Alghonaim
- King Salman Bin Abdulaziz Chair for Kidney Disease, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Afsaneh Lavasanifar
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada.,Department of Chemical and Material Engineering, University of Alberta, Edmonton, Alberta, T6G 2V4, Canada
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Update on mesenchymal stromal cell studies in organ transplant recipients. Curr Opin Organ Transplant 2020; 25:27-34. [DOI: 10.1097/mot.0000000000000716] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
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Hanaoka K, Maeda M, Tsujimoto S, Oshima S, Fukahori H, Nakamura K, Noto T, Higashi Y, Hirose J, Takakura S, Morokata T. Benefits of a loading dose of tacrolimus on graft survival of kidney transplants in nonhuman primates. Transpl Immunol 2019. [DOI: 10.1016/j.trim.2018.10.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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Bae E, Han SS, Park DJ, Lee H, Yu MY, Kim KH, Kim MC, Cho JY, Min SI, Ha J, Kim YS, Yang SH. The level of intracellular tacrolimus in T cell is affected by CD44 +ABCB1 +activities triggered by inflammation. EUR J INFLAMM 2019. [DOI: 10.1177/2058739219845155] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Rejection is an important issue in kidney transplant. Although with adequate trough level of tacrolimus, acute rejection occurs, and we are focused on these cases. We hypothesized that the lower concentration of tacrolimus in the peripheral blood mononuclear cell would be a cause of rejection; in this regard, we describe ABCB1, which regulates intracellular concentration of tacrolimus. The effect of inflammation on the intracellular concentration of tacrolimus was evaluated, as was the association between that concentration and ABCB1 and CD44 activities. Seven kidney recipients experiencing acute rejection were prospectively enrolled. Both the whole blood concentration of tacrolimus and intracellular concentration of tacrolimus were measured at the time of enrollment and after stabilization. A human T lymphoblastoid cell line (Jurkat T cell) was treated with various concentrations of tacrolimus for 21 h and then stimulated for 3 h. The levels of mRNA interleukin-2, interleukin-8, and interferon-γ decreased dose dependently by tacrolimus. Furthermore, a fluorescence-activated cell sorter was used to count cells expressing CD44 and ABCB1; changes in intracellular concentration of tacrolimus were explored after tacrolimus treatment and stimulation. Also, B6 splenocytes were tested in the same manner as previous Jurkat T cell experiments. The tacrolimus ratio of three patients was lower at the time of acute rejection than when patients were stabilized. In vitro, the intracellular concentration of tacrolimus decreased after stimulation. Under the same conditions, CD44+ABCB1+cells increased in proportion on tacrolimus treatment and stimulation. This work supports the hypothesis that inflammation reduces the intracellular tacrolimus level, possibly via drug efflux mediated by CD44+ABCB1+and inflammation could lead to acute rejection.
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Affiliation(s)
- Eunjin Bae
- Department of Internal Medicine, College of Medicine, Gyeongsang National University, Jinju, Korea
- Gyeongsang National University Changwon Hospital, Changwon, Korea
| | - Seung Seok Han
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Dong Jun Park
- Department of Internal Medicine, College of Medicine, Gyeongsang National University, Jinju, Korea
- Gyeongsang National University Changwon Hospital, Changwon, Korea
| | - Hajeong Lee
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Mi-Yeon Yu
- Department of Internal Medicine, Hanyang University Guri Hospital, Guri, Korea
| | - Kyu Hong Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Min Chang Kim
- Department of Clinical Pharmacology and Therapeutics, College of Medicine, Seoul National University, Seoul, Korea
| | - Joo-Youn Cho
- Department of Clinical Pharmacology and Therapeutics, College of Medicine, Seoul National University, Seoul, Korea
| | - Sang-Il Min
- Department of Surgery, College of Medicine, Seoul National University, Seoul, Korea
| | - Jongwon Ha
- Department of Surgery, College of Medicine, Seoul National University, Seoul, Korea
| | - Yon Su Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Department of Kidney Research Institute, Seoul National University, Seoul, Korea
| | - Seung Hee Yang
- Department of Kidney Research Institute, Seoul National University, Seoul, Korea
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12
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Claus M, Herro R, Wolf D, Buscher K, Rudloff S, Huynh-Do U, Burkly L, Croft M, Sidler D. The TWEAK/Fn14 pathway is required for calcineurin inhibitor toxicity of the kidneys. Am J Transplant 2018; 18:1636-1645. [PMID: 29266762 DOI: 10.1111/ajt.14632] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 11/09/2017] [Accepted: 12/03/2017] [Indexed: 01/25/2023]
Abstract
Calcineurin inhibitor toxicity (CNT) is a frequent occurrence in transplanted renal grafts and autochthone kidneys from patients undergoing long-term treatment with calcineurin inhibitors, notably cyclosporin A (CsA) and tacrolimus. Here, we show an indispensable role of the tumor necrosis factor superfamily (TNFS) molecule TNF-related weak inducer of apoptosis (TWEAK) (TNFSF12) in the pathogenesis of acute CNT lesions in mice. A deficiency in TWEAK resulted in limited tubulotoxicity after CsA exposure, which correlated with diminished expression of inflammatory cytokines and reduced intraparenchymal infiltration with immune cells. We further identified tubular epithelial cells of the kidney as major targets of CsA activity and found that Fn14 (tumor necrosis factor receptor superfamily 12A), the receptor for TWEAK, is a highly CsA-inducible gene in these cells. Correlating with this, CsA pretreatment sensitized tubular epithelial cells specifically to the pro-inflammatory activities of recombinant TWEAK in vitro. Moreover, injection of rTWEAK alone into mice induced moderate disease similar to CsA, and rTWEAK combined with CsA resulted in synergistic nephrotoxicity. These findings support the importance of tubular epithelial cells as cellular targets of CsA toxicity and introduce TWEAK as a critical contributor to CNT pathogenesis.
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Affiliation(s)
- Meike Claus
- Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA
| | - Rana Herro
- Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA
| | - Dennis Wolf
- Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA
| | - Konrad Buscher
- Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA
| | - Stefan Rudloff
- Department for Nephrology, Hypertension and Clinical Pharmacology, University Hospital Bern, Bern, Switzerland
| | - Uyen Huynh-Do
- Department for Nephrology, Hypertension and Clinical Pharmacology, University Hospital Bern, Bern, Switzerland
| | - Linda Burkly
- Department of Immunology, Biogen, Cambridge, MA, USA
| | - Michael Croft
- Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA
| | - Daniel Sidler
- Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA.,Department for Nephrology, Hypertension and Clinical Pharmacology, University Hospital Bern, Bern, Switzerland
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13
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Oates A, Ahuja S, Lee MM, Phelps AS, Mackenzie JD, Courtier JL. Pediatric renal transplant biopsy with ultrasound guidance: the 'core' essentials. Pediatr Radiol 2017; 47:1572-1579. [PMID: 28573315 DOI: 10.1007/s00247-017-3905-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Revised: 04/03/2017] [Accepted: 05/11/2017] [Indexed: 12/16/2022]
Abstract
This review provides a comprehensive and practical approach to pediatric percutaneous renal transplant biopsies, highlighting techniques and strategies to optimize adequate sample yield and ensure patient safety. In children with end-stage renal disease, transplantation is the preferred choice of therapy, providing for overall lower long-term morbidity and mortality compared with dialysis. In the ongoing management of renal transplant patients, core tissue sampling via a percutaneous renal biopsy remains the gold standard when transplant dysfunction is suspected. Indications for renal transplant biopsy and techniques/tools for adequate sample yield are discussed. Strategies for common challenges such as poor visualization and renal transplant mobility are addressed. We discuss the clinical signs, techniques and imaging findings for common complications including hematomas, arteriovenous fistulas and pseudoaneurysms. Although the percutaneous renal transplant biopsy procedure is generally safe with rare complications, care must be taken to ensure major complications are promptly recognized and treated. Adequate tissue samples obtained via renal biopsy are imperative to promptly identify transplant rejection to provide valuable information for patient diagnosis, treatment and outcomes. Radiologist and nephrologist attention to proper ultrasound techniques and optimal biopsy tools are critical to ensure tissue adequacy and minimize complications.
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Affiliation(s)
- Aris Oates
- Division of Nephrology, Department of Pediatrics, University of California, 550 16th St., 5th floor, Mailstop 3214, San Francisco, CA, 94143- 3214, USA.
| | - Saveen Ahuja
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA
| | - Marsha M Lee
- Division of Nephrology, Department of Pediatrics, University of California, 550 16th St., 5th floor, Mailstop 3214, San Francisco, CA, 94143- 3214, USA
| | - Andrew S Phelps
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA
| | - John D Mackenzie
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA
| | - Jesse L Courtier
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA
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14
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Ye Q, Zhang M, Wang Y, Fu S, Han S, Wang L, Wang Q. Sirtinol regulates the balance of Th17/Treg to prevent allograft rejection. Cell Biosci 2017; 7:55. [PMID: 29090089 PMCID: PMC5658927 DOI: 10.1186/s13578-017-0182-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Accepted: 09/04/2017] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Current immunosuppressive medications used after transplantation induce significant toxicity , and a new medication regimen is needed. Based on recent research, Sirt1 exerts a proinflammatory effect on the immune response. Sirtinol is a Sirt1 inhibitor, but its impact on allograft rejection and its molecular mechanisms of action have not yet been reported. RESLUTS In this study, we examined the effect of sirtinol on prolonging allograft survival in a mouse cervical heterotopic heart transplantation model. Based on an examination of the allograft, allografts from sirtinol-treated recipients show significantly lower levels of IL-17A expression and higher levels of Foxp3 expression. In vivo, sirtinol reduces the proportion of Th17 cells and increases the proportion of Treg cells in splenocytes from recipients. In vitro, sirtinol reduces the proportion of Th17 cells and decreases the expression of IL-17A and RORγt in an isolated CD4+ T cell population. Moreover, we identified synergistic effects of sirtinol and FK506 on prolonging allograft survival, and sirtinol synergizes with FK506 to promote Foxp3 expression. CONCLUSION Sirtinol, a Sirt1 inhibitor, may be a promising immunosuppressive drug to prevent the rejection reaction in combination with FK506.
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Affiliation(s)
- Qing Ye
- Institute of Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Mingjian Zhang
- National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai, China
| | - Yang Wang
- Department of Clinical Surgery, Chinese PLA General Hospital, 28th Fuxing Road, Beijing, China
| | - Shangxi Fu
- Institute of Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Shu Han
- Institute of Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Liming Wang
- Institute of Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Quanxing Wang
- National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai, China
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15
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Newell KA, Mehta AK, Larsen CP, Stock PG, Farris AB, Mehta SG, Ikle D, Armstrong B, Morrison Y, Bridges N, Robien M, Mannon RB. Lessons Learned: Early Termination of a Randomized Trial of Calcineurin Inhibitor and Corticosteroid Avoidance Using Belatacept. Am J Transplant 2017; 17:2712-2719. [PMID: 28556519 PMCID: PMC5623170 DOI: 10.1111/ajt.14377] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Revised: 04/26/2017] [Accepted: 05/21/2017] [Indexed: 01/25/2023]
Abstract
The intent of this National Institutes of Health-sponsored study was to compare a belatacept-based immunosuppressive regimen with a maintenance regimen of tacrolimus and mycophenolate. Nineteen primary, Epstein-Barr virus-immune renal transplant recipients with a negative cross-match were randomized to one of three groups. All patient groups received perioperative steroids and maintenance mycophenolate mofetil. Patients in groups 1 and 2 were induced with alemtuzumab and maintained on tacrolimus or belatacept, respectively. Patients in group 3 were induced with basiliximab, received 3 mo of tacrolimus, and maintained on belatacept. There was one death with a functioning allograft due to endocarditis (group 1). There were three graft losses due to vascular thrombosis (all group 2) and one graft loss due to glomerular disease (group 1). Biopsy-proven acute cellular rejection was more frequent in the belatacept-treated groups, with 10 treated episodes in seven participants compared with one episode in group 1; however, estimated GFR was similar between groups at week 52. There were no episodes of posttransplant lymphoproliferative disorder or opportunistic infections in any group. Protocol enrollment was halted prematurely because of a high rate of serious adverse events. Such negative outcomes pose challenges to clinical investigators, who ultimately must weigh the risks and benefits in randomized trials.
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Affiliation(s)
- Kenneth A. Newell
- Department of Surgery, Emory University School of Medicine, Atlanta GA
| | - Aneesh K. Mehta
- Department of Surgery, Emory University School of Medicine, Atlanta GA
- Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, Atlanta GA
| | | | - Peter G. Stock
- Department of Surgery, Division of Transplantation, University of California San Francisco, San Francisco, CA
| | - A. Bradley Farris
- Department of Surgery, Emory University School of Medicine, Atlanta GA
| | - Shikha G. Mehta
- Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, Birmingham, AL
| | | | | | - Yvonne Morrison
- Transplantation Branch, National Institute Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | - Nancy Bridges
- Transplantation Branch, National Institute Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | - Mark Robien
- Transplantation Branch, National Institute Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | - Roslyn B. Mannon
- Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, Birmingham, AL
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16
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Pihlstrøm HK, Gatti F, Hammarström C, Eide IA, Kasprzycka M, Wang J, Haraldsen G, Svensson MHS, Midtvedt K, Mjøen G, Dahle DO, Hartmann A, Holdaas H. Early introduction of oral paricalcitol in renal transplant recipients. An open-label randomized study. Transpl Int 2017; 30:827-840. [PMID: 28436117 DOI: 10.1111/tri.12973] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Revised: 12/31/2016] [Accepted: 04/18/2017] [Indexed: 02/01/2023]
Abstract
In stable renal transplant recipients with hyperparathyroidism, previous studies have indicated that vitamin D agonist treatment might have anti-proteinuric effects. Animal studies indicate possible anti-fibrotic and anti-inflammatory effects. Early introduction of paricalcitol in de novo renal transplant recipients might reduce proteinuria and prevent progressive allograft fibrosis. We performed a single-center, prospective, randomized, open-label trial investigating effects of paricalcitol 2 μg/day added to standard care. Participants were included 8 weeks after engraftment and followed for 44 weeks. Primary end point was change in spot urine albumin/creatinine ratio. Exploratory microarray analyses of kidney biopsies at study end investigated potential effects on gene expression. Secondary end points included change in glomerular filtration rate (GFR), pulse wave velocity (PWV), and endothelial function measured by peripheral arterial tonometry as reactive hyperemia index (RHI). Seventy-seven de novo transplanted kidney allograft recipients were included, 37 receiving paricalcitol. Paricalcitol treatment lowered PTH levels (P = 0.01) but did not significantly reduce albuminuria (P = 0.76), change vascular parameters (PWV; P = 0.98, RHI; P = 0.33), or influence GFR (P = 0.57). Allograft gene expression was not influenced. To summarize, in newly transplanted renal allograft recipients, paricalcitol reduced PTH and was well tolerated without negatively affecting kidney function. Paricalcitol did not significantly reduce/prevent albuminuria, improve parameters of vascular health, or influence allograft gene expression.
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Affiliation(s)
- Hege Kampen Pihlstrøm
- Department of Surgery, Inflammation Medicine and Transplantation, Section of Nephrology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Franscesca Gatti
- Department of Pathology, Oslo University Hospital, Oslo, Norway.,Laboratory of Immunohistochemistry and Immunopathology, K.G. Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway
| | - Clara Hammarström
- Department of Pathology, Oslo University Hospital, Oslo, Norway.,Laboratory of Immunohistochemistry and Immunopathology, K.G. Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway
| | - Ivar Anders Eide
- Department of Surgery, Inflammation Medicine and Transplantation, Section of Nephrology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.,Department of Nephrology, Oslo University Hospital Ullevål, Oslo, Norway
| | - Monika Kasprzycka
- Department of Pathology, Oslo University Hospital, Oslo, Norway.,Laboratory of Immunohistochemistry and Immunopathology, K.G. Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway
| | - Junbai Wang
- Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - Guttorm Haraldsen
- Department of Pathology, Oslo University Hospital, Oslo, Norway.,Laboratory of Immunohistochemistry and Immunopathology, K.G. Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway
| | | | - Karsten Midtvedt
- Department of Surgery, Inflammation Medicine and Transplantation, Section of Nephrology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Geir Mjøen
- Department of Surgery, Inflammation Medicine and Transplantation, Section of Nephrology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Dag Olav Dahle
- Department of Surgery, Inflammation Medicine and Transplantation, Section of Nephrology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Anders Hartmann
- Department of Surgery, Inflammation Medicine and Transplantation, Section of Nephrology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.,Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Hallvard Holdaas
- Department of Surgery, Inflammation Medicine and Transplantation, Section of Nephrology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
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17
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Paliege A, Bamoulid J, Bachmann F, Staeck O, Halleck F, Khadzhynov D, Brakemeier S, Dürr M, Budde K. [Immunosuppression and its use in kidney transplantation]. Urologe A 2016; 54:1376-84. [PMID: 26459580 DOI: 10.1007/s00120-015-3909-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Current immunosuppressive protocols effectively prevent acute rejection of renal allografts. Extensive drug toxicity and the deleterious effects of long-term immunosuppression are associated with significant morbidity and mortality. OBJECTIVES The purpose of this article is to provide an overview over modern immunosuppressants and their unwanted side effects and to discuss strategies for improved long-term transplant survival. METHODS Review of the current topic-related literature and discussion of our own experience. RESULTS The use of antibody induction together with an initial combination therapy of calcineurin inhibitors, mycophenolate and steroids is recommended and results in excellent early outcomes. Detrimental effects include an increased incidence of infections, malignomas, and cardiovascular diseases. Long-term transplant survival is impaired by extensive drug toxicity and the frequent development of donor specific antibodies. Reduction of overall cumulative exposure to immunosuppressants or the reduction of specific toxic drugs such as calcineurin inhibitors and steroids may improve long-term results. Alternative immunosuppressants like mTOR inhibitors and belatacept appear to be effective and safe but their long-term effects on patient and allograft survival needs to be established in clinical trials. CONCLUSIONS Current immunosuppressants provide effective protection from renal allograft rejection. However, their use is complicated by serious side effects. In the future, development of novel immunosuppressants and optimization of minimization strategies may help to improve long-term success after kidney transplantation.
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Affiliation(s)
- A Paliege
- Medizinische Klinik mit Schwerpunkt Nephrologie, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 10117, Berlin, Deutschland
| | - J Bamoulid
- Medizinische Klinik mit Schwerpunkt Nephrologie, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 10117, Berlin, Deutschland
| | - F Bachmann
- Medizinische Klinik mit Schwerpunkt Nephrologie, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 10117, Berlin, Deutschland
| | - O Staeck
- Medizinische Klinik mit Schwerpunkt Nephrologie, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 10117, Berlin, Deutschland
| | - F Halleck
- Medizinische Klinik mit Schwerpunkt Nephrologie, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 10117, Berlin, Deutschland
| | - D Khadzhynov
- Medizinische Klinik mit Schwerpunkt Nephrologie, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 10117, Berlin, Deutschland
| | - S Brakemeier
- Medizinische Klinik mit Schwerpunkt Nephrologie, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 10117, Berlin, Deutschland
| | - M Dürr
- Medizinische Klinik mit Schwerpunkt Nephrologie, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 10117, Berlin, Deutschland
| | - K Budde
- Medizinische Klinik mit Schwerpunkt Nephrologie, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 10117, Berlin, Deutschland.
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18
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Bamgbola O. Metabolic consequences of modern immunosuppressive agents in solid organ transplantation. Ther Adv Endocrinol Metab 2016; 7:110-27. [PMID: 27293540 PMCID: PMC4892400 DOI: 10.1177/2042018816641580] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Among other factors, sophistication of immunosuppressive (IS) regimen accounts for the remarkable success attained in the short- and medium-term solid organ transplant (SOT) survival. The use of steroids, mycophenolate mofetil and calcineurin inhibitors (CNI) have led to annual renal graft survival rates exceeding 90% in the last six decades. On the other hand, attrition rates of the allograft beyond the first year have remained unchanged. In addition, there is a persistent high cardiovascular (CV) mortality rate among transplant recipients with functioning grafts. These shortcomings are in part due to the metabolic effects of steroids, CNI and sirolimus (SRL), all of which are implicated in hypertension, new onset diabetes after transplant (NODAT), and dyslipidemia. In a bid to reduce the required amount of harmful maintenance agents, T-cell-depleting antibodies are increasingly used for induction therapy. The downsides to their use are greater incidence of opportunistic viral infections and malignancy. On the other hand, inadequate immunosuppression causes recurrent rejection episodes and therefore early-onset chronic allograft dysfunction. In addition to the adverse metabolic effects of the steroid rescue needed in these settings, the generated proinflammatory milieu may promote accelerated atherosclerotic disorders, thus setting up a vicious cycle. The recent availability of newer agent, belatacept holds a promise in reducing the incidence of metabolic disorders and hopefully its long-term CV consequences. Although therapeutic drug monitoring as applied to CNI may be helpful, pharmacodynamic tools are needed to promote a customized selection of IS agents that offer the most benefit to an individual without jeopardizing the allograft survival.
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Affiliation(s)
- Oluwatoyin Bamgbola
- State University of New York Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203-2098, USA
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19
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Casiraghi F, Perico N, Cortinovis M, Remuzzi G. Mesenchymal stromal cells in renal transplantation: opportunities and challenges. Nat Rev Nephrol 2016; 12:241-53. [DOI: 10.1038/nrneph.2016.7] [Citation(s) in RCA: 106] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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20
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Newell KA, Asare A, Sanz I, Wei C, Rosenberg A, Gao Z, Kanaparthi S, Asare S, Lim N, Stahly M, Howell M, Knechtle S, Kirk A, Marks WH, Kawai T, Spitzer T, Tolkoff-Rubin N, Sykes M, Sachs DH, Cosimi AB, Burlingham WJ, Phippard D, Turka LA. Longitudinal studies of a B cell-derived signature of tolerance in renal transplant recipients. Am J Transplant 2015; 15:2908-20. [PMID: 26461968 PMCID: PMC4725587 DOI: 10.1111/ajt.13480] [Citation(s) in RCA: 75] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Revised: 06/29/2015] [Accepted: 07/07/2015] [Indexed: 01/25/2023]
Abstract
Biomarkers of transplant tolerance would enhance the safety and feasibility of clinical tolerance trials and potentially facilitate management of patients receiving immunosuppression. To this end, we examined blood from spontaneously tolerant renal transplant recipients and patients enrolled in two interventional tolerance trials using flow cytometry and gene expression profiling. Using a previously reported tolerant cohort as well as newly identified tolerant patients, we confirmed our previous finding that tolerance was associated with increased expression of B cell-associated genes relative to immunosuppressed patients. This was not accounted for merely by an increase in total B cell numbers, but was associated with the increased frequencies of transitional and naïve B cells. Moreover, serial measurements of gene expression demonstrated that this pattern persisted over several years, although patients receiving immunosuppression also displayed an increase in the two most dominant tolerance-related B cell genes, IGKV1D-13 and IGLL-1, over time. Importantly, patients rendered tolerant via induction of transient mixed chimerism, and those weaned to minimal immunosuppression, showed similar increases in IGKV1D-13 as did spontaneously tolerant individuals. Collectively, these findings support the notion that alterations in B cells may be a common theme for tolerant kidney transplant recipients, and that it is a useful monitoring tool in prospective trials.
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Affiliation(s)
| | - Adam Asare
- Immune Tolerance Network, Bethesda, Maryland USA,Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Ignacio Sanz
- Department of Surgery, Emory University, Atlanta, GA
| | - Chungwen Wei
- Department of Surgery, Emory University, Atlanta, GA
| | - Alexander Rosenberg
- Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY
| | - Zhong Gao
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Sai Kanaparthi
- Immune Tolerance Network, Bethesda, Maryland USA,Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Smita Asare
- Immune Tolerance Network, Bethesda, Maryland USA,Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Noha Lim
- Immune Tolerance Network, Bethesda, Maryland USA,Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Michael Stahly
- Immune Tolerance Network, Bethesda, Maryland USA,Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | | | | | - Allan Kirk
- Department of Surgery, Emory University, Atlanta, GA
| | | | - Tatsuo Kawai
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Thomas Spitzer
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Nina Tolkoff-Rubin
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Megan Sykes
- Departments of Medicine, and Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, NY
| | - David H. Sachs
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - A. Benedict Cosimi
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | | | | | - Laurence A. Turka
- Immune Tolerance Network, Bethesda, Maryland USA,Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA,Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
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21
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Matz M, Fabritius K, Liu J, Lorkowski C, Brakemeier S, Unterwalder N, Dürr M, Mashreghi MF, Neumayer HH, Budde K. Conversion to Belatacept based regimen does not change T-cell phenotype and function in renal transplantation. Transpl Immunol 2015; 33:176-84. [PMID: 26478531 DOI: 10.1016/j.trim.2015.10.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Revised: 10/08/2015] [Accepted: 10/13/2015] [Indexed: 11/19/2022]
Abstract
Belatacept offers a new option for renal allograft recipients who are suffering from side effects of calcineurin inhibitors or mTOR inhibitors,which may result in renal and extrarenal benefits.We prospectively performed flow cytometric immunophenotyping with a T-cell panel. In total we were able to fully investigate the immunophenotypic change in 8 patients before and after conversion from calcineurin inhibitor (n = 5) or mTOR inhibitor (n=2) to Belatacept or additional administration (n=1). Cells were analysed pre conversion, 1 month, 3 months, 6 months and 12 months after first Belatacept administration. The percentage of central memory, naïve, effector memory and terminally differentiated effector memory CD4+ and CD4− T-cells was determined. CD28, CD25 and CD69 expression on CD4+ and CD4− T-cells was measured ex vivo and also after 3 days of mitogen stimulation. Intracellular cytokines IFNgamma and IL-2 were measured after polyclonal cellular stimulation. The expression of activation markers and intracellular cytokines as well as the percentage of T-cell subsets did not change significantly during the observation period compared to the time-point pre conversion. Therefore the conversion of calcineurin inhibitor or mTOR inhibitor to Belatacept seems to have no obvious impact on the immunophenotype of T-cells in patients after kidney transplantation.
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Affiliation(s)
- Mareen Matz
- Department of Nephrology, Universitätsmedizin Charité Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany.
| | - Katharina Fabritius
- Department of Nephrology, Universitätsmedizin Charité Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany
| | - Juan Liu
- Department of Nephrology, Universitätsmedizin Charité Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany
| | - Christine Lorkowski
- Department of Nephrology, Universitätsmedizin Charité Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany
| | - Susanne Brakemeier
- Department of Nephrology, Universitätsmedizin Charité Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany
| | - Nadine Unterwalder
- Labor Berlin GmbH, Immunology Department, Universitätsmedizin Charité Campus Virchow, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Michael Dürr
- Department of Nephrology, Universitätsmedizin Charité Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany
| | | | - Hans-H Neumayer
- Department of Nephrology, Universitätsmedizin Charité Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany
| | - Klemens Budde
- Department of Nephrology, Universitätsmedizin Charité Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany
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22
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Zsom L, Wagner L, Fülöp T. Minimization vs tailoring: Where do we stand with personalized immunosuppression during renal transplantation in 2015? World J Transplant 2015; 5:73-80. [PMID: 26421259 PMCID: PMC4580929 DOI: 10.5500/wjt.v5.i3.73] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Revised: 06/13/2015] [Accepted: 07/11/2015] [Indexed: 02/05/2023] Open
Abstract
The introduction of novel immunosuppressive agents over the last two decades and the improvement of our diagnostic tools for early detection of antibody-mediated injury offer us an opportunity, if not a mandate, to better match the immunosuppression needs of the individual patients with side effects of the therapy. However, immunosuppressive regimens in the majority of programs remain mostly protocol-driven, with relatively little inter-program heterogeneity in certain areas of the world. Emerging data showing different outcomes with a particular immunosuppressive strategy in populations with varying immunological risks underscore a real potential for "personalized medicine" in renal transplantation. Studies demonstrating marked differences in the adverse-effect profiles of individual drugs including the risk for viral infections, malignancy and renal toxicity call for a paradigm shift away from a "one size fits all" approach to an individually tailored immunosuppressive therapy for renal transplant recipients, assisted by both screening for predictors of graft loss and paying close attention to dose or class-related adverse effects. Our paper explores some of the opportunities during the care of these patients. Potential areas of improvements may include: (1) a thorough assessment of immunological and metabolic risk profile of each renal transplant recipient; (2) screening for predictors of graft loss and early signs of antibody-mediated rejection with donor-specific antibodies, protocol biopsies and proteinuria (including close follow up of adverse effects with dose adjustments or conversions as necessary); and (3) increased awareness of the possible link between poor tolerance of a given drug at a given dose and non-adherence with the prescribed regimen. Altogether, these considerations may enable the most effective use of the drugs we already have.
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Baron D, Giral M, Brouard S. Reconsidering the detection of tolerance to individualize immunosuppression minimization and to improve long-term kidney graft outcomes. Transpl Int 2015; 28:938-59. [DOI: 10.1111/tri.12578] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Revised: 02/03/2015] [Accepted: 04/02/2015] [Indexed: 01/03/2023]
Affiliation(s)
- Daniel Baron
- INSERM; UMR 1064; Nantes France
- CHU de Nantes; ITUN; Nantes France
- Faculté de Médecine; Université de Nantes; Nantes France
| | - Magali Giral
- INSERM; UMR 1064; Nantes France
- CHU de Nantes; ITUN; Nantes France
- Faculté de Médecine; Université de Nantes; Nantes France
| | - Sophie Brouard
- INSERM; UMR 1064; Nantes France
- CHU de Nantes; ITUN; Nantes France
- Faculté de Médecine; Université de Nantes; Nantes France
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Hutchinson JA, Geissler EK. Now or never? The case for cell-based immunosuppression in kidney transplantation. Kidney Int 2015; 87:1116-24. [PMID: 25738251 DOI: 10.1038/ki.2015.50] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Revised: 12/20/2014] [Accepted: 01/02/2015] [Indexed: 02/07/2023]
Abstract
By exploiting mechanisms of immunological regulation against donor alloantigen, it may be possible to reduce the dependence of kidney transplant recipients upon calcineurin inhibitor-based maintenance immunosuppression. One means to strengthen regulatory responses is treating recipients with preparations of regulatory cells obtained by ex vivo manipulation. This strategy, which is a well-established experimental method, has been developed to the point that early-phase clinical trials in kidney transplantation are now feasible. Cell-based therapies represent a radical departure from conventional treatment, so what grounds are there for this new approach? This article offers a three-part justification for trialing cell-based therapies in kidney transplantation: first, a clinical need for alternatives to standard immunosuppression is identified, based on the inadequacies of calcineurin inhibitor-based regimens in preventing late allograft loss; second, a mechanistic explanation of how cell-based therapies might address this clinical need is given; and third, the possible benefit to patients is weighed against the potential risks of cell-based immunosuppressive therapy. It is concluded that the safety of cell-based immunosuppressive therapy will not be greatly improved by further basic scientific and preclinical development. Only trials in humans can now tell us whether cell-based therapy is likely to benefit kidney transplant recipients, but these should be conservative in design to minimize any potential harm to patients.
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Affiliation(s)
- James A Hutchinson
- Department of Surgery, Section of Experimental Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Edward K Geissler
- Department of Surgery, Section of Experimental Surgery, University Hospital Regensburg, Regensburg, Germany
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Schlickeiser S, Boës D, Streitz M, Sawitzki B. The use of novel diagnostics to individualize immunosuppression following transplantation. Transpl Int 2015; 28:911-20. [PMID: 25611562 DOI: 10.1111/tri.12527] [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] [Received: 11/10/2014] [Revised: 12/19/2014] [Accepted: 01/16/2015] [Indexed: 12/14/2022]
Abstract
Despite major improvements in short-term survival of organ allografts, long-term graft survival has not changed significantly. It is also known that toxic side effects of current immunosuppressive drugs (IS) especially calcineurin inhibitors (CNI) contribute to the unsatisfactory graft and patient survival following transplantation. Thus, clinicians strive to reduce or wean IS in potentially eligible patients. Research in the last 10 years has focussed on identification of biomarkers suitable for patient stratification in minimization or weaning trials. Most of the described biomarkers have been run retrospectively on samples collected within single-centre trials. Thus, often their performance has not been validated in other potentially multicentre clinical trials. Ultimately, the utility of biomarkers to identify potential weaning candidates should be investigated in large randomized prospective trials. In particular, for testing in such trials, we need more information about the accuracy, reproducibility, stability and limitations of the described biomarkers. Also, data repositories summarizing crucial information on biomarker performance in age- and gender-matched healthy individuals of different ethnicity are missing. This together with improved bioinformatics tools might help in developing better scores for patient stratification. Here, we will summarize the current results, knowledge and limitations on biomarkers for drug minimization or weaning trials.
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Affiliation(s)
- Stephan Schlickeiser
- Institute of Medical Immunology, CCM, Charité University Berlin, Berlin, Germany
| | - David Boës
- Institute of Medical Immunology, CCM, Charité University Berlin, Berlin, Germany
| | - Mathias Streitz
- Institute of Medical Immunology, CCM, Charité University Berlin, Berlin, Germany
| | - Birgit Sawitzki
- Institute of Medical Immunology, CCM, Charité University Berlin, Berlin, Germany.,Berlin-Brandenburg Center for Regenerative Therapies (BCRT), CVK, Charité University Berlin, Berlin, Germany
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Budde K, Lehner F, Sommerer C, Reinke P, Arns W, Eisenberger U, Wüthrich RP, Mühlfeld A, Heller K, Porstner M, Veit J, Paulus EM, Witzke O. Five-year outcomes in kidney transplant patients converted from cyclosporine to everolimus: the randomized ZEUS study. Am J Transplant 2015; 15:119-28. [PMID: 25521535 DOI: 10.1111/ajt.12952] [Citation(s) in RCA: 91] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Revised: 06/26/2014] [Accepted: 07/12/2014] [Indexed: 01/25/2023]
Abstract
ZEUS study was an open-label, 12-month, multicenter study in which 300 de novo kidney transplant recipients were randomized to continue receiving cyclosporine (CsA) or convert to everolimus at 4.5 months posttransplant. Five-year follow-up data were available for 245/269 patients (91.1%) who completed the core 12-month study (123 everolimus, 109 CsA). At 5 years, adjusted estimated GFR was 66.2 mL/min/1.73 m(2) with everolimus versus 60.9 mL/min/1.73 m(2) with CsA; the mean difference was 5.3 mL/min/1.73 m(2) in favor of everolimus (95% CI 2.4, 8.3; p < 0.001 [intent-to-treat population]). In a post hoc analysis of patients remaining on study drug at 5 years (everolimus 77, CsA 86), mean difference was 8.2 mL/min/1.73 m(2) (95% CI 4.3, 12.1; p < 0.001) in favor of everolimus. The cumulative incidence of biopsy-proven acute rejection postrandomization was 13.6% with everolimus versus 7.5% with CsA (p = 0.095), largely accounted for by grade I rejection (16/21 patients and 7/11 patients, respectively). Postrandomization, graft loss, mortality, serious adverse events and neoplasms were similar in both arms. In conclusion, conversion of kidney transplant patients to everolimus at 4.5 months posttransplant is associated with a significant improvement in renal function that is maintained to at least 5 years. The increase in early mild acute rejection did not affect long-term graft function.
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Affiliation(s)
- K Budde
- Department of Nephrology, Charité Universitätsmedizin Berlin, Berlin, Germany
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Mujtaba MA, Sharfuddin AA, Taber T, Chen J, Phillips CL, Goble M, Fridell JA. Conversion from tacrolimus to belatacept to prevent the progression of chronic kidney disease in pancreas transplantation: case report of two patients. Am J Transplant 2014; 14:2657-61. [PMID: 25179306 DOI: 10.1111/ajt.12863] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2013] [Revised: 05/27/2014] [Accepted: 05/28/2014] [Indexed: 01/25/2023]
Abstract
Belatacept is a novel immunosuppressive agent that may be used as an alternative to calcineurin inhibitors (CNI) in immunosuppression (IS) regimens. We report two cases of pancreas transplant that were switched from tacrolimus (TAC) to belatacept. Case 1: 38-year-old female with pancreas transplant alone maintained on TAC-based IS regimen whose serum creatinine (SCr) slowly deteriorated from 0.6 mg/dL at baseline to 2.2 mg/dL, 16 months posttransplant. A native kidney biopsy performed showed CNI toxicity. The patient was started on belatacept and TAC was eliminated. Case 2: 49-year-old female with simultaneous pancreas-kidney transplant, maintained on TAC-based regimen where the SCr worsened over an initial 3-month period from a baseline of 1.0 to 3.0 mg/dL. Belatacept was started and TAC was lowered. Due to persistent graft dysfunction and kidney transplant biopsy still showing changes consistent with CNI toxicity, the TAC was then discontinued. At >1 year postbelatacept and off TAC follow-up, kidney function as measured by SCr remains stable at 1.0±0.2 mg/dL in both recipients. Neither patient developed rejection following the switch, and pancreas allograft function remains stable in both recipients.
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Affiliation(s)
- M A Mujtaba
- Division of Nephrology and Transplant, Indiana University School of Medicine, Indianapolis, IN
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Wilmes A, Aschauer L, Limonciel A, Pfaller W, Jennings P. Evidence for a role of claudin 2 as a proximal tubular stress responsive paracellular water channel. Toxicol Appl Pharmacol 2014; 279:163-72. [DOI: 10.1016/j.taap.2014.05.013] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Revised: 05/16/2014] [Accepted: 05/27/2014] [Indexed: 01/04/2023]
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Furuzawa-Carballeda J, Bostock IC, Lima G, Mancilla-Urrea E, Mondragón G, Reyes-Acevedo R, Chevaile A, Morales-Buenrostro LE, Llorente L, Alberú J. Immunophenotyping of peripheral immunoregulatory as well as Th17A and Th22 cell subpopulations in kidney transplant recipients under belatacept or cyclosporine treatment. Transpl Immunol 2014; 30:107-13. [DOI: 10.1016/j.trim.2014.02.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Revised: 02/04/2014] [Accepted: 02/06/2014] [Indexed: 01/30/2023]
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Zaza G, Tomei P, Granata S, Boschiero L, Lupo A. Monoclonal antibody therapy and renal transplantation: focus on adverse effects. Toxins (Basel) 2014; 6:869-91. [PMID: 24590384 PMCID: PMC3968366 DOI: 10.3390/toxins6030869] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Revised: 02/07/2014] [Accepted: 02/21/2014] [Indexed: 02/06/2023] Open
Abstract
A series of monoclonal antibodies (mAbs) are commonly utilized in renal transplantation as induction therapy (a period of intense immunosuppression immediately before and following the implant of the allograft), to treat steroid-resistant acute rejections, to decrease the incidence and mitigate effects of delayed graft function, and to allow immunosuppressive minimization. Additionally, in the last few years, their use has been proposed for the treatment of chronic antibody-mediated rejection, a major cause of late renal allograft loss. Although the exact mechanism of immunosuppression and allograft tolerance with any of the currently used induction agents is not completely defined, the majority of these medications are targeted against specific CD proteins on the T or B cells surface (e.g., CD3, CD25, CD52). Moreover, some of them have different mechanisms of action. In particular, eculizumab, interrupting the complement pathway, is a new promising treatment tool for acute graft complications and for post-transplant hemolytic uremic syndrome. While it is clear their utility in renal transplantation, it is also unquestionable that by using these highly potent immunosuppressive agents, the body loses much of its innate ability to mount an adequate immune response, thereby increasing the risk of severe adverse effects (e.g., infections, malignancies, haematological complications). Therefore, it is extremely important for clinicians involved in renal transplantation to know the potential side effects of monoclonal antibodies in order to plan a correct therapeutic strategy minimizing/avoiding the onset and development of severe clinical complications.
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Affiliation(s)
- Gianluigi Zaza
- Renal Unit, Department of Medicine, University-Hospital of Verona, Piazzale A. Stefani 1, Verona 37126, Italy.
| | - Paola Tomei
- Renal Unit, Department of Medicine, University-Hospital of Verona, Piazzale A. Stefani 1, Verona 37126, Italy.
| | - Simona Granata
- Renal Unit, Department of Medicine, University-Hospital of Verona, Piazzale A. Stefani 1, Verona 37126, Italy.
| | - Luigino Boschiero
- First Surgical Clinic, Kidney Transplantation Center, University-Hospital of Verona, Piazzale A. Stefani 1, Verona 37126, Italy.
| | - Antonio Lupo
- Renal Unit, Department of Medicine, University-Hospital of Verona, Piazzale A. Stefani 1, Verona 37126, Italy.
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Spivey CA, Chisholm-Burns MA, Damadzadeh B, Billheimer D. Determining the effect of immunosuppressant adherence on graft failure risk among renal transplant recipients. Clin Transplant 2013; 28:96-104. [DOI: 10.1111/ctr.12283] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/25/2013] [Indexed: 01/06/2023]
Affiliation(s)
| | | | - Bita Damadzadeh
- Zuckerman College of Public Health; University of Arizona; Tucson AZ USA
| | - Dean Billheimer
- College of Agriculture and Life Sciences; BIO5 Institute; University of Arizona; Tucson AZ USA
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Siepert A, Brösel S, Vogt K, Ahrlich S, Schmitt-Knosalla I, Loddenkemper C, Kühl A, Baumgrass R, Gerstmayer B, Tomiuk S, Tiedge M, Viklický O, Brabcova I, Nizze H, Lehmann M, Volk HD, Sawitzki B. Mechanisms and rescue strategies of calcineurin inhibitor mediated tolerance abrogation induced by anti-CD4 mAb treatment. Am J Transplant 2013; 13:2308-21. [PMID: 23855618 DOI: 10.1111/ajt.12352] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2012] [Revised: 05/26/2013] [Accepted: 05/29/2013] [Indexed: 01/25/2023]
Abstract
To ensure safety tolerance induction protocols are accompanied by conventional immunosuppressive drugs (IS). But IS such as calcineurin inhibitors (CNI), for example, cyclosporin A (CsA), can interfere with tolerance induction. We investigated the effect of an additional transient CsA treatment on anti-CD4mAb-induced tolerance induction upon rat kidney transplantation. Additional CsA treatment induced deteriorated graft function, resulting in chronic rejection characterized by glomerulosclerosis, interstitial fibrosis, tubular atrophy and vascular changes. Microarray analysis revealed enhanced intragraft expression of the B cell attracting chemokine CXCL13 early during CsA treatment. Increase in CXCL13 expression is accompanied by enhanced B cell infiltration with local and systemic IgG production and C3d deposition as early as 5 days upon CsA withdrawal. Adding different CNIs to cultures of primary mesangial cells isolated from glomeruli resulted in a concentration-dependent increase in CXCL13 transcription. CsA in synergy with TNF-α can enhance the B cell attracting and activating potential of mesangial cells. Transient B cell depletion or transfer of splenocytes from tolerant recipients 3 weeks after transplantation could rescue tolerance induction and did inhibit intragraft B cell accumulation, alloantibody production and ameliorate chronic rejection.
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Affiliation(s)
- A Siepert
- Institute of Medical Biochemistry and Molecular Biology, University of Rostock, Rostock, Germany
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Heeg MHJ, Mueller GA, Bramlage C, Homayounfar K, Muehlhausen J, Leha A, Koziolek MJ. Improvement of renal graft function after conversion from a calcineurin inhibitor including immunosuppression to a mycophenolate sodium including regimen: a 4-year follow-up. Transplant Proc 2013; 45:142-7. [PMID: 23375288 DOI: 10.1016/j.transproceed.2012.10.028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2012] [Accepted: 10/09/2012] [Indexed: 01/07/2023]
Abstract
BACKGROUND The most common immunosuppressive regimens after renal transplantation include calcineurin inhibitors (CNI). However, due to renal toxicity long-term graft survival does not seem to be positively affected by CNIs. METHODS In the present study, we investigated 17 patients, in which the CNI immunosuppression was converted to a CNI-free, mycophenolate sodium (MPS) regimen. Conversion was performed due to progressive impairment of the graft function from suspected CNI toxicity. We retrospectively analyzed graft function as well as toxicity and surrogate markers for 4 years before and 4 years after conversion using a repeated-measures mixed model data analysis and/or a paired sample t-test. RESULTS The mean time point of therapy conversion was 11.2 ± 4.6 years after transplantation. Within 1 month of CNI discontinuation, allograft function improved significantly, remaining at a significant level for 2 years. The estimated glomerular filtration rate increased from 43.4 ± 14.8 to a maximum of 55.7 ± 21.7 mL/min at 1 year after conversion (P = .0027). After 4 years, the end of the observation period, renal function was similar to the baseline. There were no significant side effects. CONCLUSION These data suggested that, when chronic CNI-toxicity is suspected, renal allograft recipients may benefit from CNI withdrawal in favor of a MPS-including immunosuppressive regimen.
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Affiliation(s)
- M H J Heeg
- Department of Nephrology and Rheumatology, University Medical Center Göttingen, Humboldtallee 32, 37073 Göttingen, Germany
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Menon MC, Murphy B. Maintenance immunosuppression in renal transplantation. Curr Opin Pharmacol 2013; 13:662-71. [PMID: 23731524 DOI: 10.1016/j.coph.2013.05.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Accepted: 05/03/2013] [Indexed: 12/28/2022]
Abstract
The need to maintain allograft recipients on immunosuppression is nearly universal. Immunosuppressive agents used in organ transplantation target one or more steps of the host alloimmune response, specifically processes related to CD4-positive T lymphocytes. Calcineurin-inhibitor based steroid-containing regimens have been the mainstay of maintenance immunosuppression over the last two decades. Newer agents have shown efficacy in this role in recent trials with comparable allograft and patient outcomes. These agents have permitted calcineurin-inhibitor minimization and steroid-sparing strategies in selected groups of patients.
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Affiliation(s)
- Madhav C Menon
- Ichan School of Medicine at Mount Sinai, New York, United States
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35
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Neudoerfl C, Mueller BJ, Blume C, Daemen K, Stevanovic-Meyer M, Keil J, Lehner F, Haller H, Falk CS. The Peripheral NK Cell Repertoire after Kidney Transplantation is Modulated by Different Immunosuppressive Drugs. Front Immunol 2013; 4:46. [PMID: 23450662 PMCID: PMC3584176 DOI: 10.3389/fimmu.2013.00046] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2012] [Accepted: 02/07/2013] [Indexed: 01/10/2023] Open
Abstract
In the context of kidney transplantation, little is known about the involvement of natural killer (NK) cells in the immune reaction leading to either rejection or immunological tolerance under immunosuppression. Therefore, the peripheral NK cell repertoire of patients after kidney transplantation was investigated in order to identify NK cell subsets that may be associated with the individual immune status at the time of their protocol biopsies for histopathological evaluation of the graft. Alterations in the peripheral NK cell repertoire could be correlated to the type of immunosuppression, i.e., calcineurin-inhibitors like Cyclosporin A vs. Tacrolimus with or without addition of mTOR inhibitors. Here, we could demonstrate that the NK cell repertoire in peripheral blood of kidney transplant patients differs significantly from healthy individuals. The presence of donor-specific antibodies was associated with reduced numbers of CD56dim NK cells. Moreover, in patients, down-modulation of CD16 and CD6 on CD56dim NK cells was observed with significant differences between Cyclosporin A- and Tac-treated patients. Tac-treatment was associated with decreased CD69, HLA-DR, and increased CD94/NKG2A expression in CD56dim NK cells indicating that the quality of the immunosuppressive treatment impinges on the peripheral NK cell repertoire. In vitro studies with peripheral blood mononuclear cells of healthy donors showed that this modulation of CD16, CD6, CD69, and HLA-DR could also be induced experimentally. The presence of calcineurin or mTOR inhibitors had also functional consequences regarding degranulation and interferon-γ-production against K562 target cells, respectively. In summary, we postulate that the NK cell composition in peripheral blood of kidney transplanted patients represents an important hallmark of the efficacy of immunosuppression and may be even informative for the immune status after transplantation in terms of rejection vs. drug-induced allograft tolerance. Thus, NK cells can serve as sensors for immunosuppression and may be utilized for future strategies of an individualized adjustment of immunosuppression.
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Affiliation(s)
- Christine Neudoerfl
- Transplant Immunology, Institute of Transplant Immunology, Integrated Research and Treatment Center Transplantation, Hannover Medical School Hannover, Germany
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Durrbach A, Francois H. Intracellular lactate flux: a new regulator of the allogenic immune response. Transpl Int 2012; 26:20-1. [PMID: 23237578 DOI: 10.1111/tri.12035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2012] [Accepted: 11/15/2012] [Indexed: 11/28/2022]
Affiliation(s)
- Antoine Durrbach
- Nephrology Department, IFRNT, INSERM UMR1014, Le Kremlin Bicetre, France.
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37
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Siepert A, Ahrlich S, Vogt K, Appelt C, Stanko K, Kühl A, van den Brandt J, Reichardt HM, Nizze H, Lehmann M, Tiedge M, Volk HD, Sawitzki B, Reinke P. Permanent CNI treatment for prevention of renal allograft rejection in sensitized hosts can be replaced by regulatory T cells. Am J Transplant 2012; 12:2384-94. [PMID: 22702307 DOI: 10.1111/j.1600-6143.2012.04143.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Recent data suggest that donor-specific memory T cells (T(mem)) are an independent risk factor for rejection and poor graft function in patients and a major challenge for immunosuppression minimizing strategies. Many tolerance induction protocols successfully proven in small animal models e.g. costimulatory blockade, T cell depletion failed in patients. Consequently, there is a need for more predictive transplant models to evaluate novel promising strategies, such as adoptive transfer of regulatory T cells (Treg). We established a clinically more relevant, life-supporting rat kidney transplant model using a high responder (DA to LEW) recipients that received donor-specific CD4(+)/ 8(+) GFP(+) T(mem) before transplantation to achieve similar pre-transplant frequencies of donor-specific T(mem) as seen in many patients. T cell depletion alone induced long-term graft survival in naïve recipients but could not prevent acute rejection in T(mem)(+) rats, like in patients. Only if T cell depletion was combined with permanent CNI-treatment, the intragraft inflammation, and acute/chronic allograft rejection could be controlled long-term. Remarkably, combining 10 days CNI treatment and adoptive transfer of Tregs (day 3) but not Treg alone also induced long-term graft survival and an intragraft tolerance profile (e.g. high TOAG-1) in T(mem)(+) rats. Our model allows evaluation of novel therapies under clinically relevant conditions.
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Affiliation(s)
- A Siepert
- Institute of Medical Biochemistry and Molecular Biology, University of Rostock, Germany.
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Zhang X, Han S, Kang Y, Guo M, Hong S, Liu F, Fu S, Wang L, Wang QX. SAHA, an HDAC inhibitor, synergizes with tacrolimus to prevent murine cardiac allograft rejection. Cell Mol Immunol 2012; 9:390-8. [PMID: 22922441 DOI: 10.1038/cmi.2012.28] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Suberoylanilide hydroxamic acid (SAHA), as a histone deacetylase (HDAC) inhibitor (HDACi), was recently found to exhibit an immunosuppressive effect. However, whether SAHA can synergize with calcineurin inhibitors (CNIs) to inhibit allograft rejection and its underlying mechanism remain elusive. In this study, we demonstrated the synergistic effects of SAHA and non-therapeutic dose of tacrolimus (FK506) in prolonging the allograft survival in a murine cardiac transplant model. Concomitant intragraft examination revealed that allografts from SAHA-treated recipients showed significantly lower levels of IL-17 expression, and no discernable difference for IL-17 expressions was detected between SAHA- and SAHA/FK506-treated allograft as compared with allografts from FK506-treated animals. In contrast, administration of FK506 significantly suppressed interferon (IFN)-γ but increased IL-10 expression as compared with that of SAHA-treated animals, and this effect was independent of SAHA. Interestingly, SAHA synergizes with FK506 to promote Foxp3 and CTLA4 expression. In vitro, SAHA reduced the proportion of Th17 cells in isolated CD4⁺ T-cell population and decreased expressions of IL-17A, IL-17F, STAT3 and RORγt in these cells. Moreover, SAHA enhances suppressive function of regulatory T (Treg) cells by upregulating the expression of CTLA-4 without affecting T effector cell proliferation, and increased the proportion of Treg by selectively promoting apoptosis of T effector cells. Therefore, SAHA, a HDACi, may be a promising immunosuppressive agent with potential benefit in conjunction with CNI drugs.
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Affiliation(s)
- Xin Zhang
- Institute of Organ Transplantation, Changzheng Hospital, Shanghai, China
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