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BTLA suppress acute rejection via regulating TCR downstream signals and cytokines production in kidney transplantation and prolonged allografts survival.

ABSTRACT: Acute rejection is a major risk for renal transplant failure. During this adverse process, activated T cells are considered the main effectors. Recently, B and T lymphocyte attenuator (BTLA), a member of the CD28 family receptor, was reported to be a novel inhibitory regulator of T cell activation in heart and pancreatic allograft rejection. Due to the similarity of acute rejection pathways among different organs, we hypothesized that BTLA might play a role in acute rejection of kidney transplant. In renal transplant patients, we observed that BTLA expression was significantly decreased in peripheral CD3+ T lymphocytes of biopsy-proven acute rejection (BPAR) recipients compared with control patients with stable transplanted kidney functions. Remarkably, overexpression of BTLA in the rat model was found to significantly inhibit the process of acute rejection, regulate the postoperative immune status, and prolong allograft survival. BTLA overexpression significantly suppressed IL-2 and IFN-γ production and increased IL-4 and IL-10 production both in vivo and in vitro. Moreover, vital factors in T-cell signaling pathways, including mitogen-associated protein kinases (MAPK), nuclear factor-kappa B (NF-κB) and nuclear factor of activated T cells (NFAT), were also significantly repressed by BTLA overexpression. Therefore, BTLA can suppress acute rejection and regulate allogeneic responses of kidney transplant by regulating TCR downstream signals and inflammatory cytokines production to improve allografts outcomes.

SUBMITTER: Zhang J

PROVIDER: S-EPMC6704067 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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BTLA suppress acute rejection via regulating TCR downstream signals and cytokines production in kidney transplantation and prolonged allografts survival.

Zhang Jiayi J Zhang Hengcheng H Wang Zijie Z Yang Haiwei H Chen Hao H Cheng Hong H Zhou Jiajun J Zheng Ming M Tan Ruoyun R Gu Min M

Scientific reports 20190821 1

Acute rejection is a major risk for renal transplant failure. During this adverse process, activated T cells are considered the main effectors. Recently, B and T lymphocyte attenuator (BTLA), a member of the CD28 family receptor, was reported to be a novel inhibitory regulator of T cell activation in heart and pancreatic allograft rejection. Due to the similarity of acute rejection pathways among different organs, we hypothesized that BTLA might play a role in acute rejection of kidney transplan ...[more]

PMID: 31434927

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Project description:BackgroundCostimulatory blockade provides new therapeutic opportunities for ensuring the long-term survival of kidney grafts. The adoption of the novel immunosuppressant Belatacept has been limited, partly due to concerns regarding higher rates and grades of acute rejection in clinical trials. In this study, we hypothesized that a combined therapy, Belatacept combined with BTLA overexpression, may effectively attenuate acute rejection after kidney transplantation.Materials and methodsThe rat kidney transplantation model was used to investigate graft rejection in single and combined therapy. Graft function was analyzed by detecting serum creatinine. Pathological staining was used to observe histological changes in grafts. The expression of T cells was observed by immunohistochemistry and flow cytometry. In vitro, we constructed an antigen-stimulated immune response by mixed lymphocyte culture, treated with or without Belatacept and BTLA-overexpression adenovirus, to observe the proliferation of receptor cells and the expression of cytokines. In addition, western blot and qRT-PCR analyses were performed to evaluate the expression of CTLA-4 and BTLA at various time points during the immune response.ResultsIn rat models, combined therapy reduced the serum creatinine levels and prolonged graft survival compared to single therapy and control groups. Mixed acute rejection was shown in the allogeneic group and inhibited by combination treatment. Belatacept reduced the production of DSA and the deposition of C4d in grafts. Belatacept combined with BTLA overexpression downregulated the secretion of IL-2 and IFN-γ, as well as increasing IL-4 and IL-10 expression. We also found that Belatacept combined with BTLA overexpression inhibited the proliferation of spleen lymphocytes. The duration of the elevated expression levels of CTLA-4 and BTLA differentially affected the immune response.ConclusionBelatacept combined with BTLA overexpression attenuated acute rejection after kidney transplantation and prolonged kidney graft survival, which suggests a new approach for the optimization of early immunosuppression after kidney transplantation.

Dataset Information

BTLA suppress acute rejection via regulating TCR downstream signals and cytokines production in kidney transplantation and prolonged allografts survival.

Publications

BTLA suppress acute rejection via regulating TCR downstream signals and cytokines production in kidney transplantation and prolonged allografts survival.

Similar Datasets

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