Abstract
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.
Highlights
Compared to classic maintenance dialysis, kidney transplantation is considered to be an optimal treatment option with improvement in life quality and prolongation of survival in end-stage renal disease patients [1, 2]
In grafts from the Allo group, we observed acute renal injury at day 1; subsequently, further manifestations with mononuclear cell infiltration, glomerulitis, and tubular injury could be seen from day 3 to day 5, which progressed to pathological mixed acute rejection characterized by moderate to severe intimal arteritis, glomerulitis, and peritubular capillaritis at day 7
Serum donor specific antibody IgG was remarkably upregulated in the Allo group. (Figures 1C–E) the Allo+Control group pretransfected by negative vector exhibited progressive aggravating acute rejection (AR) from day 3 to day 7, clear C4d sedimentation and IgG positivity at day 7 (Figure S2)
Summary
Compared to classic maintenance dialysis, kidney transplantation is considered to be an optimal treatment option with improvement in life quality and prolongation of survival in end-stage renal disease patients [1, 2]. Ensuring the long-term survival of kidneys after transplantation remains an important objective that involves the consideration of a number of immunological and nonimmunological factors, especially acute rejection [4, 5]. Acute rejection occurs most commonly within three months after transplantation and clinically results in decreased urine, increased serum creatinine, swelling and pain of graft [7]. There are two types of acute kidney allograft rejection: T-Cell Mediated Rejection (TCMR) and Antibody-Mediated Rejection (ABMR). Costimulatory blockade provides new therapeutic opportunities for ensuring the long-term survival of kidney grafts. We hypothesized that a combined therapy, Belatacept combined with BTLA overexpression, may effectively attenuate acute rejection after kidney transplantation
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