*Purpose: Belatacept as a high-affinity variant of CTLA-4Ig, has been applied into kidney transplantation to against acute rejection. However, adoption of Belatacept has been limited in part due to concerns regarding higher rates and grades of acute rejection in clinical trials specially in TCMR. Our previous research found that BTLA pathway was involved in pathogenesis of acute rejection in biopsy-proven patients and attenuated T cell mediated rejection in rat transplantation model.

*Methods: In this study we supposed a combined therapy, Belatacept combined with BTLA, could more effectively attenuated acute rejection after kidney transplantation. In vitro, we extracted the mature DCs and splenocyte from rats to do mixed lymphocyte reaction treated with or without Belatacept and BTLA-overexpression adenovirus. The cell proliferation was measured by BrdU analysis. Then the rat kidney transplantation model was used to research the graft rejection in single and combined therapy. The rats (n=5 each group and each time-point) were harvested for renal function, histology, immunohistochemical and flow cytometry analysis. 8 recipients from each group were observed the graft survival.

*Results: Firstly, we found that Belatacept combined with overexpressed BTLA inhibited proliferation of spleen lymphocytes. In rat models, the combined therapy reduced the SCr levels and prolonged the graft survival compared to the single therapy and the control group. Mixed acute rejection (TCMR and ABMR) was showed in the allogeneic group, glomerulonephritis, perirenal capillary vasculitis, arteritis, interstitial inflammatory cell infiltration, but Belatacept Combined with overexpressed BTLA can attenuated the acute rejection. We also found Belatacept attenuated the antibody medicated rejection remarkably as well as BTLA attenuated the T cell mediated rejection obviously. Belatacept inhibited the Th1 cells and activated the Th2 cells whereas overexpressed BTLA reduced the frequency of CD4+ cells by inhibiting Th1 cells remarkably. Also, the combined therapy increased the expression of Foxp3 in spleen. The high-expression time of CTLA-4 and BTLA showed differently in graft and overexpressed BTLA upregulated the expression of CTLA-4 in graft and MLR.

*Conclusions: BTLA and CTLA-4 played different role in the inhibiting process. Belatacept Combined with overexpressed BTLA attenuated acute rejection after kidney transplantation.

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