Background: Programmed death (PD)-1 has been implicated in peripheral tolerance, and the coinhibitory receptor B and T lymphocyte attenuator (BTLA) has been implicated in the regulation of autoimmune and may potentially play an important role in alloimmune responses. In this study, we investigated the effect of combination of anti-BTLA monoclonal antibody (mAb) (6B2) and anti-PD-1 mAb (PIM-2) in the survival of fully MHC-mismatched murine cardiac allograft transplantation.

Methods: CBA mice (H2^k) underwent transplantation of C57BL/6 (B6, H2^b) hearts and received a single dose (100Μg) of anti-BTLA mAb (6B2) or anti-PD-1 mAb (PIM-2) by intraperitoneal injection on the day of transplantation and for 3rd, 6th and 9th day thereafter (four times), or on the day of transplantation only (one time). A flow cytometry study was performed to determine whether CD4⁺CD25⁺Foxp3⁺ regulatory cells were generated. Cell-proliferation and cytokine assessments were performed.

Result: Untreated CBA mice rejected B6 cardiac grafts acutely (median survival time [MST], 7 days). When CBA mice were treated with anti-BTLA mAb (6B2) and anti-PD-1 mAb (PIM-2) for one time, the allograft survival were significantly prolonged (MSTs, 46 and 25 days, respectively). Moreover, when CBA mice were treated with anti-BTLA mAb (6B2) or anti-PD-1 mAb (PIM-2) for four times, the allograft survival were also significantly prolonged (MSTs, >100 and 15 days, respectively). However, when CBA mice were treated with combination of anti-BTLA mAb (6B2) and anti-PD-1 mAb (PIM-2) for one time, the allograft survival was indefinitely prolonged (MST, >100 days). Proliferation of splenocytes and interferon (IFN)-Γ production were suppressed in 6B2-treated mice compared to those from splenocytes of untreated recipients. Flow cytometry studies showed an increased CD4⁺CD25⁺Foxp3⁺ cell population in splenocytes from 6B2-treated mice.

Conclusion: Combination of anti-BTLA mAb (6B2) and anti-PD-1 mAb (PIM-2) could induce hyporesponsiveness of fully MHC-mismatched cardiac allografts.

« Back to 2013 American Transplant Congress