Background: The co-inhibitory receptor B and T lymphocyte attenuator (BTLA) and Programmed death (PD)-1 had been suggested to have immunomodulatory activity. This study investigated the effect of combination of anti-BTLA monoclonal antibody (mAb) (6B2) and anti-PD-1 mAb (PIM-2) on alloimmune responses in a murine model of cardiac allograft transplantation.

Methods: CBA male mice underwent transplantation of C57BL/6(B6) hearts and received a single dose (100μg) of 6B2 on the day of transplantation (day 0) or four doses on day 0, 3, 6 and 9. Moreover, CBA recipients were also given one dose of combination of 6B2 and PIM-2 on day 0. Adoptive transfer was performed to determine whether regulatory cells were generated. Cell-proliferation and cytokine assessments were also performed.

Result: CBA recipients with no treatment rejected B6 cardiac graft acutely (median survival time [MST], 7 days). CBA mice treated with one dose of 6B2 and PIM-2 prolonged allograft survival (MSTs, 46 and 25 days, respectively). Moreover, when CBA mice were given one dose of combination of 6B2 and PIM-2, the allograft survival was indefinitely prolonged (MST, >100 days). Secondary CBA recipients showed prolonged survival of B6 hearts after treatments with whole splenocytes from primary combination-treated CBA recipients carrying B6 cardiac allografts for 30 days (MST, >30 days). Proliferation of splenocytes and interferon-γ production were suppressed and interleukin-4 production was increased in combination-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 and generate regulatory cells.

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