*Purpose: The co-inhibitory receptor B and T lymphocyte attenuator (BTLA; CD272) has been implicated in the regulation of autoimmune and may potentially play an important role in alloimmune responses. We investigated the effect of anti-BTLA monoclonal antibody (6B2) in the survival of fully MHC-mismatched murine 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. Adoptive transfer and flow cytometry study was performed to determine whether regulatory cells were generated. Cell-proliferation and cytokine assessments were also performed.

*Results: CBA recipients with no treatment rejected B6 cardiac graft acutely (median survival time [MST], 7 days). CBA mice treated with one and four doses of 6B2 prolonged allograft survival (MSTs, 46 and >100 days, respectively). 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). Flow cytometry studies showed an increased CD4⁺CD25⁺Foxp3⁺ cell population in splenocytes from 6B2-treated mice. Cell proliferation of splenocytes was suppressed in 6B2-treated mice compared to that from splenocytes of untreated recipients.

*Conclusions: Anti-BTLA monoclonal antibody (6B2) could induce hyporesponsiveness of fully MHC-mismatched cardiac allografts and generation of CD4⁺CD25⁺Foxp3⁺ regulatory T cells.

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