Donor Specific Transfusion Combined With Anti-CD134L and Rapamycin Inhibits Accelerated Rejection Mediated By Alloantigen-Primed Memory Cells in Mice.

Abstract

Background Donor-reactive memory cells threaten the survival of transplanted organs, and hamper maintenance of transplant tolerance. In this study, we investigated the inhibitory effect of donor splenocyte transfusion(DST) combined with anti-CD134L and rapamycin on memory cells-mediated accelerated rejection in an allogeneic heart transplantation model in mice. Methods Male Balb/c and C57BL/6 mice were used as the donor and recipient. After sensitization with donor skin allografts, splenocytes from the alloantigen-primed C57BL/6 mice were prepared and adoptively transferred (5×106) to a naïve recipient followed by heart transplantation (HTx). Thus, we established a memory cells-mediated accelerated rejection model of heart transplantation. Mitomycin C-treated donor splenocytes were transfused to HTx recipients seven days prior to transplantation, and short-term low dose of rapamycin and anti-CD134L were initiated after transplantation. Graft survival and pathology of rejection was examined. Memory cells proliferation, functionand the proportion of regulatory T and B cell populations were also examined. Results The mean survival time (MST) of grafts in thecontrolgroup was 5.3 days,and more than 40 days in the group treated with DST/anti-CD134L/rapamycin. The DST/anti- CD134L/rapamycinregimen prevented lymphocytic infiltration in the grafts, inhibited memory cells proliferation in the spleen, reduced donor specific antibody level, and increased proportion of CD4+Foxp3+regulatory T cells (Tregs) as well as CD1d+CD5+regulatoryB cells (Bregs). Conclusions Our data suggest that DST combined with rapamycin and anti-CD134L can synergistically inhibit accelerated rejection mediated by memory cells and thus prolong heart allograft survival in mice. Both regulatory T cells and regulatory B cells may play important roles in modulation of memory cells.