Combination of antibodies inhibits accelerated rejection mediated by memory T cells in xenoantigen-primed mice.

Background: Donor-reactive memory T cells are known to accelerate allograft rejection; in our previous study, we reported that combined monoclonal antibodies (mAbs) could prolong islet allograft survival in alloantigen-primed mice. In this study, we examine the effects of donor-reactive memory T cells on the xenograft survival and methods to prolong the islet graft survival. Methods: To collect donor-reactive T cells, we performed full-thickness rat skin xenografting on BALB/c mice and isolated the T cells from the mice after 6-8 weeks. These cells were then adoptively transferred to syngenic mice 1 day before rat-to-mouse islet transplantation. Three experimental groups were established in the adoptive transfer model: recipient mice treated with isotype mAbs (isotype group); mice treated with anti-CD40L mAb (anti-CD40L group); and mice treated with anti-CD40L, anti-OX40L, and anti-CD122 mAbs (3-combined group). Results: Lewis rat islet xenografts transplanted in naive mice showed a mean survival time (MST) of 12.8 days, while the graft rejection was accelerated if the recipient mice were treated with adoptively transferred donor-reactive T cells (MST, 8.67 days). Treatment with anti-CD40L mb could not reverse the accelerated rejection (MST, 9.3 days). However, when anti-CD40L mb was combined with anti-OX40L and anti-CD122 mAbs, there was a considerable increase in the MST, which was 72.2 days. Compared to the isotype group, the 3-combined group had significantly lesser proportion of memory T cells and greater proportion of regulatory T cells (Tregs) in the spleen. Meanwhile, in the 3-combined group, the production of anti-rat antibodies was markedly inhibited. Conclusion: Treatment with a combination of antibodies could significantly reverse the accelerated rejection mediated by donor-reactive memory T cells by inhibiting cellular and humoral immune responses.