Pretransplant Immune-Regulation Predicts Allograft Tolerance

CD4+ Tregs specific for noninherited maternal antigens (NIMAd) are detectable in some but not all B6 x BDF(1) backcross, H-2b homozygous offspring, and their presence is strongly correlated with extent of maternal (BDF(1)) microchimerism. We hypothesized that the level of pretransplant donor antigen-specific Tregs could predict allograft tolerance. To test this idea, mice were screened for bystander suppression in a DTH assay, followed 1 week later by DBA/2 heterotopic heart transplantation. NIMAd-exposed, H-2b offspring that failed to suppress DTH uniformly rejected heart allografts (12/12) by d15. In contrast, 5/6 NIMAd-exposed DTH 'regulators' accepted their allografts > 100 days. The defect in 'nonregulator offspring could be corrected by transfer of CD4+CD25+, but not CD4+CD25neg or CD8+T cells from transplant acceptor mice. In conclusion, donor-specific T reg screening of F1 backcross offspring correctly predicted which recipients would accept a heart allograft. If translated to the clinic, similar pretransplant Treg screening could greatly enhance the effectiveness of tolerance as a clinical strategy in transplantation between family members.