Pretransplant immune-regulation predicts allograft tolerance

CD4⁺ Tregs specific for noninherited maternal antigens (NIMA^d) are detectable in some but not all B6 × BDF₁ backcross, H-2^b homozygous offspring, and their presence is strongly correlated with extent of maternal (BDF₁) 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. NIMA^d-exposed, H-2^b offspring that failed to suppress DTH uniformly rejected heart allografts (12/12) by d15. In contrast, 5/6 NIMA^d-exposed DTH 'regulators' accepted their allografts >100 days. The defect in 'nonregulator" offspring could be corrected by transfer of CD4⁺CD25⁺, but not CD4 ⁺CD25^neg 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. The authors show that tolerance or rejection of a heart allograft in F1 backcross mice can be predicted by pre-transplant, trans-vivo DTH analysis of T regulatory cells specific for noninherited maternal antigens.