Even though CD154 mAb (MR-1) plus donor splenocyte transfusion (DST) is very effective at inducing tolerance of various allografts, such as those of hearts, kidneys or islets in mice, using fully MHC-disparate combinations such as BALB/c->C57BL/6, it was ineffective at prolonging corresponding hindlimb VCA survival. However, after RPM was added to the peri-transplant therapeutic protocol, long-term VCA survival was achieved (>100 days, p<0.01). We tested whether this long-term graft survival was donor specific tolerance or not by challenging recipients with third party (C3H) cardiac allografts. Surprisingly, long-surviving VCA recipients did not reject the third-party cardiac allografts, but instead rejected the original VCA tissues. Analysis of blood samples within the early post-Tx period showed almost equal effectiveness of CD154/DST and CD154/DST/RPM protocols at inhibiting T cell alloresponses, with the exception that T cell proliferation (Ki-67+) was higher in recipients that did not receive RPM therapy. To test whether RPM impaired tolerance induction by CD154/DST to non-VCA samples, we transplanted BALB/c cardiac allografts into C57BL/6 recipients and treated the recipients with either CD154/DST alone, or with RPM. One month later, the recipients were challenged with third party (C3H) hearts. As anticipated, recipients treated with CD154/DST rejected the third-party C3H allografts but maintained their original BALB/c allografts. However, recipients treated with CD154/DST plus RPM did not reject their third-party allografts or their original cardiac allografts. Hence, RPM erases the fundamental tolerogenicity of CD154/DST therapy. In the case of VCA, peri-transplant RPM therapy dampened immune function to a useful extent, facilitating long-term VCA survival, but the rejection of VCA tissues as a result of third party cardiac allografting suggests the incomplete regulation of host alloresponses by Treg or other cells in the face of ongoing expression of skin-associated antigens (and is consistent with some clinical VCA data). We have previously shown that calcineurin inhibitor therapy completely abrogates the benefits of CD154/DST in allograft models. Taken together with the current data, immunosuppressive agents may be able to promote VCA long-term survival but cannot induce tolerance, and host alloresponses are decreased but by no means absent long-term.

CITATION INFORMATION: Wang L, Wang Z, Han R, Bhatti T, Levin L, Levine M, Hancock W. Rapamycin (RPM) Synergizes with CD154 mAb and DST to Promote Long-Term Vascularized Composite Allograft (VCA) Survival, but Prevents Induction of Donor-Specific Tolerance. Am J Transplant. 2016;16 (suppl 3).

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