Higher Frequency of Host Cd8+ Memory T Cells Correlates with Failure to Achieve Heart Allograft Tolerance via Mixed Chimerism and Il-6 Blockade in Multiparous Female Non-Human Primates.

Memory T cells (T mems) represent a major barrier to allograft tolerance in clinical transplantation. Alloreactive T mems form in response to MHC alloantigen exposure from prior transplant, blood transfusion or pregnancy. Here we investigated the ability to achieve cardiac allograft tolerance in multiparous female non-human primates (NHPs) using IL-6 blockade and mixed chimerism. Eight NHPs (Group A (n=6): male recipients; Group B (n=2): multiparous female recipients) underwent heart and donor bone marrow transplantation with non-myeloablative conditioning including total body and thymic irradiation, ATGAM, aCD154 mAb, cyclosporine, and aIL-6R mAb (tocilizumab, 10 mg/kg IV x7) through day 84 post-transplant (pTx). NHPs were then monitored off immunosuppression. In Group A, 4/6 recipients had >400 days allograft survival pTx; 2 failed from rejection (169, 383 days pTx) [Table]. In Group B, 2/2 failed from rejection by 200 days pTx. Group A had substantially lower CD8+ pre-Tx circulating T mems than Group B [Figure], including the 2 Group A rejectors. Group A had similar magnitude but longer duration of lymphocyte chimerism (median 4.9%, 180 days pTx) than Group B (median 5.3%, 90 days pTx). Mixed chimerism failed to achieve cardiac allograft tolerance in multiparous female NHPs using a protocol successful in males, presumably due to higher pre-transplant host T mem burden. This suggests the need for additional therapy for successful clinical application of this tolerance protocol in specific patient populations. [ABSTRACT FROM AUTHOR]