Enhanced Costimulation Blockade With αCD154, αCD2, and αCD28 to Promote Heart Allograft Tolerance in Nonhuman Primates

Long-term renal allograft acceptance has been achieved in macaques using a transient mixed hematopoetic chimerism protocol, but similar regimens have proven unsuccessful in heart allograft recipients unless a kidney transplant was performed simultaneously. Here, we test whether a modified protocol based on targeting CD154, CD2, and CD28 is sufficient to prolong heart allograft acceptance or promote the expansion of regulatory T cells. Eight macaques underwent heterotopic allo-heart transplantation from major histocompatibility complex-mismatched donors. Induction treatment for donor bone marrow transplantation (BMT) was administered after a 4-mo delay period under TNX-1500 monotherapy. The BMT induction regimen comprised 1 (group 1, G1; n = 3) or 2 (group 2, G2; n = 5) doses of total body irradiation, thymic irradiation, and antithymocyte globulin, followed by 2 (G1) or 5 (G2) weekly doses of αCD2 and 5 weekly treatments with αCD28 and TNX-1500. During the delay period, 1 G1 graft was rejected and 2 (1 in each group) exhibited moderate rejection on protocol biopsy before BMT. Lymphocyte chimerism was seen in 3 of 5 G2 animals and in 1 of 2 G1 recipients. One G1 graft was rejected despite chimerism, whereas the other recipient succumbed to anti-cytomegalovirus treatment. Two G2 monkeys succumbed due to infection (cytomegalovirus, bacteremia) post-BMT and 3 due to posttransplantation lymphoproliferative disease. Intensive costimulation pathway blockade with αCD2, αCD154, and αCD28 promotes lymphocyte chimerism at the cost of high incidence of posttransplantation lymphoproliferative disease and opportunistic infections, preventing assessment of the effectiveness of the regimen to promote alloimmune tolerance.