Selective blockade of IL-15 by soluble IL-15 receptor α-chain enhances cardiac allograft survival

IL-15 is a T cell growth factor that shares many functional similarities with 1L-2 and has recently been shown to be present in tissue and organ allografts, leading to speculation that IL-15 may contribute to graft rejection. Here, we report on the in vivo use of an IL-15 antagonist, a soluble fragment of the murine IL-15R alpha -chain, to investigate the contribution of IL-15 to the rejection of fully vascularized cardiac allografts in a mouse experimental model. Administration of soluble fragment of the murine IL-15R alpha -chain (sIL-15R alpha) to CBA/Ca (H-2(k)) recipients for 10 days completely prevented rejection of minor histocompatibility complex-mismatched BIO,BR (H-2(k)) heart grafts (median survival time (MST) of >100 days vs MST of 10 days for control recipients) and led to a state of donor-specific immunologic tolerance. Treatment of CPA/Ca recipients with sIL-15R alpha alone had only a modest effect on the survival of fully MHC-mismatched BALB/c (H-2(d)) heart grafts. However, administration of sIL-15R alpha together with a single dose of a nondepleting anti-CD4 mAb (YTS 177.9) delayed mononuclear cell infiltration of the grafts and markedly prolonged graft survival (MST of 60 days vs MST of 20 days for treatment with anti-CD4 alone). Prolonged graft survival was accompanied in vitro by reduced proliferation and IFN gamma production by spleen cells, whereas CTL and alloantibody levels were similar to those in animals given anti-CD4 mAb alone. These findings demonstrate that IL-15 plays an important role in the rejection of a vascularized organ allograft and that antagonists to IL-15 may be of therapeutic value in preventing allograft rejection.