Selective blockade of IL-15 by soluble IL-15 receptor alpha-chain enhancescardiac allograft survival

IL-15 is a T cell growth factor that shares many functional similarities wi th 1L-2 and has recently been shown to be present in tissue and organ allog rafts, 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 fragm ent of the murine IL-15R alpha -chain, to investigate the contribution of I L-15 to the rejection of fully vascularized cardiac allografts in a mouse e xperimental 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 comp letely prevented rejection of minor histocompatibility complex-mismatched B IO,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 im munologic tolerance. Treatment of CPA/Ca recipients with sIL-15R alpha alon e 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 wit h a single dose of a nondepleting anti-CD4 mAb (YTS 177.9) delayed mononucl ear 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). Prolon ged graft survival was accompanied in vitro by reduced proliferation and IF N gamma production by spleen cells, whereas CTL and alloantibody levels wer e similar to those in animals given anti-CD4 mAb alone. These findings demo nstrate that IL-15 plays an important role in the rejection of a vasculariz ed organ allograft and that antagonists to IL-15 may be of therapeutic valu e in preventing allograft rejection.