Selective blockade of IL-15 by soluble IL-15 receptor alpha-chain enhances cardiac allograft survival.
IL-15 is a T cell growth factor that shares many functional similarities with IL-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-15Ralpha) to CBA/Ca (H-2k) recipients for 10 days completely prevented rejection of minor histocompatibility complex-mismatched B10.BR (H-2k) 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 CBA/Ca recipients with sIL-15Ralpha alone had only a modest effect on the survival of fully MHC-mismatched BALB/c (H-2d) heart grafts. However, administration of sIL-15Ralpha 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.
Smith
X G
XG
Department of Surgery, University of Cambridge, Cambridge, United Kingdom.
Bolton
E M
EM
Ruchatz
H
H
Wei
X
X
Liew
F Y
FY
Bradley
J A
JA
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic; D006082:Graft Enhancement, Immunologic / Q000379:methods; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D007274:Injections, Intraperitoneal; D019409:Interleukin-15 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007518:Isoantibodies / Q000096:biosynthesis / Q000097:blood; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000008:administration & dosage* / Q000502:physiology*; D012995:Solubility; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014184:Transplantation, Homologous
D016207:Cytokines; C508025:Il15ra protein, mouse; D019409:Interleukin-15; D007518:Isoantibodies; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2