Selective Blockade of IL-15 by Soluble IL-15 Receptor α-Chain Enhances Cardiac Allograft Survival

Abstract

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 α-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 α-chain (sIL-15Rα) 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-15Rα alone had only a modest effect on the survival of fully MHC-mismatched BALB/c (H-2d) heart grafts. However, administration of sIL-15Rα 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-γ 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.

Mast Cells Express Novel Functional IL-15 Receptor α Isoforms

“…IL-15 almost equally, clearly demonstrating that deletion of exon 4; exons 3 and 4; and exons 3, 4, and 5 does not affect the essential elements involved in IL-15 binding, such as the sushi domain of IL-15R␣ (47). These data are supported by the work of Anderson et al (41), showing that the exon 3-encoded linker sequence is dispensable for IL-15 binding and signaling.…”

The Sushi Domain of Soluble IL-15 Receptor α Is Essential for Binding IL-15 and Inhibiting Inflammatory and Allogenic Responses In Vitro and In Vivo

“…This finding also suggests that IL-15 is associated with the initiation of chronic allograft rejection process, including the amplification of acquired immunity. This is consistent with our observation that hosts accepting the heart graft, as the results of T1 treatment, were able to mount a normal rejection of a third-party skin graft (21). IL-15 is therefore required as an accessory signal for the full expansion of activated T cells, or alternatively, it acts as a paracrine growth factor for activated T cells.…”

“…The results reported here extend our earlier findings on the anti-inflammatory role of sIL-15␣ in collagen-induced arthritis (20) and the prolongation of allograft survival (21) in the murine models by providing insight into the mechanisms involved. It was previously shown that IL-15 is a growth factor capable of rescuing cells from apoptosis and necrosis, which occur through specific activation or neglect (8,27).…”

“…The finding that a short course of sIL-15R␣ treatment can markedly prolong the survival of allogenic heart graft opens up the possibility that T1 could have a potential therapeutic value in preventing transplantation rejections (21). This finding also suggests that IL-15 is associated with the initiation of chronic allograft rejection process, including the amplification of acquired immunity.…”

“…As part of our investigation into the functional role of IL-15 in rheumatoid arthritis, we have cloned and expressed a soluble fragment of IL-15R␣ and found that this protein profoundly suppressed the development of collagen-induced arthritis in DBA/1 mice (20). More recently, we demonstrated that soluble murine IL-15R␣ (sIL-15R␣) 3 administered for a short period at the beginning of transplantation markedly prolonged the survival of allogenic heart grafts (21). These findings suggest that sIL-15R␣ or its analogs may have considerable therapeutic potential in a wide range of diseases.…”