Abstract
IL-21 is the most recently discovered common gamma-chain cytokine that promotes persistent T-cell responses in chronic infections, autoimmunity and cancer. However, the therapeutic potential of inhibiting the IL-21-BATF signaling axis, particularly in transplant rejection, remains unclear. We used heart transplant models to examine the effects of IL-21 blockade in prevention of chronic cardiac allograft vasculopathy (CAV) using genetic knock-out and therapeutic approaches. Both wild-type C57BL/6 and IL-21-/- strains acutely rejected Balb/c skin grafts and once immunized with this skin graft, rejected Balb/c heart allografts in an accelerated fashion. However, when transplanted with heart grafts from the class-II major histocompatibility complex mutant, B6bm12 mice; wild-type recipients developed CAV, while IL-21-/- recipients were protected, even at day 100 post-transplant. Similarly, BATF-/- recipients, lacking the transcription factor BATF responsible for IL-21 production, did not develop CAV in B6-bm12 heart allografts. Strikingly, in a transient treatment protocol, the development of CAV in wild-type recipients of B6-bm12 hearts allografts was blocked by the administration of IL-21 receptor fusion protein (R-Fc). Thus, we demonstrate that CAV is regulated at least in part by IL-21 signaling and its blockade by genetic approaches or therapy with IL-21R-Fc prevents CAV in mice.
Highlights
While advances in immunosuppressive therapies and donor selection through immunological pre-testing have greatly improved the survival of heart transplants, their long-term survival remains a challenge
An accelerated rejection model showed no difference in the survival of BALB/c heart transplants grafted to Wild-type C57BL/6J (WT) or IL-21-/- mice after pre-sensitization with BALB/c skin allografts (Fig 1B)
Our results demonstrate that IL-21 is critical for the development of chronic cardiac allograft vasculopathy (CAV) but dispensable in the setting of acute and accelerated rejection of skin and cardiac allografts
Summary
While advances in immunosuppressive therapies and donor selection through immunological pre-testing have greatly improved the survival of heart transplants, their long-term survival remains a challenge. Long-term survival is especially hindered by the process of cardiac allograft vasculopathy (CAV), which is a slowly progressing occlusion of the coronary arteries beginning immediately after transplantation[1]. Human heart transplants develop CAV relatively quickly producing fatal graft failure within 1–2 years post-transplant. CAV develops slowly contributing to the eventual graft failure often years after transplantation [2]. Since CAV development in heart transplants is responsible for up to 30% of deaths by 5-years post-transplant, finding an effective therapy should be a priority in heart transplantation research[6]
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