BACKGROUND: IL-21 is a cytokine expressed almost exclusively by cells of the adaptive immune system. This makes it an attractive target for reducing chronic allograft rejection while avoiding innate immune side effects. Our work has shown that IL-21 signaling is critical for maintaining T-cell survival under IL-2 deprivation conditions as well as in sustaining autoimmune responses to islets and cardiac allografts. METHODS: We performed heart transplants in IL21-/-, BATF-/-, and wild-type B6 mouse recipients with or without transient therapy with an IL-21 receptor fusion protein (IL21R.Fc). RESULTS: Donor class-II mismatched Bm12 heart allografts were protected from chronic rejection in IL21-/- mice (>100 days) but not in control B6 mice (56.3 ± 22.9 days; p<0.001). In contrast, both IL21-/- and B6 mice acutely rejected fully mismatched Balb/c cardiac allografts (<10 days). The central role of IL-21 signaling in chronic rejection was also seen in BATF-/- mice (>100 days), which lack this regulator of IL-21 production, and in IL21R.Fc treated B6 recipients of Bm12 heart allografts (>100 days). The figure below shows the overall impact of these components of the IL-21 signaling pathway with respect to heart allograft survival. These data indicating protection from chronic rejection were further confirmed by significant reductions in graft arterial disease (GAD) scores and decreased vasculopathy. Allografts in IL21-/- mice develop significantly fewer tertiary lymphoid organs (TLOs) than do allografts in control B6 mice. Furthermore, the presence of IL-21 or its signaling components influenced the architecture of TLOs with respect to size and composition. CONCLUSION: In summary, IL-21 signaling promotes T cell survival in chronic allograft rejection and regulates the creation and maintenance of TLOs within the allograft tissue.

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