There is mounting evidence that IL21 may be a specialized cytokine that controls chronic rather than acute immune responses. Herein, we evaluated the role of IL21 in acute and chronic allograft rejection. In our acute and accelerated rejection models, C57BL/6 (B6) or IL21-deficient B6 (IL21-/-) mice were transplanted with Balb/c skin allografts and later with Balb/c heart allografts. To test the role of IL21 in a chronic rejection model, B6 or IL21-/- mice were transplanted with heart grafts from B6.bm12 mice. Both B6 and IL21-/- recipients acutely rejected Balb/c skin allografts with mean survival times (MSTs) of 9 ± 1 days and 9 ± 2 days, respectively (n = 9 per group; p = NS). Similarly, Balb/c skin-sensitized B6 and IL21-/- recipients both exhibited accelerated rejection of Balb/c heart allografts with MSTs of 3.5 ± 0.6 days and 4.5 ± 0.6 days, respectively (n = 4 per group; p = NS). In our model of chronic rejection the heartbeats of the bm12 grafts were graded by a blinded observer from – (no heartbeat) to +4 (strong heartbeat). Although both B6 and IL21-/- recipients of bm12 grafts demonstrated similar grades immediately after transplant (all +2 to +4 ; n = 3 per group), by day 30 the grafts in the B6 recipients had reduced grades (+2, +1, +1) while those in the IL21-/- recipients had stronger grades (+4, +3, +2). By day 60, the bm12 hearts in the B6 mice were rejected (+/-, -, -) and the grafts in the IL21-/- mice maintained strong grades (+3, +3, +2). Gross and histological analysis of the grafts at day 60 demonstrated marked inflammation and changes consistent with chronic allograft vasculopathy (CAV) in the grafts harvested from B6 recipients, while those harvested from IL21-/- recipients showed reduced inflammation and minor indications of CAV. Preliminary results have also demonstrated the efficacy of an IL21 receptor fusion protein (IL21RFc) in treating autoimmune type 1 diabetes, which along with the current results, have encouraged us to explore the use of IL21RFc therapy for treating chronic graft rejection as a future direction. Together these results implicate IL21 as a crucial cytokine for the chronic graft rejection process, but not the acute or accelerated graft rejection processes. These results demonstrate that the IL21 signaling pathway may serve as a putative therapeutic target for interventions that could slow or inhibit the process of chronic allograft injury, which currently has no specific therapeutic options.

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