Introduction: Tolerance induction for xenogeneic islet transplant remains a challenge. We have previously shown that peri-transplant infusion of donor cells treated with 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide (ECDI) is effective in inducing long-term allograft protection. The current study tested the efficacy and mechanisms of this therapy in discordant xenogeneic islet transplantation.

Method: ECDI-treated porcine splenocytes (SP) were infused to B6 mice at day -7, +1. 3,000 IEQ of porcine islets were transplanted in B6 mice on day 0.

Results: In this model, we found that donor-stimulated IL-17 production played a prominent role in the early rejection of porcine islets. The anti-donor IL-17 response was induced by both direct and indirect stimulation, and was seen in both CD4 and CD8 compartments. Recipient treatment with donor porcine ECDI-SP significantly reduced anti-donor IL-17, however by itself did not provide significant protection (MST = 12 days). Interestingly, rejecting porcine islet xenografts were heavily infiltrated with B220⁺ B cells, and transient depletion of B cells extended islet xenograft survival (MST = 45 days). When we further added a short course of rapamycin (1mg/kg, day -8 to +10), the resulting triple therapy led to long-term (> 100 days) graft survival in ~65% recipients. The protection provided by the triple therapy correlated with sustained inhibition of anti-donor IL-17 response. However, recipients with islet xenograft survival >100 days experienced late rejection between 100 – 200 days. The late rejection coincided with the emergence of robust anti-donor IFN-γ response and extensive B cell infiltration in the graft, although a complete absence of anti-xenogeneic antibodies.

Conclusions: Early rejection of discordant islet xenografts is predominantly driven by anti-donor IL-17 response, whereas late rejection in triple therapy treated recipients is driven predominantly by anti-donor IFN-γ response and possibly graft-infiltrating B cells exerting a direct graft effect beyond their capacity in xenogeneic antibody production.

CITATION INFORMATION: Kang H, Wang S, Zhang X, Singh A, Zhang L, Suarez-Pinzon W, Miller S, Hering B, Luo X. Long-Term Islet Xenograft Survival Requires Effective Control of Early Xenogeneic IL-17 Response and Late Xenogeneic IFN-γ Response. Am J Transplant. 2016;16 (suppl 3).

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