T-cell-mediated rejection is likely to present a significant barrier to porcine islet xenotransplantation. Little is known, however, about human anti-porcine islet rejection because no suitable model exists to study this process. To address this problem, we have developed an immunodeficient mouse model to study rejection of fetal porcine islet cell clusters (ICCs) by human lymphocytes. Transplantation of porcine ICCs into hyperglycemic recombinase activating gene-deficient (R-) mice restores normal blood glucose levels within 5 weeks. Adoptive transfer of in vitro-stimulated human peripheral blood mononuclear cells into R- mice before islet cell transplantation leads to acute cellular rejection of porcine ICCs. The first human cells observed to infiltrate rejecting grafts are CD4+ T-cells. Although CD8+ T-cells are observed within the grafts at later time points, CD4+ T-cells predominate until the graft is destroyed. Adoptive transfer of purified human CD4+ T-cells before ICC transplantation is sufficient to cause acute cellular rejection. These data demonstrate that human CD4+ T-cells play a critical role in porcine ICC xenograft rejection.

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