A critical role for human CD4(+) T-cells in rejection of porcine islet cell xenografts

T-cell-mediated rejection is likely to present a significant barrier to por cine islet xenotransplantation. Little is known, however, about human anti- porcine islet rejection because no suitable model exists to study this proc ess. To address this problem, we have developed an immunodeficient mouse mo del to study rejection of fetal porcine islet cell clusters (ICCs) by human lymphocytes. Transplantation of porcine ICCs into hyperglycemic recombinas e activating gene-deficient (R-) mice restores normal blood glucose levels within 5 weeks. Adoptive transfer of in vitro-stimulated human peripheral b lood mononuclear cells into R- mice before islet cell transplantation leads to acute cellular rejection of porcine ICCs, The first human cells observe d to infiltrate rejecting grafts are CD4(+) T-cells, Although CD8(+) T-cell s are observed within the grafts at later time points, CD4(+) T-cells predo minate until the graft is destroyed. Adoptive transfer of purified human CD 4(+) T-cells before ICC transplantation is sufficient to cause acute cellul ar rejection. These data demonstrate that human CD4(+) T-cells play a criti cal role in porcine ICC xenograft rejection.