Rat xenograft survival in mice treated with donor-specific transfusion andanti-CD154 antibody is enhanced by elimination of host CD4(+) cells

Background. Treatment with a donor-specific transfusion (DST) and a brief c ourse of anti-mouse CD154 (anti-CD40-ligand) monoclonal antibody (mAb) prol ongs the survival of both allografts and rat xenografts in mice. The mechan ism by which allograft survival is prolonged is incompletely understood, bu t depends in part on the presence of CD4(+) cells and the deletion of allor eactive CD8(+) T cells. Less is known about the mechanism by which this pro tocol prolongs xenograft survival, Methods. We measured rat islet and skin xenograft survival in euthymic and thymectomized mice treated with combinations of DST, anti-CD154 mAb, anti-C D4 mAb, and anti-CD8 mAb, Recipients included C57BL/6, C57BL/6-scid, C57BL/ 6-CD4(null), and C57BL/6-CD8(null) mice. Results, Pretreatment with a depleting anti-CD4 mAb markedly prolonged the survival of both skin and islet xenografts in mice given DST plus anti-CD15 4 mAb, Comparable prolongation of xenograft survival was obtained in C57BL/ 6-CD4(null) recipients treated with DST and anti-CD154 mAb, In contrast, an ti-CD8 mAb did not prolong the survival of either islet or skin xenografts in mice treated with DST and anti-CD154 mAb, Thymectomy did not influence x enograft survival in any treatment group. Adoptive transfer of splenocytes from C57BL/6-CD4(null) recipients treated with DST and anti-CD154 mAb and b earing long-term skin xenografts revealed the presence of residual xenoreac tive cells. Conclusions. These data suggest that treatment with DST and anti-CD154 mAb induces a state of "functional" transplantation tolerance. They also suppor t the hypothesis that both the induction and maintenance of graft survival based on this protocol depend on different cellular mechanisms in allogenei c and xenogeneic model systems.