DERMAL MICROVASCULAR INJURY IN THE HUMAN PERIPHERAL-BLOOD LYMPHOCYTE RECONSTITUTED SEVERE COMBINED IMMUNODEFICIENT (HUPBL-SCID) MOUSE SKIN ALLOGRAFT MODEL IS T-CELL MEDIATED AND INHIBITED BY A COMBINATION OF CYCLOSPORINE AND RAPAMYCIN/

We hare analyzed the mechanism of human endothelial injury in a human peripheral blood lymphocyte-severe combined immunodeficient (huPBL-SCI D) mouse/human skin graft model of allograft injury and examined the e ffect of immunosuppressive drugs on this process, In this model, split -thickness human skin containing the superficial dermal microvessels w as grafted onto immunodeficient C.B-17 SCID or SCID/beige mice and all owed to heal. Human peripheral blood mononuclear cells (PBMCs) allogen eic to the skin, when subsequently introduced by intraperitoneal injec tion, caused destruction of the human dermal microvasculature by day 1 6, evident as endothelial cell sloughing and thrombosis. In the same s pecimens, mouse microvessels that invaded the human skin graft were un injured. Human microvascular cell. injury was accompanied by a mononuc lear cell. infiltrate consisting of approximately equal numbers of hum an CD4+ and CD8+ T cells, some of which contained perforin-positive gr anules. We found no evidence of human natural killer cells and noted o ccasional human, but not mouse, macrophages at a frequency indistingui shable from that resident in skin on animals not receiving human PBMCs . These human T cell infiltrates did not extend into adjacent mouse sk in, Human immunoglobulin G antibody was detected in the blood and was diffusely present throughout mouse and human tissues in SCID mice rece iving PBMCs. Mouse C3 was detected on human dermal vessels in both unr econstituted control animals and those that received PBMCs. Blood and tissues from mice injected with PBMCs depleted of B cells showed no hu man immunoglobulin, but circulating CD3+ cells were detected by how cy tometry at levels comparable with those of animals receiving whole PBM Cs. Significantly, skin graft infiltration by human T cells and human dermal microvascular injury were equivalent in the B cell-depleted and whole-PBMC-reconstituted mice. Mice inoculated with PBMCs depleted of CD8+ T cells developed microvascular injury and infiltrates containin g perforin-expressing CD4+ T cells. These data suggested a cytolytic T cell-dependent mechanism of microvessel injury. We then tested the ab ility of T cell immunosuppressants, cyclosporine and rapamycin, to att enuate vessel damage.