SEVERE COMBINED IMMUNODEFICIENT MICE ENGRAFTED WITH HUMAN SPLENOCYTESHAVE FUNCTIONAL HUMAN T-CELLS AND REJECT HUMAN ALLOGRAFTS

Previous studies have shown that human hemopoietic cells can be adopti vely transferred into immunodeficient C.B-17 scid/scid (SCID) mice tha t lack autologous T and B lymphocytes, to generate chimeric animals. T he future development of novel immunomodulatory drugs in transplantati on will depend increasingly on experimental animal models to investiga te the properties of the agents on human cells before starting clinica l trials. However, in previous models of SCID mice engrafted with huma n PBLs, human T cells have been found either to be in an unresponsive state, unable to respond to mitogenic stimulations in vitro, or to med iate skin graft rejection only when HLA-primed in vivo before their ad optive transfer into SCID mice. In addition, T cells and other leukocy te subsets engraft quite poorly in the lymphoid tissues of the animals . In an attempt to develop a useful model for transplantation research , we have inoculated SCID mice with fresh human splenocytes from cadav eric organ donors (hu-Spl-SCID mice). In this model, various leukocyte subsets engraft effectively in different lymphoid compartments. In ad dition, human T cells retain their proliferative responses to mitogens and to alloantigens when tested 3 wk after engraftment into SCID mice . Finally, mice engrafted with unprimed human spleen cells acutely rej ect human foreskin allografts. Treatment of hu-Spl-SCID mice with OKT3 , an immunosuppressive mAb directed against the human CD3 complex asso ciated with the TCR, prevents the rejection of most human skin allogra fts, indicating a major role for human T cells in this phenomenon. Thu s, this hu-Spl-SCID model may be useful for the study of immunosuppres sive therapies in a preclinical in vivo setting.