Human organ rejection in SCID-hu mice

In SCID mice constructed with human fetal liver and thymus (SCID-hu mice) functional mature T cells, with a polyclonal TcR repertoire, develop in the human thymus. Three to six months after construction, these SCID-hu mice were transplanted with HLA mismatched fetal human pancreas or skin. Cellular infiltration and tissue destruction of these human allogeneic tissues were observed by histology. In addition, the human insulin serum levels in mice with rejected pancreas were undetectable, in contrast to control mice. Immunostaining of the rejected tissues showed strong expression of the HLADR antigens and infiltration of human CD3+ T lymphocytes of thymic origin, expressing either CD4 or CDS, and the CD45RO isoform. CD4⁺ and CD8⁺ T cell clones specific for the HLA class II and class I molecules respectively, expressed by the pancreas or skin donors, were obtained from the rejected tissues. The CD8⁺ T cell clones were cytotoxic against the EBV transformed B cell Unes (EBV-LCL) derived from the allotransplanted tissues, whereas a high proportion of the CD4+ T cell clones proliferated vigorously when stimulated with these EBV-LCL. Interestingly, the majority of these CD4+ T cell clones displayed a strong allospecific cytotoxic activity against the EBVLCL derived from the pancreas or skin donors. These data provide evidences that human T lymphocytes maturing in SCID-hu mice are able to mount an in vivo response against allogeneic organs, resulting in tissue infiltration and rejection. Furthermore this model shows that both CD4⁺ and CZ?8⁺ allospecific cytotoxic T lymphocytes contribute to the rejection process.