Antigen-specific cytotoxic T cells mediate human fetal pancreas allograft rejection in SCID-hu mice

Human allograft rejection was studied in SCID mice transplanted with human fetal liver and thymus tissue (SCID-hu mice), These SCID-hu mice have functional, mature T cells with a polyclonal TCR repertoire. Within 12 to 36 wk after construction, SCID-hu mice were transplanted with an HLA-mismatched human fetal pancreas, In contrast to control SCID mice transplanted with pancreas alone, cellular infiltration, induction of HLA-DR on pancreatic epithelial cells, and tissue destruction of the allogenic pancreata were observed in SCID-hu mice, In addition, human insulin was not detected in the serum of SCID-hu mice in which pancreas rejection occurred. The infiltrating cells were mainly human CD3(+) T lymphocytes of thymic origin, expressing the CD45RO isoform, T cell lines and CD4(+) T cell clones obtained from the rejected tissues proliferated vigorously when stimulated with EBV-transformed B cell lines of pancreas donor origin. Furthermore, the majority of these CD4(+) T cell clones displayed strong allospecific cytotoxicity, In addition, CD8(+) T cell clones cytotoxic for EBV-transformed B tell lines of pancreas donors were isolated. Blocking experiments with anti-HLA mAbs and panel studies with HLA-matched cell lines showed that these CD4(+) and CD8(+) T cell clones were specific for the HLA class II and class I molecules, respectively, expressed by the pancreas donor, These data indicate that human T lymphocytes developing in SCID-hu mice are able to mount in vivo responses against allogenic organs, resulting in tissue infiltration and rejection, In addition, they show that both CD4(+)- and CD8(+)-allospecific CTL can be isolated from rejected allogenic pancreata.