T-CELLS IN ISLET-LIKE CELL CLUSTER XENOGRAFT REJECTION - A STUDY IN THE PIG-TO-MOUSE MODEL

Background. The aim of the present study was to evaluate the nature of T cells involved in and, presumably, critical to fetal porcine islet- like cell cluster (ICC) xenograft rejection, Methods. Normal mice and T cell receptor (TCR)-beta-, TCR-delta-, or TCR-beta x delta-deficient mice were transplanted with fetal porcine ICC under the kidney capsul e. Perforin- or granzyme B (GraB)-deficient mice were used to further characterize T cell-dependent pathways, For evaluation of the role of T cells in the activation process of macrophages, TCR-beta x delta mut ants were treated with recombinant mouse tumor necrosis factor (TNF)-a lpha. In addition, normal mice transplanted with porcine ICC were trea ted with MDL 201,449A, a novel transcriptional inhibitor of TNF-alpha, Results. In normal mice, the majority of the infiltrating cells were large, macrophage-like cells expressing the macrophage specific phenot ype marker F4/80, CD3(+) T lymphocytes were found to be mainly accumul ated in the peripheral parts of the ICC xenograft, TCR-beta mutants an d TCR-beta x delta mutants exhibited no signs of xenograft rejection, whereas TCR-delta mutants and perforin- and GraB-deficient animals rej ected the ICC xenograft. Posttransplant high-dose recombinant mouse TN F-alpha-treatment of TCR-beta x delta mutants did not result in fetal porcine ICC xenograft rejection. However, a somewhat increased amount of F4/80(+) and Mac-1(+) cells was observed within the xenograft area. Similarly, although graft survival was not found to be prolonged, red uced numbers of CD4(+) T cells were observed in mice treated with MDL 201,449A, Conclusions, In the pig-to-mouse model, fetal porcine ICC xe nograft rejection is exclusively dependent on T cells bearing TCR-alph a beta chains. In addition, the absence of perforin or GraB has no inf luence on the rejection process, suggesting that xenospecific cytolyti c T cells are of minor importance, Even if TNF-alpha is of importance to the developing process of ICC xenograft rejection, other cytokines, i.e., interferon-gamma, might efficiently substitute for the lack of TNF-alpha.