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T cells in islet-like cell cluster xenograft rejection: a study in the pig-to-mouse model
B Benda1, J O Sandberg, M Holstad
1Department of Oncology, Radiology, and Clinical Immunology, Uppsala University, Sweden. Birgitta.Benda@klinimm.uu.se
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-betaxdelta-deficient mice were transplanted with fetal porcine ICC under the kidney capsule. 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-betaxdelta mutants were treated with recombinant mouse tumor necrosis factor (TNF)-alpha. In addition, normal mice transplanted with porcine ICC were treated 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 phenotype marker F4/80. CD3+ T lymphocytes were found to be mainly accumulated in the peripheral parts of the ICC xenograft. TCR-beta mutants and TCR-betaxdelta mutants exhibited no signs of xenograft rejection, whereas TCR-delta mutants and perforin- and GraB-deficient animals rejected the ICC xenograft. Posttransplant high-dose recombinant mouse TNF-alpha-treatment of TCR-betaxdelta 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, reduced numbers of CD4+ T cells were observed in mice treated with MDL 201,449A.
Conclusions:
In the pig-to-mouse model, fetal porcine ICC xenograft rejection is exclusively dependent on T cells bearing TCR-alphabeta chains. In addition, the absence of perforin or GraB has no influence on the rejection process, suggesting that xenospecific cytolytic 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.