In conclusion, mouse cell-mediated reaction against xenogeneic adult pig islet cells mainly involves class II-restricted CD4+ T lymphocytes of Th1 and Th2 subtypes, with an indirect pathway for the recognition. Although of low intensity, this cell-mediated reaction constitutes an obstacle to pig islet engraftment in the mouse, although one not necessarily more insurmountable than alloreactivity. The peculiarity of NOD mouse splenocytes, in terms of proliferation against pig islets, suggests that the study of islet xenograft rejection should take the immunogenetic context of diabetes into account, in which case the use of non-diabetes-prone mice has its limitations.

Type I diabetes could be treatable by a graft of pig islets [1]. Rejection of this discordant xenograft remains, however, a major problem. Despite advances in the understanding of hyperacute rejection that have made short-term engraftment of porcine tissue a feasible objective, cell-mediated rejection can occur. This cellular rejection could be a serious problem in the case of islets, which are possibly less susceptible to hyperacute rejection [2,3].In vitro human cellular recognition in the discordant human-pig situation has been mainly investigated with stimulator pig lymphocytes or endothelial cells [4±6], i. e. cells which are not intended to be grafted in diabetes. In terms of the disease which islet grafts are intended to combat, it is thus important to characterise human anti-pig islet response since islets have particularities different to lymphocytes, e. g. they do not constitutively express class II molecules Diabetologia (1999) Summary The intensity and mechanisms of cell-mediated rejection of pig islet cells were studied in 49 Type I diabetic and 34 healthy subjects. Human peripheral mononuclear cells proliferated strongly in response to pig islet cells (p < 0.001), though with notable interindividual variations (stimulation index 2 to 215). The variance of stimulation index was higher in diabetic than healthy subjects (p < 0.0001). The response to islet cells was stronger (p < 0.01) than that to pig splenocytes. Proliferation in response to islet cells was strongly decreased (p < 0.01) when CD 4 + T cells were blocked with monoclonal antibodies, whereas the blocking of CD 8 + cells or NK cells gave less pronounced effects. The response to islet cells was decreased (p < 0.01), but not abolished, after antigen-presenting cells were removed. Purified CD 4 + cells alone did not proliferate in response to islet cells but recovered their proliferative ability when mixed with antigen-presenting cells, whereas CD 8 + cells alone proliferated in the presence of interleukin-2 in response to islet cells. Proliferation was blocked (p < 0.01) by anti-DR monoclonal antibodies. During proliferation in response to islet cells, interleukin-10 increased 43-fold (p < 0.01) but interferon-g increased only slightly. No statistical differences were detected between diabetic and control subjects with respect to lymphocyte subsets and the recognition mechanisms or to interferon-g / interleukin-10 production in response to islet cells. These results provide the first detailed information on human cell-mediated xenoreaction to pig islet cells. This situation involves a dominant CD 4 class II-restricted Th2 response, with an indirect recognition pathway, as well as a CD 8 T-cell response resulting from direct recognition. This strong reaction constitutes a serious obstacle which may vary in degree among subjects. [Diabetologia (1999) 42: 330±335]

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This study provides the first data on in vitro comparison of baboon and human cell-mediated recognition and impairment of PICs. Proliferation of PBMCs against PICs involves mainly CD4 T cells, with indirect recognition mediated by baboon or human MHC class II+ APCs. The Th2/Th1 profile of cytokines secreted in response to PICs was similar in baboon and human PBMCs. The model based on alteration of insulin secretion indicates that PIC impairment by whole mononuclear cells was strong and rapid and that a crucial role was played by MHC class II+ and plastic-adherent cells. Two mechanisms appear to be responsible for the role of these cells: (1) early and strong direct effect, which is potentially involved in vivo in primary nonfunction of islets aggressed by monocytes and macrophages; and (2) presentation of PIC xenoantigens, which leads to impairment by T lymphocytes possibly involved in in vivo-specific cellular rejection. The mechanisms and intensity of baboon cellular reactions to PICs in vitro were similar to those observed in humans, which suggests that the baboon is a suitable model for the study of cellular mechanisms during preclinical trials of pig islet xenografts.