The present historical review reports the clinical experiences of transplantations from animal to human. The first transplantation attempts were made without any knowledge of the species barrier. The pioneers of xenotransplantation realized xenotransfusions as early as the 16th century, then cell and tissue xenotransplantations in the 19th century. At the beginning of the 20th century, xenotransplantation of testicles became the latest craze. At the same time, and later in the 1960s, organ xenotransplantations were attempted, with disappointing results. Mathieu Jaboulay, Serge Voronoff, Keith Reemtsma, James Hardy, Denton Cooley, Thomas Starzl, Christiaan Barnard and Leonard Bailey were among the pionneers of xenotransplantation. Recent trials concerned above all tissue and cell xenotransplantations. Nowadays, with encapsulation, transgenesis, and cloning, great advances have been made for controlling xenograft rejection, but ethical questions linked to the risk of infections have become a major pre-occupation within the scientific community and the general population.

When diabetic patients learned about potential infectious risks and other risks associated with immunosuppression, reluctance to undergo xenotransplantation gained in significance or even led to refusal of the procedure.

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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