Down-regulation of xenophile antibodies by 15-deoxyspergualin in an experimental animal model.

THE SUCCESS of clinical allogeneic organ transplantation has led to a shortage of human organ donors. A solution to this increasing problem is the use of donor organs from outside the human species; Since nonhuman primates are not available in sufficient numbers, are too expensive to breed and keep, and their use is limited by ethical concern, they are very unlikely candidates for xenotransplantation. Animals that are readily available in sufficient numbers, however, are cattle and pigs. Although it is a discordant donor species, the pig has been used as a donor species in initial clinical trials of fetal pancreatic islet transplantation. 1 Successful clinical xenotransplaritation is limited not least by pre-existing natural antibodies (NXA) in the serum of the human recipient and by xenophile antibodies (XA) , which are induced by the porcine xenograft. The solution to these humoral problems requires a threefold experimental approach: (a) a careful antibody analysis in the potential xenograft recipient; (b) the elimination of NXA from the recipient's serum before transplantation; and (c) the down-regulation of xenosensitizatiori-dependent XA. This report continues and extends previous attempts from our laboratory to analyze and down-regulate these antibodies. 2-4 It deals with the manipulation of xenophile antibodies in the experimental model "rat-antihuman" using 15-deoxyspergualin (I5-DOS) and compares the effects with those obtained with leflunomide (LF) and cyclophosphamide (CY). 15-DOS was chosen for this study because there were preliminary reports indicating its efficacy also on B-Iymphocyte reactivity5 after our laboratory, among others, had shown that 15-DOS was not only well-tolerated, but was highly efficient in suppressing cell-mediated alloreactivity in the rat. 6