Xenograft rejection of fetal porcine islet-like cell clusters in the rat: effects of active and passive immunization

The process of islet xenograft rejection is still poorly understood. To elu cidate further possible mechanism(s) involved in xenograft rejection, the e ffect of different immunization protocols was investigated. Fetal porcine i slet-like cell clusters (ICCs) were transplanted under the kidney capsule i n otherwise untreated rats, rats pre-immunized by s.c. injections of ICCs a nd in rats passively immunized with immune serum. The rejection process was evaluated with regard to antibody and complement deposition in the graft, as well as to morphology and phenotype of the infiltrating cells. In otherw ise untreated animals, a moderate perigraft mononuclear cell infiltrate was seen after 3 days. Graft destruction became evident on day 6 with marked i ntragraft infiltration by macrophages (ED1 positive), whereas T cells were in the minority and mainly located in the perigraft area. In contrast to th e findings in nonimmunized rats, the rejection process in pre-immunized rat s was characterized by marked intragraft infiltration by macrophages 3 days after transplantation. Moreover, both T cells and macrophages heavily infi ltrated the adjacent kidney parenchyma, and major histocompatibility comple x (MHC) class II expression in surrounding kidney tubular cells was concomi tantly enhanced. Syngeneic rat islets mixed with porcine ICCs escaped the r ejection process in nonimmunized rats but were affected in pre-immunized an imals. Thus, the specificity of the rejection process in non-immunized anim als seems to be lost in pre-immunized animals. The early macrophage infiltr ation was also accelerated in rats passively immunized with immune serum, b ut no early switch from perigraft to intragraft infiltration or subsequent cellular infiltration in the adjacent kidney parenchyma was seen. Circulati ng xenoreactive antibodies of the IgG isotype increased after transplantati on in normal and otherwise untreated rats. No distinct IgG deposition in th e ICC xenografts was observed until day 12 after transplantation in untreat ed rats, whereas perigraft deposition of IgG was found 1 day after transpla ntation in pre-immunized rats and in rats given immune serum. No deposition of complement was observed within the ICC xenograft in any of the groups d uring the observation period. The dependence on T cells, the massive infilt ration of macrophages with a unique phenotype, the cellular distribution, a nd the loss of specificity (bystander killing) of the rejection process in immunized rats suggest that ICC xenograft rejection shares some of its main characteristics with a delayed type hypersensitivity-like (DTH) immune res ponse.