Xenograft Rejection : A Study of Cytokine mRNA Expression in Experimental Models

Abstract: Acute cellular xenograft rejection of ICCs triggered mRNA expression of proinflammatory cytokines (IL-1b and TNF-a), Th1 associated cytokines (IL-12p40, IL-2 and IFN-g) and Th2 associated cytokines (IL-4 and IL-10). The peak values and the kinetics of the mRNA expression indicated that acute cellular xenograft rejection is enhanced by the proinflammatory response and mediated by the Th1 associated response, whereas the function of the Th2 associated response most likely is to counteract the Th1 associated cytokines and thereby inhibit bystander damage by the delayed type hypersensitivity like rejection process. Tacrolimus was shown to have a protective effect on the ICC xenografts, which was linked with inhibition of Th1 associated cytokines. This beneficial effect was paradoxically abrogated by prednisolone. The cytokines were interpreted to mediate the same response during cellular rejection of vascularized xenografts in the mouse-to-rat heart transplant model as in the non vascularized ICC model, even though the the response includes intragraft antibody deposits. Also the xenogeneic neural grafts implanted into the CNS displayed a similar cytokine response, but this process was slower and had less distinguished peak values compared to the ICC xenografts.The shortage of organs is the major limitation for clinical allotransplantation. For making clinical xenotransplantation possible and thereby eliminate the organ shortage, issues regarding ethical dilemmas, microbiological hazards, physiological incompatibilities and immunological problems need to be addressed. The aim of the studies in this thesis was to investigate the mechanisms behind acute cellular xenograft rejection. The immunological response, with a focus on the cytokine mRNA expression, was analysed at different time points in rats transplanted with fetal porcine islet like cell clusters (ICCs), mouse hearts, or syngeneic, allogeneic, concordant or discordant xenogeneic neural tissue grafts.In conclusion, both the cytokine mRNA expression and the morphology of acute cellular xenograft rejection bear a close resemblance to a delayed type hypersensitivity reaction, primarily mediated by indirect antigen presentation. This might explain why clinically used immunosuppressive protocols normally are inefficient for use in xenotransplantation, since these are presumed to primarily suppress T cell response triggered direct antigen presentation, which dominates during allogeneic acute rejection.