Preclinical assessment of the immunosuppressive properties of an anti-CD4 monoclonal antibody (MAB) in an allogeneic foetal rat pancreatic transplantation model

[摘要] ENGLISH ABSTRACT:IntroductionDespite advances in insulin therapy, the side effects associated with diabetes mellitus stillremain. Pancreas transplantation has benefited diabetics with end-stage renal failure byreversing the diabetic state and preventing or reversing the progression of diabetes associateddiseases. Currently the side effects associated with lifelong immunosuppression precludepancreas transplantation as a viable treatment option for both type I and II diabetics.In the laboratory, transplanted rat foetal pancreata have been shown to be able to reverse theclinical signs of streptozotocin-induced diabetes in an isogeneic model. Reversal of diabetesby allogeneic foetal rat pancreas transplantation, although possible has proved to be moredifficult due to fierce rejection of the grafts and the diabetogenic effects of conventionalimmunosuppressants.AimsOne of the goals, focus and intentions of this laboratory study in rodents, is to contribute newinformation to the scientific literature. The potential to 'reverse the diabetic state byallogeneic foetal pancreatic transplantation, was the main stimulus for this study.MethodsFoetal pancreata of 16-18 days gestation were transplanted into a surgically prepared renalsubcapsular space. Immunosuppressive protocols used to prevent rejection of the allogeneicfoetal rat pancreata included donor specific transfusion (DST), cyclosporine [a calcineurininhibitor (CsA)], mycophenolate mofetil [a purine syntase inhibitor (MMF)], and a mouseanti-rat CD4 monoclonal antibody (W3/25). Immunosuppressants were used asmonotherapies and in combination. ResultsIsogeneic foetal rat pancreas transplantation resulted in the growth and development ofmature insulin producing islets of Langerhans at the site of engraftment. Allogeneic foetalpancreatic transplantation without immunosuppression resulted in complete rejection of thegrafts at 14 days post-transplantation.Histological assessment of allografts at 14 and 30 days post-transplantation showed that CsAwas able to prevent acute rejection in our rat models although graft scores and survival wereimproved if CsA was combined with MMF. Intraperitoneal anti-CD4 monoclonal injectionswere well tolerated, and if given daily effectively prolonged graft survival up to 30 days.Combining DST with anti-CD4 and CsA induction therapy provided long-term graft survivalwithout daily immunosuppression. This combination, together with allogeneic foetal ratpancreas transplantation, was effective in reversing the clinical signs of experimentallyinduced diabetes. To my knowledge these are the first published results in which reversal ofstreptozotocin induced diabetes was achieved by fully MHC mismatched foetal rat pancreatictransplantation.ConclusionFoetal rat pancreatic transplantation is a potential source of endocrine replacement, which,with effective immunosuppression allows for the development of functional islets able toreverse the clinical signs of experimentally induced diabetes in an allogeneic rat model. Anunique immunosuppressive protocol, with potential clinical relevance in the human,combines anti-CD4 mAb, CsA and DST induction therapy, which alleviates the burden ofdaily immunosuppression and associated side effects.

[发布机构] Stellenbosch University