XENOGRAFTS OF PORCINE ISLETS IMMUNOPROTECTED IN HOLLOW FIBERS REDUCE THE INCIDENCE OF DIABETES IN NONOBESE DIABETIC MICE

Non-obese diabetic (NOD) mice develop an autoimmune disease with a lon g prodromal period and constitute a model for investigating the preven tion of human insulin-dependent diabetes mellitus. Since insulin injec ted prophylactically has been shown to reduce incidence of diabetes in NOD mice, we tested a new strategy consisting of prophylactic xenogra fts of porcine pancreatic islets immunoprotected in semipermeable holl ow fibres. Female NOD mice were transplanted twice (at 60 and 180 days of age) with islet-containing or empty fibres. Within the group graft ed with protected islets, the incidence of diabetes was reduced (37 vs 75%;p < 0.01), the onset of disease was delayed (p < 0.02), and the s everity of lymphocytic inflammation of endogenous islets was reduced ( p < 0.02). When already diabetic mice were not taken into account for analysis, blood glucose level was slightly lower in those grafted with islet-containing fibres (p < 0.04). Graft function was also evidenced by HPLC separation of porcine insulin in NOD sera. Histological and p erifusion studies of fibres retrieved from recipients confirmed immuno protection. During co-transfer, T splenocytes from mice grafted with i slet-containing fibres were able to reduce the capacity of T cells fro m diabetic donors to adoptively transfer the disease (p < 0.01). Antig ens for islet-cell autoantibodies (ICA) in pancreata from both groups were compared by immunofluorescence with the same ICA-positive human s era to ensure that differences were due to antigen quantitative change s. These antigens, which could serve as an index of a possibly more ex tensive antigen beta-cell rest, were decreased (p < 0.01) in mice graf ted with protected islets. Reduction of diabetes and insulitis followi ng early islet transplantation may thus be due to generation of cellul ar mechanisms that actively suppress disease, and possibly in part to a decrease in antigens which make beta cells less vulnerable to autoim mune aggression. These effects can be obtained with xenogeneic islets protected in hollow fibres, thereby eliminating the need for immunosup pression. Based on the concept of prophylactic insulin therapy, this f orm of insulin administration offers a controlled means of delivering insulin to meet the physiological needs of recipients.