Xenografts of porcine islets immunoprotected in hollow fibres reduce the incidence of diabetes in non-obese diabetic mice.
Non-obese diabetic (NOD) mice develop an autoimmune disease with a long prodromal period and constitute a model for investigating the prevention of human insulin-dependent diabetes mellitus. Since insulin injected prophylactically has been shown to reduce incidence of diabetes in NOD mice, we tested a new strategy consisting of prophylactic xenografts of porcine pancreatic islets immunoprotected in semipermeable hollow fibres. Female NOD mice were transplanted twice (at 60 and 180 days of age) with islet-containing or empty fibres. Within the group grafted 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 severity 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 perifusion studies of fibres retrieved from recipients confirmed immunoprotection. During co-transfer, T splenocytes from mice grafted with islet-containing fibres were able to reduce the capacity of T cells from diabetic donors to adoptively transfer the disease (p < 0.01). Antigens for islet-cell autoantibodies (ICA) in pancreata from both groups were compared by immunofluorescence with the same ICA-positive human sera to ensure that differences were due to antigen quantitative changes. These antigens, which could serve as an index of a possibly more extensive antigen beta-cell rest, were decreased (p < 0.01) in mice grafted with protected islets. Reduction of diabetes and insulitis following early islet transplantation may thus be due to generation of cellular mechanisms that actively suppress disease, and possibly in part to a decrease in antigens which make beta cells less vulnerable to autoimmune aggression. These effects can be obtained with xenogeneic islets protected in hollow fibres, thereby eliminating the need for immunosuppression. Based on the concept of prophylactic insulin therapy, this form of insulin administration offers a controlled means of delivering insulin to meet the physiological needs of recipients.
Chaillous
L
L
Laboratory of Cellular and Molecular Immuno-Endocrinology associated with INRA/ENVN, University School of Medicine, Nantes, France.
Darquy
S
S
Maugendre
S
S
Rivereau
A S
AS
Reach
G
G
Saï
P
P
D000375:Aging; D000818:Animals; D000941:Antigens / Q000032:analysis; D001323:Autoantibodies / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000503:physiopathology / Q000517:prevention & control*; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive; D015994:Incidence; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000276:immunology; D016381:Islets of Langerhans Transplantation / Q000379:methods / Q000502:physiology*; D017710:Lymphocyte Transfusion; D051379:Mice; D016688:Mice, Inbred NOD; D013552:Swine; D013601:T-Lymphocytes; D013997:Time Factors; D014183:Transplantation, Heterologous / Q000379:methods / Q000502:physiology*
D000941:Antigens; D001323:Autoantibodies; D001786:Blood Glucose; D007328:Insulin; C024211:islet cell antibody