Alpha1-antitrypsin monotherapy prolongs islet allograft survival in mice.
Islet transplantation for type 1 diabetic patients shows promising results with the use of nondiabetogenic immunosuppressive therapy. However, in addition to compromising the immune system of transplant recipients, long-term studies demonstrate that islet viability is impaired. Here, we demonstrate that, in the absence of immunosuppressive agents, monotherapy with clinical-grade human alpha1-antitrypsin (hAAT), the major serum serine-protease inhibitor, prolongs islet graft survival and normoglycemia in transplanted allogeneic diabetic mice, lasting until the development of anti-hAAT antibodies. Compared to untreated or albumin-control-treated graft recipients, which rejected islets at day 10, AAT-treated mice displayed diminished cellular infiltrates and intact intragraft insulin production throughout treatment. Using peritoneal infiltration models, we demonstrate that AAT decreases allogeneic fibroblast-elicited natural-killer-cell influx by 89%, CD3-positive cell influx by 44%, and thioglycolate-elicited neutrophil emigration by 66%. ATT also extended islet viability in mice after streptozotocin-induced beta cell toxicity. In vitro, several islet responses to IL-1beta/IFNgamma stimulation were examined. In the presence of AAT, islets displayed enhanced viability and inducible insulin secretion. Islets also released 36% less nitric oxide and 82% less macrophage inflammatory protein 1 alpha and expressed 63% fewer surface MHC class II molecules. TNFalpha release from IL-1beta/IFNgamma-stimulated islet cells was reduced by 99%, accompanied by an 8-fold increase in the accumulation of membrane TNFalpha on CD45-positive islet cells. In light of the established safety record and the nondiabetogenic potential of AAT, these data suggest that AAT may be beneficial as adjunctive therapy in patients undergoing islet transplantation.
Lewis
Eli C
EC
Department of Medicine, University of Colorado at Denver and Health Sciences Center, Denver, CO 80262, USA.
Shapiro
Leland
L
Bowers
Owen J
OJ
Dinarello
Charles A
CA
D000704:Analysis of Variance; D000818:Animals; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D003922:Diabetes Mellitus, Type 1 / Q000601:surgery*; D005260:Female; D006098:Granulocytes / Q000187:drug effects; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D007694:Killer Cells, Natural / Q000187:drug effects; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009569:Nitric Oxide / Q000378:metabolism; D023001:Transplantation Tolerance / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000494:pharmacology*
D054405:Chemokine CCL3; D054407:Chemokine CCL4; D000949:Histocompatibility Antigens Class II; D007375:Interleukin-1; D019402:Macrophage Inflammatory Proteins; D014409:Tumor Necrosis Factor-alpha; D000515:alpha 1-Antitrypsin; D009569:Nitric Oxide; D007371:Interferon-gamma