Combination therapy with sirolimus and interleukin-2 prevents spontaneous and recurrent autoimmune diabetes in NOD mice.
Sirolimus is an immunosuppressant that inhibits interleukin (IL)-2 signaling of T-cell proliferation but not IL-2-induced T-cell apoptosis. Therefore, we hypothesized that administration of IL-2, together with sirolimus, might shift T-cell proliferation to apoptosis and prevent autoimmune destruction of islet beta-cells. We found that sirolimus and IL-2 therapy of female NOD mice, beginning at age 10 weeks, was synergistic in preventing diabetes development, and disease prevention continued for 13 weeks after stopping sirolimus and IL-2 therapy. Similarly, sirolimus and IL-2 were synergistic in protecting syngeneic islet grafts from recurrent autoimmune destruction after transplantation in diabetic NOD mice, and diabetes did not recur after stopping sirolimus and IL-2 combination therapy. Immunocytochemical examination of islet grafts revealed significantly decreased numbers of leukocytes together with increased apoptosis of these cells in mice treated with sirolimus and IL-2, whereas beta-cells were more numerous, and significantly fewer were apoptotic. In addition, Th1-type cells (gamma-interferon-positive and IL-2(+)) were decreased the most, and Th2-type cells (IL-4(+) and IL-10(+)) and Th3-type cells (transforming growth factor-beta1(+)) were increased the most in islet grafts of sirolimus and IL-2-treated mice. We conclude that 1) combination therapy with sirolimus and IL-2 is synergistic in protecting islet beta-cells from autoimmune destruction; 2) diabetes prevention continues after withdrawal of therapy; and 3) the mechanism of protection involves a shift from Th1- to Th2- and Th3-type cytokine-producing cells, possibly due to deletion of autoreactive Th1 cells.
Rabinovitch
Alex
A
Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. alex.rabinovitch@ualberta.ca
Suarez-Pinzon
Wilma L
WL
Shapiro
A M James
AM
Rajotte
Ray V
RV
Power
Robert
R
D000818:Animals; D017209:Apoptosis; D001327:Autoimmune Diseases / Q000517:prevention & control*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000517:prevention & control*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000032:analysis; D007376:Interleukin-2 / Q000008:administration & dosage / Q000032:analysis / Q000627:therapeutic use*; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D051379:Mice; D016688:Mice, Inbred NOD; D020123:Sirolimus / Q000008:administration & dosage / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D007166:Immunosuppressive Agents; D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D020123:Sirolimus