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Diabetes 53:1700-1705, 2004
© 2004 by the American Diabetes Association, Inc.
Cure of Overt Diabetes in NOD Mice by Transient Treatment With Anti-Lymphocyte Serum and Exendin-4
1 Transplant Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts
2 Laboratory of Endocrinology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
Treatment of overtly diabetic NOD mice with anti-lymphocyte serum (ALS), a polyclonal anti–T-cell antibody, abrogates autoimmunity and achieves partial clinical remission. Here we investigated whether the addition of exendin-4, a hormone that stimulates insulin secretion and ß-cell replication and differentiation, improves induction of remission by ALS. Transient treatment of overtly diabetic NOD mice with ALS and exendin-4 achieved complete remission in 23 of 26 mice (88%) within 75 days, accompanied by progressive normalization of glucose tolerance, improved islet histology, increased insulin content in the pancreas, and insulin release in response to a glucose challenge. Syngeneic islets transplanted into mice cured by treatment with ALS plus exendin-4 remained intact, and cotransfer of lymphocytes from cured mice delayed diabetes induction by adoptive transfer, suggesting the long-lasting presence of autoimmune regulatory cells. Although ALS alone also achieved reversal of diabetes, the frequency of remission was low (40%). No treatment or exendin-4 alone failed to produce remission. These results show that exendin-4 synergistically augments the remission-inducing effect of ALS. The addition of ß-cell growth factors, such as exendin-4, to immunotherapy protocols with anti–T-cell antibodies presents a potential novel approach to the cure of patients with new-onset type 1 diabetes.
Address correspondence and reprint requests to Takashi Maki, MD, PhD, Beth Israel Deaconess Medical Center, Harvard Institute of Medicine, Rm. 1024, 77 Avenue of Louis Pasteur, Boston, MA 02215. E-mail: tamaki{at}caregroup.harvard.edu
Abbreviations: ALS, anti-lymphocyte serum; GLP, glucagon-like peptide; IPGTT, intraperitoneal glucose tolerance test; PDX, pancreas duodenum homeobox; STZ, streptozotocin
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