Cure of Overt Diabetes in NOD Mice by Transient Treatment With Anti-Lymphocyte Serum and Exendin-4

Cure of Overt Diabetes in NOD Mice by Transient Treatment With Anti-Lymphocyte Serum and Exendin-4 Norihiko Ogawa 1 , James F. List 2 , Joel F. Habener 2 and Takashi Maki 1 1 Transplant Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts 2 Laboratory of Endocrinology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 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 Abstract 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 β-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 β-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. ALS, anti-lymphocyte serum GLP, glucagon-like peptide IPGTT, intraperitoneal glucose tolerance test PDX, pancreas duodenum homeobox STZ, streptozotocin Footnotes Accepted April 5, 2004. Received January 21, 2004. DIABETES