Cure of overt diabetes in NOD mice by transient treatment with anti-lymphocyte serum and exendin-4.
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 beta-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 beta-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.
Ogawa
Norihiko
N
Transplant Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
List
James F
JF
Habener
Joel F
JF
Maki
Takashi
T
D019264:Adoptive Transfer; D000818:Animals; D000961:Antilymphocyte Serum / Q000008:administration & dosage*; D001786:Blood Glucose / Q000032:analysis; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D004334:Drug Administration Schedule; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D000077270:Exenatide; D005260:Female; D006943:Hyperglycemia / Q000209:etiology / Q000473:pathology; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D016035:Pancreas Transplantation / Q000276:immunology; D010455:Peptides / Q000008:administration & dosage*; D014688:Venoms / Q000008:administration & dosage*
D000961:Antilymphocyte Serum; D001786:Blood Glucose; D007166:Immunosuppressive Agents; D007328:Insulin; D010455:Peptides; D014688:Venoms; D000077270:Exenatide