Modification of adverse inflammation is required to cure new-onset type 1 diabetic hosts.
In nonobese diabetic (NOD) mice with overt new-onset type 1 diabetes mellitus (T1DM), short-term treatment with a "triple-therapy" regimen [rapamycin plus agonist IL-2-related and antagonist-type, mutant IL-15-related Ig fusion proteins (IL-2.Ig and mutIL-15.Ig)] halts autoimmune destruction of insulin-producing beta cells and restores both euglycemia and immune tolerance to beta cells. Increases in the mass of insulin-producing beta cells or circulating insulin levels were not linked to the restoration of euglycemia. Instead, the restoration of euglycemia was linked to relief from an inflammatory state that impaired the host's response to insulin. Both restoration of immune tolerance to beta cells and relief from the adverse metabolic effects of an inflammatory state in insulin-sensitive tissues appear essential for permanent restoration of normoglycemia in this T1DM model. Thus, this triple-therapy regimen, possessing both tolerance-inducing and select antiinflammatory properties, may represent a prototype for therapies able to restore euglycemia and self-tolerance in T1DM.
Koulmanda
Maria
M
Department of Surgery, Harvard Medical School, and Islet Transplantation Research Laboratory, Massachusetts General Hospital, Boston, MA 02115, USA. mkoulman@bidmc.harvard.edu
Budo
Ejona
E
Bonner-Weir
Susan
S
Qipo
Andi
A
Putheti
Prabhakar
P
Degauque
Nicolas
N
Shi
Hang
H
Fan
Zhigang
Z
Flier
Jeffrey S
JS
Auchincloss
Hugh
H
Zheng
Xin Xiao
XX
Strom
Terry B
TB
D000818:Animals; D015551:Autoimmunity; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D005260:Female; D007108:Immune Tolerance; D007249:Inflammation / Q000188:drug therapy*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000276:immunology / Q000473:pathology; D019409:Interleukin-15 / Q000008:administration & dosage; D007376:Interleukin-2 / Q000008:administration & dosage; D051379:Mice; D016688:Mice, Inbred NOD; D020123:Sirolimus / Q000008:administration & dosage
D007328:Insulin; D019409:Interleukin-15; D007376:Interleukin-2; D020123:Sirolimus