Modulating autoimmune responses to GAD inhibits disease progression and prolongs islet graft survival in diabetes-prone mice.
In nonobese diabetic (NOD) mice, beta-cell reactive T-helper type 1 (Th1) responses develop spontaneously and gradually spread, creating a cascade of responses that ultimately destroys the beta-cells. The diversity of the autoreactive T-cell repertoire creates a major obstacle to the development of therapeutics. We show that even in the presence of established Th1 responses, it is possible to induce autoantigen-specific anti-inflammatory Th2 responses. Immune deviation of T-cell responses to the beta-cell autoantigen glutamate decarboxylase (GAD65), induced an active form of self-tolerance that was associated with an inhibition of disease progression in prediabetic mice and prolonged survival of syngeneic islet grafts in diabetic NOD mice. Thus, modulation of autoantigen-specific Th1/Th2 balances may provide a minimally invasive means of downregulating established pathogenic autoimmune responses.
Tian
J
J
Department of Molecular and Medical Pharmacology, University of California-Los Angeles 90095, USA.
Clare-Salzler
M
M
Herschenfeld
A
A
Middleton
B
B
Newman
D
D
Mueller
R
R
Arita
S
S
Evans
C
C
Atkinson
M A
MA
Mullen
Y
Y
Sarvetnick
N
N
Tobin
A J
AJ
Lehmann
P V
PV
Kaufman
D L
DL
D019264:Adoptive Transfer; D000818:Animals; D001323:Autoantibodies / Q000097:blood; D001324:Autoantigens / Q000627:therapeutic use*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000517:prevention & control* / Q000601:surgery; D018450:Disease Progression; D005260:Female; D005968:Glutamate Decarboxylase / Q000627:therapeutic use*; D006085:Graft Survival / Q000187:drug effects*; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D015848:Interleukin-5 / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D008213:Lymphocyte Activation; D051379:Mice; D016688:Mice, Inbred NOD; D010194:Pancreatin / Q000276:immunology; D017634:Self Tolerance; D013154:Spleen / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*
D001323:Autoantibodies; D001324:Autoantigens; D015848:Interleukin-5; D015847:Interleukin-4; D010194:Pancreatin; D007371:Interferon-gamma; D005968:Glutamate Decarboxylase