IL-4 prevents insulitis and insulin-dependent diabetes mellitus in nonobese diabetic mice by potentiation of regulatory T helper-2 cell function.
Beginning at the time of insulitis, nonobese diabetic (NOD) mice demonstrate a thymocyte and peripheral T cell proliferative hyporesponsiveness induced by TCR cross-linking, which is associated with reduced IL-2 and IL-4 secretion. We previously reported that NOD CD4+ T cell hyporesponsiveness is reversed completely in vitro by exogenous IL-4, and that administration of IL-4 to NOD mice prevents the onset of insulin-dependent diabetes mellitus (IDDM). This result suggested that T cell-mediated destruction of pancreatic islet beta cells may result from a hyporesponsiveness in regulatory Th2 cells favoring a Th1 cell-mediated environment in the pancreas. In the present study, we tested this possibility by analysis of the mechanisms of protection from IDDM afforded by IL-4 treatment in NOD mice. We show that IL-4 protects NOD mice from insulitis and IDDM when administered i.p. three times a week for 10 wk beginning at 2 wk of age. This occurs by the modulation of the homing of autoreactive cells to inflammatory sites and the stabilization of a protective Th2-mediated environment in the thymus, spleen, and pancreatic islets. Thus, IL-4 treatment favors the expansion of regulatory CD4+ Th2 cells in vivo and prevents the onset of insulitis and IDDM mediated by autoreactive Th1 cells.
Cameron
M J
MJ
The John P. Robarts Research Institute, University of Western Ontario, London, Canada.
Arreaza
G A
GA
Zucker
P
P
Chensue
S W
SW
Strieter
R M
RM
Chakrabarti
S
S
Delovitch
T L
TL
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control*; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000187:drug effects; D007073:Immunoglobulin E / Q000097:blood; D015994:Incidence; D007274:Injections, Intraperitoneal; D015847:Interleukin-4 / Q000008:administration & dosage / Q000627:therapeutic use*; D007515:Islets of Langerhans / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D008137:Longitudinal Studies; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010179:Pancreas / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D012793:Sialadenitis / Q000517:prevention & control; D013154:Spleen / Q000166:cytology / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology; D013966:Thyroiditis / Q000517:prevention & control; D013997:Time Factors
D000276:Adjuvants, Immunologic; D018960:Hyaluronan Receptors; D015847:Interleukin-4; D007073:Immunoglobulin E