title: Th1 to Th2 cytokine shifts in nonobese diabetic mice: sometimes an outcome, rather than the cause, of diabetes resistance elicited by immunostimulation.
abstract: Numerous immunostimulatory protocols inhibit the development of T cell-mediated autoimmune insulin-dependent diabetes mellitus (IDDM) in the nonobese diabetic (NOD) mouse model. Many of these protocols, including treatment with the nonspecific immunostimulatory agents CFA or bacillus Calmette-Guérin (BCG) vaccine, have been reported to mediate protection by skewing the pattern of cytokines produced by pancreatic beta-cell autoreactive T cells from a Th1 (IFN-gamma) to a Th2 (IL-4 and IL-10) profile. However, most of these studies have documented associations between such cytokine shifts and disease protection rather than a cause/effect relationship. To partially address this issue we produced NOD mice genetically deficient in IFN-gamma, IL-4, or IL-10. Elimination of any of these cytokines did not significantly alter the rate of spontaneous IDDM development. Additional experiments using these mice confirmed that CFA- or BCG-elicited diabetes protection is associated with a decreased IFN-gamma to IL-4 mRNA ratio within T cell-infiltrated pancreatic islets, but this is a secondary consequence rather than the cause of disease resistance. Unexpectedly, we also found that the ability of BCG and, to a lesser extent, CFA to inhibit IDDM development in standard NOD mice is actually dependent upon the presence of the Th1 cytokine, IFN-gamma. Collectively, our studies demonstrate that while Th1 and Th2 cytokine shifts may occur among beta-cell autoreactive T cells of NOD mice protected from overt IDDM by various immunomodulatory therapies, it cannot automatically be assumed that this is the cause of their disease resistance.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609. Department of Medicine, University of Alberta, Edmonton, Canada. dvs@jax.org
authors.forename: D V
authors.initials: DV
authors.lastname: Serreze
authors.forename: H D
authors.initials: HD
authors.lastname: Chapman
authors.forename: C M
authors.initials: CM
authors.lastname: Post
authors.forename: E A
authors.initials: EA
authors.lastname: Johnson
authors.forename: W L
authors.initials: WL
authors.lastname: Suarez-Pinzon
authors.forename: A
authors.initials: A
authors.lastname: Rabinovitch
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D001500:BCG Vaccine / Q000008:administration & dosage; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000235:genetics* / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D005260:Female; D005620:Freund's Adjuvant / Q000008:administration & dosage; D017353:Gene Deletion; D007113:Immunity, Innate / Q000235:genetics; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology; D016753:Interleukin-10 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D015847:Interleukin-4 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016853:Muromonab-CD3 / Q000494:pharmacology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000276:Adjuvants, Immunologic; D001500:BCG Vaccine; D016207:Cytokines; D016853:Muromonab-CD3; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; D005620:Freund's Adjuvant