Th1 to Th2 cytokine shifts in nonobese diabetic mice: sometimes an outcome, rather than the cause, of diabetes resistance elicited by immunostimulation.
Document Type
Article
Publication Date
2001
Keywords
Animal, BCG-Vaccine, Cells-Cultured, Cytokines, Diabetes-Mellitus, Female, Freund's-Adjuvant, Gene-Deletion, Immunity-Natural, Injections-Subcutaneous, Interferon-Type-II, Interleukin-10, Interleukin-4, Islets-of-Langerhans, Lymphocyte-Transformation, Mice-Inbred-NOD, Mice-Knockout, Muromonab-CD3, RNA-Messenger, Receptors-Antigen-T-Cell, Th1-Cells, Th2-Cells, Transforming-Growth-Factor-beta
First Page
1352
Last Page
1359
JAX Source
J Immunol 2001 Jan; 166(2):1352-9.
Grant
AI41469/AI/NIAID, DK46266/DK/NIDDK, DK51090/DK/NIDDK
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-Guerin (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.
Recommended Citation
Serreze DV,
Chapman HD,
Post CM,
Johnson EA,
Suarez PW,
Rabinovitch A.
Th1 to Th2 cytokine shifts in nonobese diabetic mice: sometimes an outcome, rather than the cause, of diabetes resistance elicited by immunostimulation. J Immunol 2001 Jan; 166(2):1352-9.