Paralytic Autoimmune Myositis Develops in Nonobese Diabetic Mice Made Th1 Cytokine-Deficient by Expression of an IFN-gamma Receptor beta-Chain Transgene.
J Immunol 2003 Mar; 170(5):2742-9.
Nonobese diabetic (NOD) mice and some human type 1 diabetes (T1D) patients manifest low to high levels of other autoimmune pathologies. Skewing their cytokine production from a Th1 (primarily IFN-gamma) to a Th2 (primarily IL-4 and IL-10) pattern is a widely proposed approach to dampen the pathogenicity of autoreactive diabetogenic T cells. However, it is important that altered cytokine balances not enhance any other autoimmune proclivities to dangerous levels. Murine CD4 T cells are characterized by a reciprocal relationship between the production of IFN-gamma and expression of the beta-chain component of its receptor (IFN-gammaRB). Thus, NOD mice constitutively expressing a CD2 promoter-driven IFN-gammaRB transgene in all T cells are Th1-deficient. Unexpectedly, NOD.IFN-gammaRB Tg mice were found to develop a lethal early paralytic syndrome induced by a CD8 T cell-dependent autoimmune-mediated myositis. Furthermore, pancreatic insulitis levels were not diminished in 9-wk-old NOD.IFN-gammaRB Tg females, and overt T1D developed in the few that survived to an older age. Autoimmune-mediated myositis is only occasionally detected in standard NOD mice. Hence, some manipulations diminishing Th1 responses can bring to the forefront what are normally secondary autoimmune pathologies in NOD mice, while also failing to dependably abrogate pancreatic beta cell destruction. This should raise a cautionary note when considering the use of protocols that induce alterations in cytokine balances as a means of blocking progression to overt T1D in at-risk humans.
Serreze, D V.; Pierce, M A.; Post, C M.; Chapman, H D.; Savage, H; Bronson, R T.; Rothman, P B.; and Cox, G A., " Paralytic Autoimmune Myositis Develops in Nonobese Diabetic Mice Made Th1 Cytokine-Deficient by Expression of an IFN-gamma Receptor beta-Chain Transgene." (2003). Faculty Research 2000 - 2009. 517.