In vivo neutralization of TNF-alpha promotes humoral autoimmunity by preventing the induction of CTL.
Neutralization of TNF-alpha in humans with rheumatoid arthritis or Crohn's disease has been associated with the development of humoral autoimmunity. To determine the effect of TNF-alpha neutralization on cell-mediated and humoral-mediated responses, we administered anti-TNF-alpha mAb to mice undergoing acute graft-vs-host disease (GVHD) using the parent-into-F(1) model. In vivo neutralization of TNF-alpha blocked the lymphocytopenic features characteristic of acute GVHD and induced a lupus-like chronic GVHD phenotype (lymphoproliferation and autoantibody production). These effects resulted from complete inhibition of detectable antihost CTL activity and required the presence of anti-TNF-alpha mAb for the first 4 days after parental cell transfer, indicating that TNF-alpha plays a critical role in the induction of CTL. Moreover, an in vivo blockade of TNF-alpha preferentially inhibited the production of IFN-gamma and blocked IFN-gamma-dependent up-regulation of Fas; however, cytokines such as IL-10, IL-6, or IL-4 were not inhibited. These results suggest that a therapeutic TNF-alpha blockade may promote humoral autoimmunity by selectively inhibiting the induction of a CTL response that would normally suppress autoreactive B cells.
Via
C S
CS
Research Service, Department of Veterans Affairs Medical Center and Division of Rheumatology and Clinical Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. cvia@umaryland.edu
Shustov
A
A
Rus
V
V
Lang
T
T
Nguyen
P
P
Finkelman
F D
FD
D000208:Acute Disease; D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015551:Autoimmunity; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D004247:DNA / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D007700:Kinetics; D008180:Lupus Erythematosus, Systemic / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009500:Neutralization Tests; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000502:physiology; D019014:fas Receptor / Q000096:biosynthesis
D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D007371:Interferon-gamma; D004247:DNA