In vivo neutralization of TNF-alpha promotes humoral autoimmunity by preventing the induction of CTL

  • Via C
  • Shustov A
  • Rus V
 et al. 
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Abstract

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.

Author-supplied keywords

  • *Autoimmunity
  • Acute Disease
  • Animals
  • Antibodies, Antinuclear/*biosynthesis
  • Antibodies, Monoclonal/pharmacology
  • Antigens, CD95/biosynthesis
  • Cells, Cultured
  • Cytotoxicity Tests, Immunologic
  • DNA/immunology
  • Graft vs Host Disease/immunology
  • Interferon-gamma/biosynthesis
  • Kinetics
  • Lupus Erythematosus, Systemic/immunology
  • Lymphocyte Activation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neutralization Tests
  • T-Lymphocytes, Cytotoxic/*immunology
  • Tumor Necrosis Factor-alpha/*antagonists & inhibit

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Authors

  • C S Via

  • A Shustov

  • V Rus

  • T Lang

  • P Nguyen

  • F D Finkelman

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