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Anti-CD3 prevents factor VIII inhibitor development in hemophilia A mice by a regulatory CD4+CD25+-dependent mechanism and by shifting cytokine production to favor a Th1 response.

Abstract
Non-Fc-receptor binding anti-CD3 Ab therapy, in the setting of several different autoimmune disorders, can induce antigen-specific and long-lasting immunologic tolerance. Because factor VIII (FVIII) inhibitor formation is the most serious treatment-related complication for hemophilia A patients, we tested the efficacy of anti-CD3 to prevent FVIII inhibitor formation in hemophilia A BALB/c and C57BL/6 mice. A short course of low-dose anti-CD3 significantly increased expression of CD25 and the proportion of CD4+CD25+ regulatory T cells in the spleen and potently prevented the production of inhibitory and non-neutralizing anti-FVIII antibodies in both strains of mouse. Depleting the CD4+CD25+ cells during anti-CD3 therapy completely ablated tolerance to FVIII. Further phenotypic characterization of regulatory cells in tolerant mice showed a consistently higher number of CD4+GITR+ and CD4+FoxP3+ cells in both strains of mice. In addition, in tolerant C57BL/6 mice we observed an increase in CD4+CD25+ CTLA-4+ and CD4+CD25+mTGF-beta1+ cells. Finally, in vitro cytokine profiling demonstrated that splenocytes from tolerant BALB/c and C57BL/6 were polarized toward a Th1-immune response. Taken together, these findings indicate that anti-CD3 induces tolerance to FVIII and that the mechanism(s) regulating this response almost certainly occurs through the generation of several distinct regulatory T-cell lineages and by influencing cytokine production and profile.
AuthorsBraden Waters, Mohammad Qadura, Erin Burnett, Rouzbeh Chegeni, Andrea Labelle, Patrick Thompson, Christine Hough, David Lillicrap
JournalBlood (Blood) Vol. 113 Issue 1 Pg. 193-203 (Jan 01 2009) ISSN: 1528-0020 [Electronic] United States
PMID18815284 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antibodies
  • CD3 Complex
  • CD4 Antigens
  • Cd3e protein, mouse
  • Interleukin-2 Receptor alpha Subunit
  • Factor VIII
Topics
  • Animals
  • Antibodies (pharmacology)
  • CD3 Complex (immunology)
  • CD4 Antigens (metabolism)
  • Cell Lineage (immunology)
  • Factor VIII (antagonists & inhibitors, immunology, pharmacology)
  • Female
  • Hemophilia A (drug therapy, genetics, immunology)
  • Immune Tolerance (immunology)
  • Immunophenotyping
  • Interleukin-2 Receptor alpha Subunit (metabolism)
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Spleen (cytology)
  • T-Lymphocytes, Regulatory (immunology, metabolism)
  • Th1 Cells (immunology, metabolism)

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