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.
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Authors | Braden Waters, Mohammad Qadura, Erin Burnett, Rouzbeh Chegeni, Andrea Labelle, Patrick Thompson, Christine Hough, David Lillicrap |
Journal | Blood
(Blood)
Vol. 113
Issue 1
Pg. 193-203
(Jan 01 2009)
ISSN: 1528-0020 [Electronic] United States |
PMID | 18815284
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antibodies
- CD3 Complex
- CD4 Antigens
- Cd3e protein, mouse
- Interleukin-2 Receptor alpha Subunit
- Factor VIII
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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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