| Autor: |
Miao, Carol H., Harmeling, Benjamin R., Ziegler, Steven F., Yen, Benjamin C., Torgerson, Troy, Chen, Liping, Yau, Roger J., Peng, Baowei, Thompson, Arthur R., Ochs, Hans D., Rawlings, David J. |
| Zdroj: |
Blood; November 2009, Vol. 114 Issue: 19 p4034-4044, 11p |
| Abstrakt: |
Gene transfer of a factor VIII(FVIII) plasmidinto hemophilia A (HemA) mice achieved supraphysiologic FVIII expression, but triggered production of high-titer FVIII-specific antibodies and loss of functional FVIII activity. To test whether FVIII-specific regulatory T cells (Tregs) can modulate immune responses against FVIII, we developed a HemAmouse model in which all T cells overexpressed Foxp3(HemA/Foxp3-Tg). FVIII plasmidtherapy did not induce antibody production in HemA/Foxp3-Tgmice. CD4+Foxp3+T cells isolated from plasmid-treated HemA/Foxp3-Tgmice significantly suppressed proliferation of FVIII-stimulated CD4+effector T cells. The percentage of CD4+T cells expressing CD25, glucocorticoid-induced tumor necrosis factor receptor, and cytotoxic T lymphocyte antigen 4 increased significantly in spleen and peripheral blood for 9 weeks. Mice receiving adoptively transferred Tregs from FVIII-exposed HemA/Foxp3-Tgmice produced significantly reduced antibody titers compared with controls after initial challenge with FVIII plasmidand second challenge 16 weeks after first plasmidtreatment. Adoptively transferred Tregs engrafted and distributed at 2% to 4% in the Treg compartment of blood, lymph nodes, and spleens of the recipient mice and induced activation of endogenous Tregs; the engraftment decreased to negligible levels over 8 to 12 weeks. Antigen-specific Tregs can provide long-lasting protection against immune responses in vivo and limit recall responses induced by a second challenge via infectious tolerance. |
| Databáze: |
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