Therapeutic treatment of EAT by inducing dendritic cell

通过诱导树突状细胞治疗 EAT

• 批准号: 7340389
• 负责人: Bellur S Prabhakar
• 金额: $ 36.48万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7340389
• 关键词: Adoptive Transfer; Affect; Antigen Presentation Pathway; Antigens; Apoptosis; Apoptotic; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmune thyroiditis; CD4 Positive T Lymphocytes; Cell physiology; Cells; Clinical; Colony-Stimulating Factors; Condition; Dendritic Cells; Dendritic cell activation; Development; Disease; Exposure to; Generations; Granulocyte-Macrophage Colony-Stimulating Factor; Hashimoto Disease; Hypothyroidism; Immune response; In Vitro; Infiltration; Inflammatory; Interferon Type II; Interleukin-10; Interleukin-12; Interleukin-4; Knockout Mice; Ligands; Literature; Lymphocyte; Mediating; Mediator of activation protein; Modeling; Mus; Pathogenesis; Personal Satisfaction; Phenotype; Production; Receptor Protein-Tyrosine Kinases; Relative (related person); Role; SCID Mice; Signal Transduction; Staging; Stimulus; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Thyroglobulin; Thyroglobulin antibody; Thyroid Gland; Thyroiditis; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor Receptor-1; base; cytokine; human TNF protein; in vivo; insight; interleukin-10 receptor; neutralizing antibody; prevent; protective effect; response

Experimental Autoimmune Thyroiditis (EAT) is characterized by eventual destruction of thyroid by infiltrating lymphocytes resulting in hypothyroidism. CD4+ T cells that produce IFN-gamma, TNF-alpha and IL-12 are critical for the pathogenesis. In a recent study, we showed that relative to thyroglobulin (mTg) immunized controls, mice treated with Flt3-L developed a more severe EAT characterized by massive thyroid lymphocytic infiltration, and IL-2and IFN-gamma production. In contrast, GM-CSF treated mice failed to develop EAT, and showed a significant increase in CD4+CD25+ regulatory T cells (Tregs). Activationof lymphocytes from these mice with mTg in vitro yielded higher levels of IL-4 and IL-10. Neutralization of IL-10, but not IL-4, and depletion of Tregs from these cultures restored mTg specific T cell proliferation, andIL-2 and IFN-gamma production. Further, adoptive transfer of Tregs to mTg immunized mice suppressed EAT while, inoculation of anti-IL-10 receptor Ab reversed GM-CSF induced suppression resulting in EAT. These results showed that suppression of EAT was mediated by Tregs most likely through enhanced production of IL-10. Based on these results we hypothesize that "selective activation of CD8a- dendritic cells using GM-CSF can activate CD4+CD25+ regulatory T cells and skew ongoing anti-thyroglobulin immune responses in favor of Th2 type, with consequent suppressive effects on the development and/or,progression of experimental autoimmune thyroiditis." In Aim-1, efficacy of GM-CSF to confer long-term antigen specific protection upon re-exposure to mTg will be tested. In Aim-2, we will test the ability of CD8a- and CD8a+ DCs to undergo maturation, capture and present the antigen, and produce cytokines, and determine the mTg specific T cell phenotype and cytokine profiles. Both DCs and T cells will be tested for their ability suppress in vitro and in vivo mTg specific responses in WT and IL-10-/- mice. In Aim-3, we will test the effects of GM-CSF, DCs and Tregs on the expression of MHC and B7 molecules, ARC function, and sensitivity to Fas induced apoptosis of thyrocytes from WT and SCID mice. These studies will provide significant insights into the mode of action of GM-CSF in suppressing EAT.

实验性自身免疫性甲状腺炎（EAT）的特点是通过浸润最终破坏甲状腺