Vitamin A and acquired immune privilege

描述(申请人提供)：维生素A缺乏会导致免疫力的病理改变。直到最近一年，维生素A的代谢产物维甲酸(RA)才被证明能显著促进效应细胞--CD4+T细胞(T细胞)、AECD4+细胞、适应性调节T细胞(ATREG)的分化。鉴于这一认识，Treg对人类健康和疾病的深刻重要性，以及RA对这些细胞的生长和分化的强大影响，我们假设RA对Treg的生长、分化和功能的作用是维生素A影响免疫的核心。这项建议将发现维生素A缺乏和补充对Treg分化和外周免疫耐受的潜在分子、细胞和免疫学后果。这些特定的目的将决定：1)控制RA诱导分化的分子机制。我们已经证明，RA显著提高了ATREG的频率。初步研究表明，RAR1和RXR1是Treg诱导的关键受体。这些受体在Treg功能中的作用将通过使用RAR/RXR的特定抑制剂和激动剂以及在RAR/RXR信号中受到遗传损害的T细胞来确定。我们还假设RA通过不同的基因表达、改变的细胞因子产生、归巢和对Treg谱系的不可逆转的承诺而诱导Treg分化为“效应者”Treg。2)体内维生素A缺乏和补充对外周T细胞耐受形成的影响。在Treg依赖的同种异体移植耐受模型中，维生素A缺乏会导致耐受性丧失和移植物排斥反应。与我们的体外数据一致，我们假设维生素A缺乏阻止了同种异体特异性Treg的体内分化。我们试图在同种异体移植耐受的体内模型中证明这一假设，从而可以对同种异体特异性Treg的分化和功能进行严格的研究和量化。我们已经确定了多种遗传模型，在这些模型中，T细胞、CD4+T细胞和Foxp3+T细胞中的RA信号可以在体内被特异性地操纵，从而导致RA依赖的T细胞信号和外周耐受。3)局部LN和免疫特许微环境中RA合成的调节。我们认为，在免疫特许微环境中，造血细胞合成RA控制Treg的分化。因此，我们认为移植物微环境或局部LN中的造血细胞通过体内RA的合成来控制TeffAETreg的分化，并在一定程度上暗示特定细胞类型的RA的产生与移植物耐受的持久性有关。我们还将评估调节控制RA产生的关键酶途径的表达的因素(细胞因子、趋化因子等)。这些研究将为RA激动剂和拮抗剂在免疫相关疾病的管理中的使用提供有价值的见解。 公共卫生相关性：大量研究表明，维生素A补充剂通过对免疫系统的恢复活力来降低传染病的发病率和死亡率。这项建议将发现维生素A缺乏和补充对健康和疾病中免疫系统的潜在分子、细胞和免疫学后果。这将为使用这种天然药物治疗免疫相关疾病提供理论依据。

DESCRIPTION (provided by applicant): Vitamin A deficiency results in pathological alterations in immunity. Only in the last year, has it been shown that retinoic acid (RA), a Vitamin A metabolite, dramatically enhances the differentiation of effector, CD4+ T cells (Teff)AECD4+, adaptive regulatory T cells (aTreg). Given this realization, the profound importance of Treg to human health and disease, and the powerful impact that RA exerts on the growth and differentiation of these cells, we hypothesize that the actions of RA on Treg growth, differentiation and function is central to the impact of Vitamin A on immunity. This proposal will discover the underlying molecular, cellular and immunologic consequences of Vitamin A deficiency and supplementation on the differentiation of Treg and peripheral immunologic tolerance. The Specific Aims will determine: 1) The molecular mechanisms which control RA-induced differentiation of Teff AETreg. We have shown that RA dramatically enhances the frequency of aTreg. Preliminary findings indicate that RAR1 and RXR1 are the critical receptors for the induction of Treg. The role of these receptors in Treg function will be determined using specific inhibitors and agonists for RAR/RXR, as well as T cells that are genetically impaired in RAR/RXR signaling. We also hypothesize that RA induces the differentiation of Treg to an "effector" Treg by virtue of differential gene expression, altered cytokine production, homing and an irreversible commitment to the Treg lineage. 2) The in vivo impact of Vitamin A depletion and supplementation on the development of peripheral T cell tolerance. In a model of Treg -dependent allograft tolerance, Vitamin A deficiency results in loss of tolerance and graft rejection. Consistent with our in vitro data, we hypothesize that Vitamin A deficiency prevents the in vivo differentiation of allospecific Treg. We seek to prove this hypothesis in in vivo models of allograft tolerance whereby the differentiation and function of allospecific Treg can be critically investigated and quantified. We have identified multiple genetic models where RA signaling in T cells, CD4+ T cells and Foxp3+ T cells can be specifically manipulated in vivo to causally implicate RA-dependent T cell signaling and peripheral tolerance. 3) Regulation of RA synthesis within the regional LN and the immune privileged microenvironment. We propose that RA synthesis by hematopoietic cells in the immune privileged microenvironment controls the differentiation of Treg. As such we propose that hematopoietic cells within the graft microenvironment or regional LN controls Teff AETreg differentiation through RA synthesis in vivo, and causally implicate the production of RA by a specific cell type to the persistence of graft tolerance. We will also evaluate the factors (cytokines, chemokines, other) that regulate the expression of key enzymatic pathways that control RA production. Such studies will provide valuable insights into the use of RA agonists and antagonists in the management of immune related diseases. PUBLIC HEALTH RELEVANCE: Numerous studies have demonstrated that Vitamin A supplementation reduces morbidity and mortality from infectious diseases through its rejuvenating impact on the immune system. This proposal will discover the underlying molecular, cellular and immunologic consequences of Vitamin A deficiency and repletion on the immune system in health and disease. This will provide a rationale basis for use of this natural medicine on the treatment of immune related disorders.