TREATMENT OF AUTOIMMUNITY WITH REGULATORY T LYMPHOCYTES

描述（由申请人提供）：促炎性Th 1和Th 17 T淋巴细胞协调许多器官特异性自身免疫性疾病，如多发性硬化症（MS）和I型糖尿病。这些细胞的病理活性可以由不同形式的调节性T淋巴细胞（Treg）调节，最显著的是表达Foxp 3转录因子的Treg。因此，使用Foxp 3 + Treg的连续免疫疗法在选择性治疗自身免疫性病症中具有希望。我们的实验室特别专注于Foxp 3 + Treg的治疗应用，这些Treg是通过用TGF-2调节原始T淋巴细胞产生的。我们证明了这些“诱导的Treg”（iTreg）的细胞特性不同于直接分离的内源性Treg（天然Treg，nTreg）的细胞特性。尽管如此，iTreg和nTreg在治疗模型自身免疫性疾病、实验性过敏性脑脊髓炎（EAE）方面是等效的，并且通过类似的机制起作用。在这个提案中，我们将解决iTreg的独特生物学，并为其临床转化为细胞免疫奠定基础。在初步研究中，我们证明了大部分iTreg，而不是nTreg，在过继转移后失去Foxp 3表达。iTreg和nTreg之间的一个关键区别在于它们的自身特异性程度。自身特异性将影响T细胞稳态，我们假设也将影响iTreg存活和功能。在目标1中，我们将研究TCR特异性在iTreg存活、Foxp 3保存和治疗活性中的作用。我们的初步数据显示，iTreg与nTreg一样，是高度有效的，以IL-10依赖性方式预防和治疗EAE，并催化额外的自身抗原特异性Treg（感染耐受性）的发展。在目标2中，我们将确定iTreg如何通过将病理性免疫应答转化为调节性应答来诱导免疫耐受，以及IL-10在其中的具体作用。我们已经进一步证明TLR配体显著增强治疗性转移的iTreg中Foxp 3表达的保存和存活。我们假设TLR激活，无论是通过APC或直接进入iTreg，促进iTreg的存活和活性。在目标3中，我们将确定先天免疫途径如何改变iTreg治疗活性，并探索TLR激动剂在iTreg诱导和免疫治疗中的可能辅助作用。这些研究将为iTreg在治疗转移后如何调节免疫力以及它们如何在功能上优化以达到最大效力和功效提供新的见解，并将促进iTreg免疫疗法的临床转化公共卫生相关性：当免疫系统无法识别个体自身的细胞和组织时，疾病就会发生，并攻击它们。效应T淋巴细胞是免疫系统中的一类细胞，在协调自身免疫反应和介导组织损伤中起关键作用。该提案的目标是促进使用不同类型的T淋巴细胞（称为调节性T淋巴细胞，能够特异性抑制效应T淋巴细胞功能）开发用于自身免疫性疾病的新细胞疗法。

DESCRIPTION (provided by applicant): Pro-inflammatory Th1 and Th17 T-lymphocytes orchestrate many organ-specific autoimmune diseases, such as multiple sclerosis (MS) and type I diabetes. The pathologic activity of these cells can be modulated by different forms of regulatory T lymphocytes (Treg), most prominently Treg expressing the Foxp3 transcription factor. Adoptive immunotherapy with Foxp3+ Treg therefore holds promise in the selective treatment of autoimmune conditions. Our laboratory has specifically focused on the therapeutic application of Foxp3+ Treg that are generated by conditioning naove T lymphocytes with TGF-2. We demonstrated that the cellular properties of these "induced Treg" (iTreg) differ from those of directly isolated endogenous Treg (natural Treg, nTreg). Despite this, iTreg and nTreg are equivalently potent in treating a model autoimmune disease, experimental allergic encephalomyelitis (EAE), and operate through similar mechanisms. In this proposal, we will address the unique biology of iTreg, and lay a foundation for their clinical translation into a cellular immunotherapeutic. In preliminary studies we demonstrated that a large proportion of iTreg, but not nTreg, lose Foxp3 expression after adoptive transfer. One key difference between iTreg and nTreg is in their extent of self-specificity. Self-specificity will impact T-cell homeostasis, and we hypothesize will also influence iTreg survival and function. In Aim 1, we will study the role of TCR specificity in iTreg survival, Foxp3 preservation, and therapeutic activity. Our preliminary data shows that iTreg, like nTreg, are highly potent, operate to prevent and treat EAE in an IL-10-dependent manner, and catalyze the development of additional autoantigen-specific Treg (infectious tolerance). In Aim 2, we will determine how iTreg induce immune tolerance by diverting a pathologic immune response into a regulatory response, and the specific role of IL-10 in this. We have further demonstrated that TLR ligands dramatically enhance the preservation of Foxp3 expression in and survival of therapeutically transferred iTreg. We hypothesize that TLR activation, either through APC or directly into iTreg, promotes the survival and activity of iTreg. In Aim 3, we will identify how innate immune pathways alter iTreg therapeutic activity, and probe a possible adjunct role for TLR agonists in iTreg induction and immunotherapy. These studies will provide new insights into how iTreg modulate immunity after therapeutic transfer and how they may be functionally optimized to maximum potency and efficacy, and will facilitate the clinical translation of iTreg immunotherapy PUBLIC HEALTH RELEVANCE: diseases develop when the immune system fails to recognize an individual's own cells and tissues as self, and attacks them. Effector T-lymphocytes, a class of cells within the immune system, are critically involved in orchestrating autoimmune responses and mediating tissue damage. This proposal's goal is to promote the development of new cellular therapies for autoimmune diseases using a different class of T lymphocytes, called regulatory T lymphocytes that are able to specifically suppress effector T lymphocyte functions.