Intervention of Immune Tolerance by Small Molecules

描述(申请人提供)：移植物抗宿主病(GVHD)是异基因造血干细胞移植后发病率和死亡率的主要原因，异基因造血干细胞移植是治疗血液系统恶性肿瘤患者的公认疗法。目前减少GVHD的策略包括T细胞耗竭和免疫抑制药物，这些药物与肿瘤复发、机会性感染和/或毒性增加相关。显然需要从本质上作用于免疫系统的新方法。髓系来源的抑制细胞(MDSCs)由一组髓系前体细胞组成，这些细胞具有强大的抑制活性，能够抑制抗肿瘤反应。 移植物抗宿主病(GVHD)和器官移植中的自身免疫和同种异体反应。我们的初步结果表明，在小鼠模型中，MDSCs具有几个吸引人的辅助细胞属性，可以在不显著损害移植物抗白血病/淋巴瘤(GVL)的情况下抑制GVHD，从而建立长期存活。最近，我们还证实MDSCs通过调节PIR-B(配对免疫球蛋白样受体B和人类对应的抑制性免疫球蛋白样受体B，LILRBs)信号获得M1或M2功能性巨噬细胞表型，这可能分别促进抗肿瘤反应的发生或介导免疫抑制和Treg激活。这项建议的目的是了解MDSC生物学功能的调节机制，并设计一种优化的方案，以指导MDSC的功能活性用于抑制GVHD，同时允许足够的GVL活性来根除肿瘤。根据OU的初步研究结果，我们假设：(I)MDSC的功能表型可以通过PIR-BL结扎来调节，(Ii)具有持续M2功能表型的MDSC的存在可能足以防止GHVD和保留GVL能力。目标1.研究MDSC功能的调节及其对移植物抗宿主病的影响。目的2.研究PIR-B结扎对MDSC的影响与其抑制移植物抗宿主病(GVHD)及相应的信号调节有关。目的3.在小鼠GVHD模型和人移植NSG小鼠模型中，研究MDSC通过PIR-B/LILRB参与调节GVHD和GVL的机制和作用。本研究将为今后的临床翻译工作提供依据和科学依据。

DESCRIPTION (provided by applicant): Graft-versus-host disease (GVHD) is the leading cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation, an established therapy for patients with hematological malignancies. Current strategies to diminish GVHD include T-cell depletion and immunosuppressive drugs, which are associated with an increased risk of tumor relapse, opportunistic infection, and/or toxicity. Novel approaches acting intrinsically on the immune system are clearly needed. Myeloid-derived suppressor cells (MDSCs) consist of a population of myeloid precursor cells that exhibit potent suppressive activities capable of dampening anti-tumor responses, autoimmunity, and allo-responses in graft-versus-host diseases (GVHD) and organ transplantation. Our preliminary results indicate that MDSCs have several attractive attributes as helper cells to inhibit GVHD without significantly compromising graft-versus-leukemia/lymphoma (GVL) in a murine model, resulting in the establishment of long-term survival. Recently, we also demonstrated that MDSCs acquire M1 or M2 functional macrophage phenotypes through regulation of PIR-B (paired immunoblobulin-like receptor B and human counterpart inhibitory immunoglobulin-like receptors B, LILRBs) signaling, which may facilitate the development of antitumor responses or mediate immune suppression and Treg activation, respectively. The objective of this proposal is to understand the mechanism by which MDSC biological function is regulated and to devise an optimized protocol for directing the functional activities of MDSC toward suppression of GVHD while allowing sufficient GVL activity to eradicate tumors. Based on the results of ou preliminary studies, we hypothesize that: (i) The functional phenotype of MDSC can be modulated by PIR-BL ligation and (ii) The presence of MDSCs with a persistent M2 functional phenotype may be sufficient to prevent GHVD and retain GVL ability. Three specific aims will be pursued: Aim 1. Study the regulation of MDSC function and the associated effects on GVHD. Aim 2. Study the effects of PIR-B ligation on MDSC as related to inhibition of GVHD and the corresponding signaling regulation in an irradiated host. Aim 3. Study the mechanism and effects of MDSC mediated regulation of GVHD vs. GVL through PIR-B/LILRB engagement in mouse GVHD models and in a human xenograft NSG mouse model. The proposed studies will provide the basis and scientific principles for future clinical translation.