Intervention of Immune Tolerance by Small Molecules

描述（由申请方提供）：移植物抗宿主病（GVHD）是异基因造血干细胞移植后发病和死亡的主要原因，异基因造血干细胞移植是恶性血液病患者的既定治疗方法。 目前减少GVHD的策略包括T细胞耗竭和免疫抑制药物，这与肿瘤复发、机会性感染和/或毒性的风险增加有关。 显然需要内在地作用于免疫系统的新方法。 髓源性抑制细胞（MDSC）由髓样前体细胞群组成，所述髓样前体细胞群表现出能够抑制抗肿瘤应答的有效抑制活性， 自身免疫和移植物抗宿主病（GVHD）和器官移植中的同种异体反应。我们的初步结果表明，MDSC具有几个有吸引力的属性作为辅助细胞，以抑制GVHD，而不显着损害移植物抗白血病/淋巴瘤（GVL）在小鼠模型中，导致建立长期生存。 最近，我们也证明了MDSC通过调节PIR-B获得M1或M2功能性巨噬细胞表型，（配对免疫球蛋白样受体B和人对应物抑制性免疫球蛋白样受体B，LILRB）信号传导，其可促进抗肿瘤应答的发展或介导免疫抑制和Treg活化，分别本提案的目的是了解MDSC生物学功能调节的机制，并设计一种优化的方案，用于指导MDSC的功能活性抑制GVHD，同时允许足够的GVL活性来根除肿瘤。 基于我们的初步研究结果，我们假设：（i）MDSC的功能表型可以通过PIR-BL连接来调节，以及（ii）具有持续M2功能表型的MDSC的存在可能足以预防GHVD并保持GVL能力。 将追求三个具体目标：目标1。 研究MDSC的功能调控及其对GVHD的影响。目标2.研究PIR-B连接对MDSC的影响，其与抑制受照射宿主的GVHD和相应的信号调节有关。 目标3. 在小鼠GVHD模型和人异种移植NSG小鼠模型中研究MDSC介导的通过PIR-B/LILRB接合调节GVHD相对于GVL的机制和作用。 这些研究将为今后的临床翻译提供依据和科学原则。

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.