Biology and Therapy of T Cell Depletion

T 细胞耗竭的生物学和治疗

• 批准号: 7292076
• 负责人: CRYSTAL L MACKALL
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7292076
• 关键词: Biology; Therapy; Cell; Depletion

The Mackall laboratory has a primary focus on the study of T cell homeostasis as it relates to lymphopenia and immune reconstitution. The goal of this work is to learn how to exploit the alterations in immune reactivity which occur during lymphopenia to enhance antitumor immunity and to identify new therapies which can enhance T cell regeneration. Both mouse and human immunology are simultaneously studied in an iterative manner using genetically engineered mice, murine allogeneic transplantation models, studies of humans rendered lymphopenic by cytotoxic chemotherapy for cancer and studies of humans following allogeneic stem cell transplantation. Our previous work identified that IL7 is a central modulator of T cell homeostasis (2001, Fry et al., Blood 97:2983), that therapy with IL7 modulates thymic-dependent and thymic-independent T cell immune reconstitution (2001, Mackall et al. Blood, 97:1491) and that effects of IL7 on peripheral T cell homeostasis can restore immunity in athymic T cell depleted hosts (2003, Fry et al., Blood 101:2294 and 2004, Moniuszko et al., J Virol 104:1419). These findings served as a basis for a Phase I clinical trial of rhIL7 in humans which is currently underway and which has confirmed a critical role for IL7 in modulating T cell number in humans. Beyond this, 8 subprojects are underway or have been recently completed within the laboratory which seek to advance our understanding of the biology and therapy for T cell depletion. 1) We have now completed a series of studies which demonstrate that IL7 is a potent adjuvant when used in the context of a dendritic cell based vaccine. This work utilized a mouse dendritic cell vaccine model to immunize toward the minor histocompatibility antigen HY, for which both immunodominant and subdominant epitopes have been characterized. We compared the efficacy of rhIL2, rhIL7, or rhIL7+rhI15 in augmenting T cell responses in this system by monitoring tetramer binding cells, IFN-gamma production via Elispot and rejection of a tumor which expressed HY. We observed potent increases in CD8+ reactive HY specific cells with both rhIL7 and rhIL15 but not with rhIL2. Both immunodominant and subdominant populations increased, but the effects on subdominant responses were most striking. IL7 also increased CD4 effectors but IL15 and IL2 did not. Both IL7 and IL15 increased the size of the memory cell pool generated and remarkably, even a short course of IL7 or IL15 administered at the time of immunization led to long-term enhancement in the viability of the CD8+ memory pool. This resulted from a substantial improvement in the long term survival of memory cells generated under the influence of IL7, suggesting that provision of this cytokine at the time of initial antigen encounter may result in long term changes to the health of the resultant memory cell pool. These results were published in a manuscript entitled, "Adjuvant IL7 or IL15 Overcomes Immunodominance and Improves Survival of the Memory Cell Pool", Melchionda et al., Journal of Clinical Investigation, 2005, 115:1177-1187. This represents the first evidence that IL7 is a potent vaccine adjuvant which has a remarkable capacity to augment subdominant immune responses and will no doubt serve as the basis for subsequent clinical studies of IL7 in the context of tumor vaccines. 2) During the past year, we also published a report which was the first to identify flt3 ligand as an immunorestorative agent (Flt3 Ligand enhances thymic dependent and thymic-independent immune reconstitution. Fry et al., Blood, 2004, 104:2794-2800). Using murine models of T cell depletion, we discovered that homeostatic peripheral expansion (which serves as the primary pathway for T cell regeneration in athymic hosts) requires the presentation of antigen by professional antigen presenting cells (APCs).

Mackall实验室主要关注T细胞稳态的研究，因为它与淋巴细胞减少和免疫重建有关。这项工作的目标是了解如何利用淋巴细胞减少症期间发生的免疫反应性改变来增强抗肿瘤免疫力，并确定可以增强T细胞再生的新疗法。使用基因工程小鼠、鼠同种异体移植模型、通过癌症细胞毒性化疗导致淋巴细胞减少的人的研究和同种异体干细胞移植后的人的研究，以迭代方式同时研究小鼠和人免疫学。我们先前的工作确定了IL 7是T细胞稳态的中心调节剂（2001，Fry et al.，Blood 97：2983），用IL 7的疗法调节胸腺依赖性和胸腺非依赖性T细胞免疫重建（2001，Mackall et al. Blood，97：1491），并且IL 7对外周T细胞稳态的作用可以恢复无胸腺T细胞耗尽的宿主中的免疫力（2003，Fry et al. Blood 101：2294和2004，Moniuszko等人，J Virol 104：1419）。这些发现为目前正在进行的rhIL 7在人体中的I期临床试验提供了基础，该试验证实了IL 7在调节人体T细胞数量中的关键作用。除此之外，8个子项目正在进行或最近在实验室内完成，旨在促进我们对T细胞耗竭的生物学和治疗的理解。1)我们现在已经完成了一系列的研究，这些研究表明，当在基于树突细胞的疫苗的情况下使用时，IL 7是有效的佐剂。这项工作利用小鼠树突状细胞疫苗模型免疫对次要组织相容性抗原HY，免疫显性和亚显性表位的特点。我们通过监测四聚体结合细胞、通过Elispot的IFN-γ产生和表达HY的肿瘤的排斥来比较rhIL 2、rhIL 7或rhIL 7 + rhI 15在该系统中增强T细胞应答的功效。我们观察到rhIL 7和rhIL 15均能有效增加CD 8+反应性HY特异性细胞，但rhIL 2则没有。免疫显性和亚显性种群均增加，但对亚显性反应的影响最为显著。IL 7也增加了CD 4效应细胞，但IL 15和IL 2没有。IL 7和IL 15都增加了所产生的记忆细胞库的大小，并且显著地，即使在免疫时施用的IL 7或IL 15的短期疗程也导致CD 8+记忆库的活力的长期增强。这是由于在IL 7的影响下产生的记忆细胞的长期存活的实质性改善，表明在初始抗原遭遇时提供该细胞因子可能导致所得记忆细胞库的健康的长期变化。这些结果发表在题为“Adjuvant IL 7 or IL 15 Overcomes Immunodynamics and Improves Survival of the Memory Cell Pool”的手稿中，Melchionda等人，临床研究杂志，2005，115：1177-1187.这代表了第一个证据，即IL 7是一种有效的疫苗佐剂，其具有增强亚显性免疫应答的显著能力，并且无疑将作为随后在肿瘤疫苗背景下IL 7临床研究的基础。2)在过去的一年中，我们还发表了一份报告，这是第一个确定flt 3配体作为免疫恢复剂（Flt 3配体增强胸腺依赖性和胸腺非依赖性免疫重建。Fry等人，Blood，2004，104：2794-2800）。使用T细胞耗竭的小鼠模型，我们发现稳态外周扩增（其作为无胸腺宿主中T细胞再生的主要途径）需要由专职抗原呈递细胞（APC）呈递抗原。