Directing T Cell Responses during Immune Reconstitution

在免疫重建过程中指导 T 细胞反应

• 批准号: 6558707
• 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/6558707
• 关键词: Primates; T lymphocyte; antiAIDS agent; antigen presenting cell; apoptosis; bladder neoplasm; cellular immunity; chemoprevention; clinical research; clinical trials; cooperative study; disease /disorder model; human subject; human therapy evaluation; immunomodulators; immunoregulation; interleukin 7; laboratory mouse; leukocyte activation /transformation; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; neoplasm /cancer relapse /recurrence; nonhuman therapy evaluation; protease inhibitor; tissue /cell culture; tumor antigens; western blottings

A primary focus of our laboratory is investigation of the biology of T cell regeneration and the identification of new approaches to enhance T cell regeneration and to direct T cell responses toward tumor antigens during the period of immune reconstitution. Our methods involve modeling in mice, studies in non-human primates and studies involving clinical samples derived from patients with T cell depletion. Much of the work in the past year has utilized mouse models of T cell depletion. Through this, we have investigated mechanisms for enhancing T cell regeneration in thymic deficient mice. We have shown that recovery of stringent immune responses (HY skin graft rejection) occurs if only 10% of the T cell repertoire is supplied to a T cell depleted host by the transfer of normal mature T cells. Such a small inocula implies that much redundancy occurs within the immune system and represents a new discovery. We also learned that one could transfer as little as 1% of the T cell repertoire with a T cell active cytokine, IL-7, and similarly restore stringent immune responses. Such results were surprising because prior to this work, IL-7 was thought of as a cytokine which was important for early T cell development, but its effects on mature T cells were not generally believed to be of primary importance (Fry TJ, Christensen BL, Komschlies KL, Gress RE and Mackall CL. IL-7 restores immunity in athymic T cell depleted hosts. Blood. 2001;97:1525-1533) (Mackall CL, Fry TJ, Bare C, Morgan P, Gailbraith A and Gress RE. IL-7 increases both thymic-dependent and thymic-independent T cell regeneration after BMT. Blood. 2001;97:1491-1497.). Simultaneously, we hypothesized that if therapeutic doses of IL-7 were able to potently restore immune responses in T cell depleted hosts, it was possible that in the normal situation, endogenous levels of IL-7 serve to enhance immune competence and contribute to the restoration of T cell homeostasis following T cell depletion. Indeed, several features of IL-7 treated mice resemble T cell depleted hosts. Thus, we investigated serum IL-7 levels in clinical cohorts of patients with T cell depletion. We observed that there was a dramatic inverse correlation between serum IL-7 and CD4 count in HIV infection, following cancer chemotherapy and in a rare disease termed idiopathic CD4 lymphopenia (Fry TJ, Connick E, Falloon J, Lederman MM, Liewehr DJ, Spritzler J, Steinberg SM, Wood LV, Yarchoan R, Zuckerman J, Landay A and Mackall CL. A potential role for IL-7 in T cell homeostasis. Blood, 2001; 97:2983-2990). These were the first insights to implicate IL-7 as a possible regulator of T cell homeostasis in humans (Fry TJ and Mackall CL, Interleukin-7: Master Regulator of T Cell Homeostasis?, Trends in Immunology, In Press, 2001). Because of these findings in both mouse models and clinical samples, we have been very actively attempting to develop IL-7 as a clinical agent which could be used to improve immunity following T cell depletion. To this end, we are engaged in trials of IL-7 administration to non-human primates through collaborations with the Monoclonal Antibody and Recombinant Protein Facility in Frederick, MD and Sanofi, Inc. in Paris, France through an MTA/CRADA with the NCI. We are hopeful that these studies will eventually lead to clinical trials of IL-7 as a new immunorestorative agent. In addition, we have identified two new agents in the past year with the potential for clinical application as immunorestorative agents. The first, flt3 ligand is known to enhance dendritic cell development. However, through our murine models of T cell depletion, we have now observed that it also enhances both thymic-dependent and thymic-independent T cell regeneration (Fry/Sinha, ASH, 2001). Secondly, we have observed that the HIV protease inhibitor, Indinavir, is active as an immunorestorative agent in mouse models, even in the absence of HIV infection. We are also engaged in two murine tumor models which will serve to answer questions regarding the ability of immune restoration to prevent recurrence of cancer. In the first, we are using a bladder tumor for which a unique tumor antigen has been defined. This antigen, termed HY, is the male associated minor histocomability antigen which is the antigen we have studied extensively in skin graft rejection models (above). We will now determine whether we can similarly enhance resistance to tumor recurrence in T cell depleted hosts using IL-7. Secondly, we are using a mouse model of osteosarcoma. In this model, the tumor is implanted into the extremity and the animal subsequently receives an amputation after tumor growth. We then attempt to modulate immune reconstitution and evaluate the effects on tumor recurrence. This model is very similar to the clinical scenario of osteosarcoma which we observe in our patients. We have made the surprising observation that non-specific immune reconstitution, in the absence of any specific tumor vaccine, is capable of preventing tumor recurrence following amputation (Melchionda et al, submitted to ASH 2001). Furthermore, we find no evidence that lymphocytes present during the phase of primary tumor growth are tolerized to the tumor antigens. These studies imply that therapies aimed at restoring general immunity in cancer patients may contribute to prevent tumor recurrence and have important implications for clinical oncology. AIDS Related 100%

我们实验室的一个主要重点是研究T细胞再生的生物学，并确定新的方法来增强T细胞再生，并在免疫重建期间指导T细胞对肿瘤抗原的反应。我们的方法包括小鼠模型、非人类灵长类动物研究和来自T细胞耗竭患者的临床样本研究。过去一年的大部分工作都是利用T细胞耗竭的小鼠模型。通过这种方法，我们研究了增强胸腺缺陷小鼠T细胞再生的机制。我们已经证明，如果只有10%的T细胞库通过正常成熟T细胞的转移提供给T细胞枯竭的宿主，则会发生严格的免疫反应（HY皮肤移植排斥反应）。如此小的接种意味着免疫系统中存在大量冗余，这代表着一项新发现。我们还了解到，人们可以用T细胞活性细胞因子IL-7转移1%的T细胞库，并类似地恢复严格的免疫反应。这样的结果令人惊讶，因为在这项工作之前，人们认为IL-7是一种对早期T细胞发育很重要的细胞因子，但它对成熟T细胞的影响通常不被认为是最重要的（Fry TJ, Christensen BL, Komschlies KL， Gress RE和Mackall CL）。IL-7恢复胸腺T细胞枯竭宿主的免疫力。血。2001;[j]，张建军，张建军，张建军，等。IL-7对胸腺依赖性和非胸腺依赖性T细胞再生的影响。血。97:1491 2001;1497)。同时，我们假设，如果治疗剂量的IL-7能够有效地恢复T细胞枯竭宿主的免疫应答，那么在正常情况下，内源性IL-7水平可能有助于增强免疫能力，并有助于T细胞枯竭后T细胞稳态的恢复。事实上，IL-7处理小鼠的一些特征类似于T细胞耗尽的宿主。因此，我们研究了T细胞耗竭患者临床队列中的血清IL-7水平。我们观察到，在HIV感染、癌症化疗后以及一种罕见的称为特发性CD4淋巴细胞减少症的疾病中，血清IL-7和CD4计数之间存在显著的负相关（Fry TJ, Connick E, Falloon J, Lederman MM, Liewehr DJ, Spritzler J, Steinberg SM, Wood LV, Yarchoan R, Zuckerman J， Landay a和Mackall CL）。IL-7在T细胞稳态中的潜在作用。血,2001;97:2983 - 2990)。这是第一次发现IL-7可能是人类T细胞稳态的调节因子（Fry TJ和Mackall CL，白细胞介素-7:T细胞稳态的主要调节因子？），免疫学趋势，出版，2001年)。由于在小鼠模型和临床样本中的这些发现，我们一直非常积极地尝试开发IL-7作为一种临床药物，可用于提高T细胞耗竭后的免疫力。为此，我们正在通过与美国马里兰州弗雷德里克的单克隆抗体和重组蛋白设施以及法国巴黎的赛诺菲公司（Sanofi, Inc.）通过NCI的MTA/CRADA合作，开展IL-7给药非人灵长类动物的试验。我们希望这些研究最终将导致IL-7作为一种新的免疫恢复剂的临床试验。