Biology of the Immune Response

免疫反应生物学

• 批准号: 7292003
• 负责人: DAVID NELSON
• 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/7292003
• 关键词: Biology; Immune; Response

The goal of this project is to identify and characterize the genetic basis for certain of the primary immunodeficiency disorders, which are associated with an increased incidence of cancer. While these disorders are rare, their study has been extremely instructive in defining previously unsuspected elements of importance in human immune function. The Immunophysiology Section conducts a clinical translational research program. Basic observations in the laboratory on recombinant immunostimulatory molecules have led to two clinical trials. A clinical trial (00-I-006) of recombinant CD40 ligand (CD40L) in patients with CD40L deficiency (XHIM, OMIM 308230) and a clinical trial of BLySTM in patients with selective IgA deficiency (OMIM 137100) have both been successfully completed with full patient accrual. Further clinical trials in patients with XHIM and selective IgA deficiency are currently being planned. Studies of the Wiskott-Aldrich syndrome (WAS) and the responsible gene (WASP) have continued. The hypothesis is that an understanding of WASP protein function(s) would provide insight into the molecular mechanisms underlying the WAS and provide important clues for innovative diagnostic and therapeutic strategies. Using monoclonal antibodies to WASP produced in the laboratory, we identified several proteins, which interacted with the WASP protein and played critical roles in cytoskeletal organization and function. We took this knowledge to the clinic to see what insights the patients might provide which could yield unique insights into a molecular understanding of the WASP protein. One of the difficulties in understanding the WAS is that no one center could accumulate sufficient patients to define the full genetic and clinical spectrum of the disease. We were interested in whether there was a correlation between the genetic mutations, which occurred in the patients, and the clinical phenotype that was observed. To accomplish this goal, the Section helped organize a large consortium, which was able to accumulate molecular and clinical data on 262 patients from 227 families. This study provided valuable information about the spectrum and frequency of the genetic defects occurring in patients and the clinical spectrum of the WAS as well as correlations between the genetic defects and the clinical disease. To further advance these studies, we used a monoclonal anti-WASP antibody to develop a strategy to measure WASP protein expression at the single cell level using multicolor cell surface and intracellular flow cytometry. We were able to measure WASP expression in the peripheral blood cells of normal individuals and document deficient WASP expression in cells from WAS patients. Moreover, this deficient expression could be corrected by allogeneic bone marrow transplantation. Bone marrow transplantation has been used as the definitive treatment of the WAS since the late 1970s. Using a somewhat empiric pre-transplant conditioning regimen, Major Histocompatibility Complex (MHC)-matched, MHC- haploidentical, and matched-unrelated hematopoetic stem cell donors have been used with varying success. While these transplants were successful to varying degrees, there was sparse data regarding what was necessary or sufficient in terms of engraftment to obtain a good clinical outcome. Moreover, there was little data about the durability of engraftment or the cell lineages engrafted. Using the available flow cytometric test for WASP expression, we studied 12 patients following allogeneic bone marrow transplantation. Six were fully engrafted with donor cells while six were a mixture of donor and host cells (chimeric) in various cell lineages. These results suggested that additional studies of bone marrow transplants in the WAS would be useful in defining the optimal conditions for bone marrow transplantation.

该项目的目标是确定和表征某些原发性免疫缺陷疾病的遗传基础，这些疾病与癌症发病率增加有关。虽然这些疾病很罕见，但他们的研究对于定义以前未被怀疑的人类免疫功能的重要因素非常有启发性。免疫生理学科开展临床转化研究项目。实验室对重组免疫刺激分子的基本观察导致了两项临床试验。在 CD40L 缺乏症患者（XHIM、OMIM 308230）中进行的重组 CD40 配体（CD40L）临床试验（00-I-006）和在选择性 IgA 缺乏症患者（OMIM 137100）中进行的 BLySTM 临床试验均已成功完成，并获得全部患者应计。目前正在计划对 XHIM 和选择性 IgA 缺乏症患者进行进一步的临床试验。对 Wiskott-Aldrich 综合征 (WAS) 和相关基因 (WASP) 的研究仍在继续。我们的假设是，对 WASP 蛋白功能的了解将有助于深入了解 WAS 的分子机制，并为创新的诊断和治疗策略提供重要线索。使用实验室生产的 WASP 单克隆抗体，我们鉴定了几种与 WASP 蛋白相互作用并在细胞骨架组织和功能中发挥关键作用的蛋白质。我们将这些知识带到诊所，看看患者可能提供哪些见解，从而对 WASP 蛋白的分子理解产生独特的见解。理解 WAS 的困难之一是没有一个中心能够积累足够的患者来定义该疾病的完整遗传和临床谱。我们感兴趣的是患者中发生的基因突变与观察到的临床表型之间是否存在相关性。为了实现这一目标，该科帮助组织了一个大型联盟，该联盟能够积累来自 227 个家庭的 262 名患者的分子和临床数据。这项研究提供了有关患者发生的遗传缺陷的范围和频率、WAS 的临床范围以及遗传缺陷与临床疾病之间的相关性的有价值的信息。为了进一步推进这些研究，我们使用单克隆抗 WASP 抗体开发了一种策略，使用多色细胞表面和细胞内流式细胞术在单细胞水平上测量 WASP 蛋白表达。我们能够测量正常个体外周血细胞中的 WASP 表达，并记录 WAS 患者细胞中 WASP 表达缺陷。此外，这种表达缺陷可以通过同种异体骨髓移植来纠正。自 20 世纪 70 年代末以来，骨髓移植一直被用作 WAS 的最终治疗方法。使用某种经验性的移植前调理方案，主要组织相容性复合物（MHC）匹配、MHC 单倍体和匹配无关的造血干细胞供体已获得不同程度的成功。虽然这些移植在不同程度上取得了成功，但关于植入方面获得良好临床结果的必要性或充分性的数据很少。此外，关于植入的耐久性或植入的细胞谱系的数据很少。我们使用现有的 WASP 表达流式细胞术测试，研究了 12 名同种异体骨髓移植后的患者。六个完全植入供体细胞，而六个是不同细胞谱系的供体和宿主细胞（嵌合）的混合物。这些结果表明，对 WAS 中骨髓移植的进一步研究将有助于确定骨髓移植的最佳条件。