Immune reconstitution following autologous and allogeneic stem cell transplant

自体和同种异体干细胞移植后的免疫重建

• 批准号: 8554082
• 负责人: Frances Hakim
• 金额: $ 81.4万
• 依托单位: DIVISION OF BASIC 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/8554082
• 关键词: Acute; Affect; Aging; Allogenic; Area; Autoimmune Diseases; Autoimmune Process; Autologous; Autologous Transplantation; Award; B-Lymphocytes; Biological Assay; Biological Markers; Biopsy; Blood Cells; Blood Circulation; Bone Marrow Transplantation; Bronchial Lavages; Bronchiolitis Obliterans; CD28 gene; CD3 Antigens; CD8B1 gene; Cells; Childhood; Chimerism; Chronic; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Color; Complication; Core Facility; Correlation Studies; Data; Dermatology; Development; Diagnostic; Drug Formulations; Effector Cell; Enzyme-Linked Immunosorbent Assay; Fibrosis; Flow Cytometry; Frequencies; Functional disorder; Funding; Gene Expression; Gene Expression Profile; Generations; Goals; Hematologic Neoplasms; Hematology; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Homologous Transplantation; Imatinib; Immune; Immunohistochemistry; Immunology; Immunotherapy; Individual; Infection; Inflammatory; Infusion procedures; Interferon Type I; Interferons; Interleukin-7; K-Series Research Career Programs; Laboratories; Latent Virus; Leukocytes; Leukotriene Receptor; Link; Lung; Lupus; Lymph; Lymphocyte; Lymphocyte Depletion; Lymphocyte Subset; Lymphokines; Lymphoma; Lymphopoiesis; Malignant Neoplasms; Marrow; Measurement; Measures; Memory; Monokines; Morbidity - disease rate; Mouthwash; Multiple Myeloma; National Heart, Lung, and Blood Institute; Natural History; Non-Hodgkin' s Lymphoma; Oral; Pathogenesis; Pathway interactions; Patients; Pattern; Phase I Clinical Trials; Plasma; Population; Predisposition; Process; Production; Protocols documentation; RNA; Recovery; Regimen; Regulatory T-Lymphocyte; Relapse; Renal carcinoma; Reporter; Reporting; Research; Role; Sampling; Scientist; Secure; Services; Signal Transduction; Sorting - Cell Movement; Stem Cell Research; Stem cell transplant; Steroids; Symptoms; Systemic Lupus Erythematosus; T cell therapy; T-Cell Receptor; T-Lymphocyte; Testing; Therapy Clinical Trials; Time; Tissues; Transforming Growth Factor beta; Transplant Recipients; Transplantation; Transplantation Immunology; Umbilical Cord Blood; United States National Institutes of Health; Vaccines; Variant; Work; arm; base; cancer site; chemokine; chronic graft versus host disease; collaborative trial; cytokine; efficacy testing; graft vs host disease; inhibitor/antagonist; innovation; leukemia/lymphoma; malignant breast neoplasm; monocyte; mortality; multidisciplinary; novel; novel therapeutic intervention; older patient; outcome forecast; peripheral blood; pre-clinical; prognostic; receptor expression; reconstitution; response; skin disorder; tumor

The Preclinical Service Core (PSC) projects have developed from transplantation protocols implemented by the clinical staff of ETIB. Using peripheral blood and marrow, and tumor and CGVHD tissue biopsies, we have evaluated lymphocyte subsets, cytokine content, T cell receptor repertoire diversity and thymopoietic activity. All data are incorporated into protocol-specific spreadsheets, linking samples to protocol arms and transplant time points, and are accessible by branch clinicians over secure NIH networks.Effects of IL-7 administration: In a Phase I clinical trial of IL-7 administration (P. I. Claude Sportes: 03-C-0152), we determined that IL-7 significantly expanded naive and central memory CD4 and CD8 T cells, as compared to effector cells, resulting in a significant increase in the diversity of the overall T cell receptor repertoire and identifying a concurrent effect on B lymphopoiesis (Sportes et al 2009;Sportes et al 2010). The PSC supports a newly initiated vaccine trial (11-C-0146; P.I. Claude Sportes), that assesses the effect of IL-7 on vaccine responses in older patients, by assessing effects of a new IL-7 formulation on T and B cell populations and T cell receptor repertoire.Cytokine and monokine production following based transplant regimens incorporating ex vivo expanded cytokine defined T effectors: An ongoing project has assessed lymphokine and monokine production capacity post transplant, focusing on allogeneic transplants incorporating immune therapy with Th2.rapa (P. I. Dan Fowler lymphoma and renal carcinoma: 04-C-0055, 08-C-0088) or T1/T2 donor-derived cells (P.I. Michael Bishop metastatic breast cancer: 04-C-0131). In the early post-transplant period, the cytokine and monokine production capacity of peripheral blood cells has been determined by generation of anti CD3/anti CD28-stimulated stimulated supernatants and by the assessment of the frequencies of cytokine producing T cells by flow cytometry. These assays support these protocols by evaluating the extent and durability of the cytokine shift resulting from the infusion of T1/T2 or Th2-rapa cells (Hardy et al, 2011). Immune reconstitution following lymphodepletion: In several ongoing ETIB clinical trials of allogeneic stem cell transplantation therapies (04-C-0055, 07-C-0195, 09-C-0210; 09-C-0096; PIs Daniel Fowler, Michael Bishop, Steven Pavletic and Dennis Hickstein) the process of immune reconstitution has been assessed, focusing on the factors contributing to individual variation in recovery. These data have contributed to a report on the efficacy of EPOCH-F, a novel non-myeloablative induction regimen, in allogeneic stem cell transplantation in patients with multiple myeloma and lymphophoid malignancies(Jamshed et al., 2011; Salit et al, 2012). We currently are using 10-color flow cytometery to characterize lymphocyte repopulation and correlate this with thymic recovery, relapse, GVHD and reactivation of chronic latent viruses. These parallel studies involve analysis of three ongoing trials (07-C-0195, 11-C-0016, 11-C-0136) that cover the breadth of current transplant practices: allogeneic transplantation with unrelated donors, autologous transplantation with addition of T1-Rapa adoptive T cell therapy, and myeloablative transplant for acute hematologic malignancies. In addition, when assessment of lineage-specific repopulation is important, we use the ETIB Flow Cytometry Core facility (William Telford) to sort lymphocytes for subset-specific donor chimerism analysis. These assays include ongoing studies on patients transplanted for monogenic immune deficiency involving GATA2 or DOCK8 (09-C-0096, PI: Dennis Hickstein) and on patients receiving dual donor umbilical cord blood (09-C-0210, PI: Michael Bishop). Finally, we have collaborated with the Hematology Branch of the NHLBI to provide analyses of T cell receptor repertoire diversity in long term recipients of allogeneic stem cell transplantation, demonstrating that recipients develop a diverse repertoire after 10 years that is comparable to the donor repertoire (Le et al., 2011).Immune populations and dysfunction in chronic graft vs host disease (CGVHD): In an ongoing natural history protocol (P.I. Steven Pavletic: 04-C-0281), patients who have developed CGVHD following allogeneic transplantation have been evaluated by a multidisciplinary clinical team. The PCS core has supported the study by contributing to the identification of CGVHD biomarkers and the understanding of CGVHD pathogenesis. Two studies of factors contributing to the development of sclerotic skin disease in CGVHD have been accepted (Martires et al.,2011; Martires et al.2011b) as well as a study of correlations of clinical laboratory tests with CGVHD prognosis (Grkovic et al., 2012). Furthermore, we have supported a therapeutic trial for bronchiolitis obliterans, a severe complication of CGVHD (P. I. Ronald Gress and Kirsten Williams: 08-C-0097), by assessing leukotriene receptor (LTR) expression in leukocytes and in bronchial lavage cells to define the role of LTR in progressive fibrosis of lung airways. We support a collaborative trial testing Imatinib therapy on sclerotic cutantaneous CGVHD (Dermatology and Pediatric Branch, protocol 08-C-0148, P.I. Edward Cowen and Kristin Baird), by assessing the effect of this TGFbeta signaling inhibitor on Th17 and Treg populations. We also support a trial testing the efficacy of a mouthwash containing a potent steroid, Clobetasol, as a topical therapy for oral CGVHD (12-C-0068; P.I. Steven Pavletic). Finally, CGVHD has become a significant focus for research in the PCS core. Three PCS projects have been initiated from this study. First, we have determined that plasma levels of the cytokine BAFF are elevated in CGVHD. This increase is significantly correlated both with elevated plasma levels of Interferon (IFN)-induced inflammatory cytokines and with reduced levels of circulating B cells. Second, we have initiated studies into the role of regulatory T cells (Treg) in CGVHD by characterizing Treg in the circulation and in affected tissues. Finally we are using tissue immunohistochemistry, plasma cytokine ELISA and assays of gene expression to test the hypothesis that IFN-induced inflammatory processes may underlie many of the systemic processes in CGVHD (Imanguli et al, 2009; Hakim, 2010). These studies formed the basis for an application for a Staff Scientist Career Development Award, funded in January 2010, This project, detailed under the Innovation Award section, used circulating monocytes as reporter cells for determining the cytokine and chemokine pathways underlying the development of the autoimmune-like symptoms of CGVHD. In coordinated studies, we have assessed plasma levels of cytokines and chemokines and have measured the gene expression patterns of sorted monocytes by microarray and quantitative multiplex RNA measurements. We determined that Type I IFN-driven processes are elevated in CGVHD patients, as compared with normal donors and with non-GVHD transplant recipients. The work may support the development of diagnostic or prognostic assays of CGVHD and contribute to new therapeutic approaches.Relevant cancer sites: Hodgkins Disease/Lymphoma, Non-Hodgkins Lymphoma, Leukemia, Multiple Myeloma. Relevant Research Areas: Immunology, Bone Marrow Transplantation, Autoimmune Disease, SLE/Lupus, Interferon, Hematology/Lymph, Aging, Stem Cell Research, Clinical Research.

临床前服务核心（PSC）项目是由Etib临床人员实施的移植协议开发的。使用外周血和骨髓以及肿瘤和CGVHD组织活检，我们评估了淋巴细胞亚群，细胞因子含量，T细胞受体库库多样性和胸腺异端活性。 All data are incorporated into protocol-specific spreadsheets, linking samples to protocol arms and transplant time points, and are accessible by branch clinicians over secure NIH networks.Effects of IL-7 administration: In a Phase I clinical trial of IL-7 administration (P. I. Claude Sportes: 03-C-0152), we determined that IL-7 significantly expanded naive and central memory CD4 and CD8 T cells, as compared to effector cells,总体T细胞受体库的多样性显着增加，并确定对B淋巴细胞的同时影响（Sportes等，2009； Sportes等，2010）。 The PSC supports a newly initiated vaccine trial (11-C-0146; P.I. Claude Sportes), that assesses the effect of IL-7 on vaccine responses in older patients, by assessing effects of a new IL-7 formulation on T and B cell populations and T cell receptor repertoire.Cytokine and monokine production following based transplant regimens incorporating ex vivo expanded cytokine defined T effectors:一个正在进行的项目在移植后评估了淋巴因子和单因子产量，重点是将免疫治疗与Th2.Rapa（P. I. Dan Fowler淋巴瘤和肾癌：04-C-0055，08-C-0088）或T1/T2供体供体细胞（P.I. P.I. P.I. Michael Borkiss cance 04-c Cancer 04）。在移植后初期，外周血细胞的细胞因子和单因子的生产能力已通过产生抗CD3/抗CD28刺激的刺激的上清液，并通过流动细胞仪评估细胞因子产生T细胞的频率。这些测定方法通过评估因输注T1/T2或Th2-Rapa细胞而导致的细胞因子转移的程度和耐用性来支持这些方案（Hardy等，2011）。 Immune reconstitution following lymphodepletion: In several ongoing ETIB clinical trials of allogeneic stem cell tr​​ansplantation therapies (04-C-0055, 07-C-0195, 09-C-0210; 09-C-0096; PIs Daniel Fowler, Michael Bishop, Steven Pavletic and Dennis Hickstein) the process of immune reconstitution has been assessed, focusing on the factors有助于恢复的个体变化。这些数据有助于一份关于一种新型非毛囊诱导方案Epoch-F的疗效的报告，在多发性骨髓瘤和淋巴样恶性肿瘤患者中同种异体干细胞移植中（Jamshed等，2011; Salit等，2012）。目前，我们正在使用10色流式细胞仪来表征淋巴细胞再生，并将其与胸腺恢复，复发，GVHD和慢性潜伏病毒的重新激活相关。这些平行研究涉及对三项正在进行的试验（07-C-0195、11-C-0016、11-C-0136）的分析，这些试验涵盖了当前移植实践的广度：与无关供体的同种异体移植，自体供体通过添加T1-rapa rapa rapa rapa firvive t cell t细胞疗法，且肌张力型肌张力症。另外，当评估谱系特异性重生很重要时，我们使用Etib流式细胞仪核心设施（William Telford）对淋巴细胞进行分类以进行亚集特异性供体嵌合分析。这些测定包括对涉及GATA2或DOCK8（09-C-0096，PI：DENNIS HICKSTEIN）的单基因免疫缺乏的患者以及接受双供体脐带血的患者（09-C-0210，PI：PI：Michael Bishop）的患者。最后，我们与NHLBI的血液学分支合作，在长期接受同种异体干细胞移植的人中对T细胞受体曲目多样性进行分析，表明受体在10年后发展了多样的曲目，与捐助者相提并论（Le等人，2011年）。在正在进行的自然历史方案（P.I. Steven Pavletic：04-C-0281）中，已通过多学科临床团队评估了在同种异体移植后开发CGVHD的患者。 PCS核心通过有助于鉴定CGVHD生物标志物和对CGVHD发病机理的理解来支持这项研究。两项研究有助于导致CGVHD中硬化皮肤疾病发展的因素（Martires等，2011; Martires等人2011b）以及对CGVHD预后的临床实验室测试相关性的研究（Grkovic等人，2012年）。此外，我们通过评估白细胞受体（P. I. Ronald Gress和Kirsten Williams：08-C-0097）的严重CGVHD的治疗试验，通过评估白细胞受体（LTR）在白细胞中的表达和液化液中的角色lungibr comperive ltry ltrtribr comperive ltrtribr intribr seprive。我们通过评估该TGFBETA信号抑制剂对TH17和Treg人口的影响，支持对硬化性胸腺CGVHD的协作试验测试伊马替尼治疗（皮肤病学和小儿分支，P.I。Edward Cowen和Kristin Baird），P.I. Edward Cowen和Kristin Baird）。我们还支持一项试验，该试验测试含有有效类固醇Clobetasol的漱口水作为口服CGVHD的局部疗法（12-C-0068； P.I. Steven Pavletic）。最后，CGVHD已成为PCS核心研究的重要重点。这项研究已经启动了三个PC项目。首先，我们确定了CGVHD中细胞因子BAFF的血浆水平升高。这种增加与干扰素（IFN）诱导的炎症细胞因子的血浆水平升高以及循环B细胞水平降低显着相关。其次，我们通过表征循环和受影响的组织中的Treg来开始研究调节性T细胞（TREG）在CGVHD中的作用。最后，我们使用组织免疫组织化学，血浆细胞因子ELISA和基因表达的测定来检验以下假设：IFN诱导的炎症过程可能是CGVHD中许多系统性过程的基础（Imanguli等，2009; Hakim，2010）。这些研究构成了申请员工科学家职业发展奖的基础，该奖项于2010年1月资助，该项目详细介绍了创新奖，使用循环单核细胞作为记者细胞，以确定CGVHD的自身免疫性症状的开发的细胞因子和趋化因子途径。在协调的研究中，我们评估了细胞因子和趋化因子的血浆水平，并通过微阵列和定量多重RNA测量测量了单核细胞的基因表达模式。我们确定与正常供体和非GVHD移植受者相比，CGVHD患者的I型IFN驱动过程升高。这项工作可以支持CGVHD诊断或预后测定法的发展，并有助于新的治疗方法。癌症部位：Hodgkins病/淋巴瘤，非霍奇金斯淋巴瘤，白血病，多发性骨髓瘤。 相关研究领域：免疫学，骨髓移植，自身免疫性疾病，SLE/狼疮，干扰素，血液学/淋巴，衰老，干细胞研究，临床研究。