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: 7969971
• 负责人: Frances Hakim
• 金额: $ 76.54万
• 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/7969971
• 关键词: Acute; Acute Graft Versus Host Disease; Affect; Aging; Allogenic; Apoptosis; Autoimmune Process; Autoimmunity; Autologous; Autologous Stem Cell Transplantation; B-Lymphocytes; Biological Assay; Biological Markers; Biopsy; Blood Cells; Blood Circulation; Bronchial Lavages; Bronchiolitis Obliterans; CD34 gene; CD8-Positive T-Lymphocytes; CD8B1 gene; CXCL9 gene; Cell Count; Cells; Chronic; Clinical; Clinical Research; Clinical Trials; Collaborations; Complication; Cutaneous; Data; Dendritic Cells; Dermis; Development; Effector Cell; Epithelial; Epithelium; Family; Fibrosis; Flow Cytometry; Frequencies; Functional disorder; Generations; Genes; Goals; Hematopoietic Stem Cell Transplantation; Homologous Transplantation; Immune; Immunohistochemistry; Immunotherapy; Infection; Infiltration; Inflammatory; Infusion procedures; Interferon Type I; Interferons; Interleukin-15; Interleukin-7; Leukocytes; Leukotriene Receptor; Leukotrienes; Link; Lipopolysaccharides; Lung diseases; Lupus; Lymphocyte; Lymphocyte Depletion; Lymphocyte Subset; Lymphokines; Lymphopoiesis; Marrow; Memory; Modality; Modeling; Monitor; Monokines; Morbidity - disease rate; Myeloid Cells; Natural History; Oral; Oral mucous membrane structure; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Plasma; Play; Population; Predisposition; Process; Production; Protocols documentation; Recovery; Research; Research Support; Role; Sampling; Secure; Services; Staging; Stem cell transplant; Symptoms; Systemic Lupus Erythematosus; T-Cell Receptor; T-Lymphocyte; TNF gene; Therapeutic; Therapy Clinical Trials; Thromboplastin; Time; Tissues; Transplantation; Transplantation Immunology; Treatment Protocols; United States National Institutes of Health; Upper arm; Vaccines; Work; base; chemokine; chemotherapy; chronic graft versus host disease; clinical effect; cytokine; cytotoxic; disease natural history; efficacy trial; follow-up; graft vs host disease; keratinocyte; migration; mortality; multidisciplinary; older patient; peripheral blood; pre-clinical; reconstitution; response; trafficking; transcription factor; tumor; Acute; Acute Graft Versus Host Disease; Affect; Aging; Allogenic; Apoptosis; Autoimmune Process; Autoimmunity; Autologous; Autologous Stem Cell Transplantation; B-Lymphocytes; Biological Assay; Biological Markers; Biopsy; Blood Cells; Blood Circulation; Bronchial Lavages; Bronchiolitis Obliterans; CD34 gene; CD8-Positive T-Lymphocytes; CD8B1 gene; CXCL9 gene; Cell Count; Cells; Chronic; Clinical; Clinical Research; Clinical Trials; Collaborations; Complication; Cutaneous; Data; Dendritic Cells; Dermis; Development; Effector Cell; Epithelial; Epithelium; Family; Fibrosis; Flow Cytometry; Frequencies; Functional disorder; Generations; Genes; Goals; Hematopoietic Stem Cell Transplantation; Homologous Transplantation; Immune; Immunohistochemistry; Immunotherapy; Infection; Infiltration; Inflammatory; Infusion procedures; Interferon Type I; Interferons; Interleukin-15; Interleukin-7; Leukocytes; Leukotriene Receptor; Leukotrienes; Link; Lipopolysaccharides; Lung diseases; Lupus; Lymphocyte; Lymphocyte Depletion; Lymphocyte Subset; Lymphokines; Lymphopoiesis; Marrow; Memory; Modality; Modeling; Monitor; Monokines; Morbidity - disease rate; Myeloid Cells; Natural History; Oral; Oral mucous membrane structure; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Plasma; Play; Population; Predisposition; Process; Production; Protocols documentation; Recovery; Research; Research Support; Role; Sampling; Secure; Services; Staging; Stem cell transplant; Symptoms; Systemic Lupus Erythematosus; T-Cell Receptor; T-Lymphocyte; TNF gene; Therapeutic; Therapy Clinical Trials; Thromboplastin; Time; Tissues; Transplantation; Transplantation Immunology; Treatment Protocols; United States National Institutes of Health; Upper arm; Vaccines; Work; base; chemokine; chemotherapy; chronic graft versus host disease; clinical effect; cytokine; cytotoxic; disease natural history; efficacy trial; follow-up; graft vs host disease; keratinocyte; migration; mortality; multidisciplinary; older patient; peripheral blood; pre-clinical; reconstitution; response; trafficking; transcription factor; 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 association with a Phase I clinical trial of IL-7 administration (P. I. Claude Sportes: 03-C-0152, in collaboration with Crystal Mackall in POB), we determined that IL-7 significantly expanded nave 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. In further studies of the clinical effects of this therapy, we determined that IL-7 produced a transient expansion of early B cell lymphopoiesis that was evident in the peripheral blood as an increase in transitional (T1) immature B cells. These studies support the use of IL-7 therapy to enhance T cell numbers and repertoire in patients with limited thymopoietic capacity, such as in aging populations and in patients with immune deficits after chemotherapy. Continuing studies will focus on the role of IL-7 in conjunction with vaccine responses in older patients. Immune reconstitution following intensive lymphodepletion and autologous CD34+ stem cell transplantation in patients with severe systemic lupus erythematosus (SLE): In an ongoing trial (P.I. Steven Pavletic 04-C-0095), T and B cell immune reconstitution has been monitored to assess the efficacy of the cytoreductive regimen in depleting T and B cells and the timecourse of immune recovery. These continuing studies contribute to development of autologous transplant as a therapeutic modality in treatment of severe lupus. 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 chronic GVHD following allogeneic transplantation have been evaluated by a multidisciplinary clinical team. The PSC core has supported the study by contributing to the identification of biomarkers and the understanding of chronic GVHD pathogenesis. Four PCS projects have been initiated from this study. First, we have determined that plasma levels of the cytokine BAFF (B cell activating factor of the TNF family) are elevated in chronic GVHD. This increase is significantly correlated both with elevated plasma levels of Interferon (IFN)-induced inflammatory cytokines and with reduced levels of circulating B cells. We have linked these elevated BAFF levels with increases in transitional B cells, consistent with a reduction in the negative selection process occurring at this maturation stage. Such a change may contribute to the development of the autoimmune symptoms that characterize CGVHD. In a second project, Matin Imanguli, an ETIB clinical research fellow working in the Core, used immunohistochemistry and PCR to determine that severe oral CGVHD of the buccal mucosa was primarily associated with infiltrating T cells expressing T-bet, a transcription factor marking Type I cytokine polarization (Th1/Tc1). Increased epithelial apoptosis, the distinctive feature of active oral CGVHD, was associated with an increase in CD8 cells with cytotoxic markers. Concurrently, we observed increased expression of interferon-induced factors including the chemokine MIG (CXCL9) and IL-15 in both infiltrating cells and keratinocytes in the affected tissues; these factors support the migration, Th1/Tc1 differentiation and expansion of the T effectors. We further observed the Type I interferon-specific gene MxA in the mucosal epithelium and plasmacytoid dendritic cells (pDC), the main producer of Type I interferons, in the infiltrate. These data support a model that oral cGVHD results from the interaction of interferon-driven inflammatory processes and Tc1/Th1 differentiated effectors. In a third project exploring IFN-induced processes in CGVHD, we have identified a similar process of infiltration of cytotoxic T effectors in the dermis in patients with erythematous cutaneous CGVHD. Again, the IFN induced chemokine MIG is produced by affected keratinocytes and infiltrating myeloid cells. We have further correlated these findings in severely affected patients with elevated levels of IFN-induced cytokines and chemokines in the patients plasma. These three studies support the hypothesis that IFN-induced inflammatory processes may underlie many of the systemic processes in CGVHD. In a fourth project, we have initiated studies into the role of regulatory T cells (Treg) in CGVHD. Treg cells have been proposed to play a critical role in controlling autoimmunity. We have characterized Treg in the circulation and in affected tissues, investigating the roles of thymopoiesis, proliferative expansion and chemokine-controlled trafficking in Treg distribution. In addition to research on patients in the CGVHD natural history protocol, we support a therapeutic trial for bronchiolitis obliterans, a severe complication of chronic GVHD (P. I. Ronald Gress and Kirsten Williams: 08-C-0097). The core provides multi-parameter flow cytometric assessment of leukotriene receptor levels in peripheral blood leukocytes and in bronchial lavage cells to support a trial of the efficacy of a drug blocking the leukotriene pathway in inhibiting the progression of fibrosis in this obstructive lung disorder. Cytokine and monokine production following Th2 and Th2/Tc2 therapy based transplant regimens: An ongoing project has assessed lymphokine and monokine production capacity post transplant, focusing on allogeneic transplants incorporating immune therapy with Th2, Th2/Tc2 or Th2.rapa donor-derived cells (P. I. Dan Fowler, 04-C-0055, 04-C-0131). In the early post-transplant period and at regular intervals thereafter, the cytokine and monokine production capacity of peripheral blood cells has been determined by generation of anti CD3/anti CD28-stimulated and bacterial lipopolysaccharide (LPS) 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 efficacy and durability of the cytokine shift resulting from the infusion of Th2/Tc2 and Th2-rapa cells. Immune reconstitution following lymphodepletion: In several ongoing ETIB clinical trials of allogeneic and autologous stem cell transplantation therapies (04-C-0055 and 07-C-0195; PIs Daniel Fowler and Michael Bishop) as well as in continuing follow-up of earlier trials (96-C-0104, 99-C-0143, 03-C-0077; P.I.s Claude Sportes, Daniel Fowler, Michael Bishop), the process of immune reconstitution has been assessed, focusing on the contributions of thymopoiesis and homeostatic cytokines to the recovery of CD4 and CD8 T cell populations following transplantation. These studies have demonstrated an inverse correlation between circulating plasma levels of IL-7 and CD4 and CD8 T cell populations. Furthermore, (in collaboration with T. Fry in POB) they have identified IL-7 levels at 2 weeks post transplant as a potential biomarker predictive of development of acute GVHD. Finally, in collaboration with Alan Wayne and Terry Fry (01-C-0125), we have assessed the contributions of donor [summary truncated at 7800 characters]

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。所有数据均纳入特定于协议的电子表格，将样品与协议臂和移植时间点联系起来，并可以通过安全的NIH网络访问分支机构。 IL-7给药的效果：与IL-7给药的I期临床试验相关（P. I. Claude Sportes：03-C-0152，与POB中的Crystal Mackall合作），我们确定IL-7显着扩展了中枢神中的和中心存储器CD4和CD8 T细胞，与效应的细胞相比，导致了CYLER propper propper e Reptor the Offer the thever the Cyper the Cyper the Myvertor the thever the Myveror the thever the Myveror the Myveror the Myveror。在对该疗法的临床作用的进一步研究中，我们确定IL-7产生了早期B细胞淋巴细胞的短暂扩张，这在外周血中很明显，这是过渡（T1）未成熟B细胞的增加。这些研究支持使用IL-7疗法来增加胸腺无能能力有限的患者（例如衰老人群和化学疗法后的免疫缺陷患者）的T细胞数量和曲目。持续研究将重点介绍IL-7与老年患者疫苗反应的作用。严重的全身性狼疮eRythematosus（SLE）患者进行强化淋巴结凝结和自体CD34+干细胞移植后，不对的重建：在正在进行的试验中（P.I. Steven Pavletic 04-C-0095），T和B细胞进行了调节，以评估TIM的效率，并确定了cy的效率，并确定了效率。免疫恢复。这些持续研究有助于自体移植作为严重狼疮治疗的治疗方式的发展。慢性移植物与宿主病（CGVHD）的免疫种群和功能障碍：在持续的自然历史方案（P.I. Steven Pavletic：04-C-0281）中，多学科临床团队评估了同种异体移植后慢性GVHD的患者。 PSC核心通过为生物标志物的鉴定和对慢性GVHD发病机理的理解做出贡献来支持这项研究。这项研究已经启动了四个PC项目。首先，我们确定了慢性GVHD中细胞因子BAFF的血浆水平（TNF家族的B细胞激活因子）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。我们已经将这些升高的BAFF水平与过渡B细胞的增加联系起来，这与在此成熟阶段发生的负选择过程的减少一致。这种变化可能有助于表征CGVHD的自身免疫性症状的发展。在第二个项目中，在核心工作的Etib临床研究研究员Matin Imanguli使用免疫组织化学和PCR确定颊粘膜的严重口服CGVHD主要与表达T型T型T-表达T-BET的T细胞（转录因子标记I型细胞因子极化（TH1/TC1））。上皮细胞凋亡的增加，即主动口服CGVHD的独特特征，与带有细胞毒性标记的CD8细胞增加有关。同时，我们观察到了干扰素诱导的因子的表达增加，包括浸润细胞和受影响组织中浸润细胞和角质形成细胞中的趋化因子MIG（CXCL9）和IL-15。这些因素支持迁移，T1/TC1分化和T效应子的扩展。我们进一步观察了I型干扰素特异性基因MXA在浸润液中的I型干扰素的主要产生者（PDC）（PDC）中。这些数据支持了一个模型，该模型是由干扰素驱动的炎症过程与TC1/TH1差异化效应子的相互作用引起的。在探索CGVHD中IFN诱导过程的第三个项目中，我们已经确定了类似的红细胞皮肤CGVHD患者真皮中细胞毒性T效应子的类似过程。同样，IFN诱导的趋化因子MIG由受影响的角质形成细胞和浸润的髓样细胞产生。在严重影响的患者中，患者血浆中IFN诱导的细胞因子和趋化因子水平升高，我们已经进一步关联了这些发现。这三项研究支持以下假设：IFN诱导的炎症过程可能是CGVHD中许多系统过程的基础。在第四个项目中，我们开始研究调节性T细胞（TREG）在CGVHD中的作用。已经提出Treg细胞在控制自身免疫方面发挥关键作用。我们已经在循环和受影响的组织中表征了Treg，研究了胸腺波索斯，增殖性扩张和趋化因子控制的运输在Treg分布中的作用。除了研究CGVHD自然历史方案中的患者外，我们还支持一项针对牙本质炎的治疗试验，这是慢性GVHD的严重并发症（P. I. Ronald Gress和Kirsten Williams：08-C-0097）。该核心提供了外周血白细胞和支气管灌洗细胞中白细胞受体水平的多参数流式细胞仪评估，以支持药物阻断白细胞途径抑制这种阻塞性肺部纤维化进展的药物疗效的试验。基于TH2和TH2/TC2治疗后的细胞因子和单因子产生基于移植方案：一个正在进行的项目已经评估了移植后的淋巴因子和单因子生产能力，重点是将免疫治疗与TH2，TH2/TC2或TH2.RAPA供体供体细胞（P. I. Dan Fowler，04-C-cy）纳入同种异体疗法，04-C-c-04-c-c-04-c-c- 04-c-cy。在移植后期和此后的定期间隔中，周围血细胞的细胞因子和单因子的产生能力已通过产生抗CD3/抗CD28刺激的抗CD3/抗CD28刺激和细菌脂多糖（LPS）刺激上清液以及通过评估细胞因子产生细胞的频率的频率流动cytry cytry的频率。这些测定方法通过评估由Th2/Tc2和Th2-rapa细胞输注而导致的细胞因子转移的功效和耐用性来支持这些方案。淋巴结序列后的免疫重建：在几项正在进行的同种异体和自体干细胞移植疗法（04-C-0055和07-C-0195; PIS Daniel Fowler和Michael Bishop）的临床试验中Sportes，Daniel Fowler，Michael Bishop），已经评估了免疫重建的过程，重点是胸腺绝位和稳态细胞因子对移植后CD4和CD8 T细胞种群恢复的贡献。这些研究表明，IL-7和CD4和CD8 T细胞种群的循环血浆水平之间存在逆相关性。此外，（与POB中的T. Fry合作）他们在移植后2周确定IL-7水平是急性GVHD发展的潜在生物标志物。最后，与艾伦·韦恩（Alan Wayne）和特里·弗莱（Terry Fry）合作（01-C-0125），我们评估了捐助者的贡献[摘要以7800个字符截断]