MECHANISMS OF GVHD PREVENTION WITH POST-TRANSPLANT CYCLOPHOSPHAMIDE

移植后环磷酰胺预防 GVHD 的机制

• 批准号: 8269451
• 负责人: Leo Luznik
• 金额: $ 43.58万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-15 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8269451
• 关键词: Acute; Acute Graft Versus Host Disease; Allogenic; Antigens; Apoptosis; Autoimmune Diseases; Autoimmunity; Cells; Chronic; Clinical Data; Clinical Trials; Cyclophosphamide; Cytomegalovirus; DNA Sequence; Data; Development; Disease; Dose; Environment; Failure; Frequencies; Genome; Hematological Disease; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Homeostasis; Immune; Immune system; Immunity; Immunologics; Immunosuppression; Immunosuppressive Agents; Immunotherapeutic agent; Incidence; Infection; Intervention; Knowledge; Laboratory Study; Measures; Memory; Molecular; Morbidity - disease rate; Non-Malignant; Patients; Predisposition; Prevention; Prevention strategy; Prophylactic treatment; Recovery; Recruitment Activity; Recurrent disease; Regulatory T-Lymphocyte; Resolution; Sampling; Staging; Stem cell transplant; Survival Rate; T cell response; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Testing; Time; Toxic effect; Transplant Recipients; Transplantation; Work; advanced disease; chronic graft versus host disease; clinically significant; complementarity-determining region 3; conditioning; disorder prevention; graft vs host disease; improved; insight; leukemia; mortality; novel; novel strategies; prevent; prophylactic; reconstitution; success; tumor

DESCRIPTION (provided by applicant): Emerging clinical data in the HLA-matched setting suggest that high-dose post-transplant cyclophosphamide (Cy) given as a single agent is effective in preventing both acute and chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (alloHSCT). Patients who undergo transplants using this strategy have a low incidence of infections, and despite advanced disease stage, their survival rate is favorable, suggesting that this approach retains the graft-versus-leukemia effect. The exact mechanisms behind the efficacy of high-dose Cy as a post-transplant immunosuppressant are not fully understood, and systematic study of the correlates of T-cell immune recovery in the context of our ongoing multiinstitutional clinical trial will be crucial for complete understandingof the mechanisms. We hypothesize that high-dose Cy prevents acute GVHD by reducing the frequency of effector T cells while sparing the critical regulatory T-cell (Treg) pool. In addition we predict that the rapid establishment of regulatory T-cell homeostasis is critical for the development of tolerance and the absence of chronic GVHD. Finally, we hypothesize that grade 2-4 acute GVHD that requires treatment with conventional immune suppression after high-dose Cy prophylaxis will be associated with a significant delay in the recovery of a diverse T-cell receptor (TCR) repertoire in the Treg compartment. To test the validity of our hypotheses, we will first test for associations between the cellular and molecular changes in the effector and regulatory T-cell subsets and the development of grade 2-4 acute GVHD in patients treated with post-transplantation Cy. Second, we will determine whether the absence of chronic GVHD and the development of tolerance are influenced by Treg repertoire reconstitution and thymic recovery. Third, by measuring the TCR 2 chain CDR3 region sequence diversity in the naive, memory and regulatory T- cell compartments using high-throughput DNA sequencing technology, we will analyze whether any significant GVHD that occurs after the high-dose Cy prophylaxis is associated with the delayed reconstitution of a diverse Treg repertoire. The work proposed is expected to provide essential mechanistic insights supporting the use of a short course of GVHD prophylaxis that promotes tolerance induction and provides immune system reconstitution in an environment free of ongoing pharmacologic immunosuppression. It will also provide a high- resolution picture of the immune spectra in T-cell subsets and illuminate a path toward better control of alloreactivity. PUBLIC HEALTH RELEVANCE: The use of post-transplantation cyclophosphamide as short-course GVHD prophylaxis that promotes tolerance induction carries the promise of decreasing the toxicities associated with chronic immunosuppression and of improving the prevention of GVHD, which is the major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplant (alloHSCT). We expect that once the operational mechanisms behind the efficacy of cyclophosphamide in GVHD prevention and tolerance induction are understood and a high- resolution picture of its effect on post-transplant immune recovery is gained, this strategy may potentially provide an optimal platform for immunotherapeutic interventions that boost tumor-specific immunity and prevent disease relapse. In addition, this approach may extend the applicability of alloHSCT to patients with non-malignant hematological and autoimmune disorders.

描述（由申请人提供）：hla匹配的新临床数据表明，移植后大剂量环磷酰胺（Cy）作为单一药物可有效预防同种异体造血干细胞移植（alloHSCT）后急性和慢性移植物抗宿主病（GVHD）。使用这种策略进行移植的患者感染发生率低，尽管疾病处于晚期，但其生存率较高，这表明这种方法保留了移植物抗白血病的效果。高剂量Cy作为移植后免疫抑制剂疗效背后的确切机制尚不完全清楚，在我们正在进行的多机构临床试验背景下，对t细胞免疫恢复相关因素的系统研究对于完全理解其机制至关重要。我们假设高剂量Cy通过减少效应T细胞的频率来预防急性GVHD，同时保留关键的调节性T细胞（Treg）池。此外，我们预测调节性t细胞稳态的快速建立对于耐受性的发展和慢性GVHD的缺失至关重要。最后，我们假设在高剂量Cy预防治疗后需要常规免疫抑制治疗的2-4级急性GVHD将与Treg室中多种t细胞受体（TCR）库恢复的显着延迟相关。为了验证我们假设的有效性，我们将首先测试效应t细胞和调节性t细胞亚群的细胞和分子变化与移植后Cy患者2-4级急性GVHD发展之间的关系。其次，我们将确定慢性GVHD的缺失和耐受性的发展是否受到Treg库重建和胸腺恢复的影响。第三，通过使用高通量DNA测序技术测量初始、记忆和调节性T细胞区室中tcr2链CDR3区域序列多样性，我们将分析高剂量Cy预防后发生的任何显著的GVHD是否与多种Treg库的延迟重建有关。这项工作预计将提供基本的机制见解，支持使用短期的GVHD预防，促进耐受性诱导，并在没有持续的药物免疫抑制的环境中提供免疫系统重建。它还将提供t细胞亚群免疫光谱的高分辨率图像，并阐明更好地控制同种异体反应性的途径。公共卫生相关性：移植后使用环磷酰胺作为短期GVHD预防，促进耐受诱导，有望减少与慢性免疫抑制相关的毒性，并改善GVHD的预防，GVHD是同种异体造血干细胞移植（alloHSCT）后发病率和死亡率的主要原因。我们期望，一旦环磷酰胺在GVHD预防和耐受诱导中的作用机制被理解，并获得其对移植后免疫恢复影响的高分辨率图像，该策略可能为免疫治疗干预提供最佳平台，从而提高肿瘤特异性免疫和预防疾病复发。此外，这种方法可能扩大同种异体造血干细胞移植对非恶性血液学和自身免疫性疾病患者的适用性。