Transplantation tolerance and immune function following mTOR inhibition.

mTOR 抑制后的移植耐受和免疫功能。

• 批准号: 8318280
• 负责人: JONATHAN D POWELL
• 金额: $ 40.59万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-18 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318280
• 关键词: Allogenic; Anemia; Animal Model; Antibody Formation; Antigens; Antiviral Agents; Antiviral Response; Autoimmunity; Back; Biochemical; Biochemical Process; Blood specimen; Bone Marrow Transplantation; CD8B1 gene; CMV pp65 Peptide; Calcineurin inhibitor; Cell physiology; Chelation Therapy; Chimerism; Chronic; Clinical; Clinical Trials; Complex; Cyclophosphamide; Cytomegalovirus; Data; Dose; Effector Cell; Engraftment; Foundations; Frequencies; Generations; Graft Rejection; Health Care Costs; Hematological Disease; Hospitalization; IL2RA gene; Immune; Immunity; Immunologics; Immunosuppression; In Vitro; Influenza; Influenza vaccination; Lymphocyte; Lymphocytic choriomeningitis virus; Measures; Mediating; Mixed Lymphocyte Culture Test; Morbidity - disease rate; Non-Malignant; Organ Transplantation; Outcome; Pain; Patients; Peptides; Phenotype; Phosphorylation; Phosphotransferases; Population; Production; Protocols documentation; Publishing; Pulmonary Hypertension; Recommendation; Recovery; Regimen; Regulatory T-Lymphocyte; Research; Resistance; Respiratory Tract Infections; Risk; Role; Sampling; Siblings; Sickle Cell Anemia; Signal Transduction; Sirolimus; Solid; Staining method; Stains; T cell anergy; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Th1 Cells; Time; Transfusion; Transplantation; Transplantation Tolerance; Vaccines; Virus Diseases; Whole-Body Irradiation; Withdrawal; alemtuzumab; anergy; base; clinically relevant; conditioning; cytokine; design; enzyme linked immunospot assay; epidemiologic data; graft failure; graft vs host disease; human FRAP1 protein; immune function; improved; kinase inhibitor; mTOR Inhibitor; mTOR inhibition; mortality; novel; peripheral blood; public health relevance; response; seasonal influenza; success

DESCRIPTION (provided by applicant): Nonmyeloablative bone marrow transplant offers a safe, potentially curative treatment for non-malignant hematological diseases such as sickle cell anemia. Unfortunately, successful nonmyeloablative transplant to treat sickle cell anemia has been limited due to immune-mediated graft rejection. Our research has demonstrated that rapamycin can promote regulatory T cell (Treg) differentiation of naive T cells and anergy of Th1 cells following T cell activation. We used these observations to develop a novel preparative regimen to inhibit rejection and graft versus host disease (GVHD) by promoting T cell tolerance. Our strategy reduces the frequency of alloreactive T cells with alemtuzumab, creates "space" for engraftment with low dose total body irradiation, and allows lymphocyte recovery under extended rapamycin treatment. In the matched sibling setting this approach has had great success, resulting in stable mixed chimerism that corrects their hematological phenotype of sickle cell anemia and reverses pulmonary hypertension. Based on this success, a second clinical trial was developed to expand the potential donor pool to include haploidentical related donors, greatly increasing potential availability of this therapy to patients. The new trial employs the same fundamental principles in the choice of preparative regimen with the addition of dose escalation of post transplant cyclophosphamide to further reduce alloreactive T cells that could contribute to rejection or GVHD. Peripheral blood samples from patients and donors on this trial will provide a unique opportunity to systematically investigate the role of T cell tolerance in promoting stable chimerism. We propose to do this by examination of mixed lymphocyte reactions (MLRs) and intracellular cytokine staining (ICS) from samples obtained pretransplant, posttransplant on rapamycin, and posttransplant after completion of rapamycin therapy. We will determine whether the continued presence of rapamycin is necessary to suppress allogeneic responses in vitro and whether the tolerance measured in the MLR is dependent on the presence of Tregs. We will test whether addition of rapamycin or Tregs is able to suppress the MLR from a patient who develops graft rejection or GVHD while receiving rapamycin. We will determine if clinical resistance to rapamycin in the form of rejection or GVHD corresponds to biochemical resistance to rapamycin at the level of mTOR target phosphorylation and whether a novel mTOR kinase inhibitor can overcome such biochemical resistance in vitro. A final aim is to determine whether prolonged mTOR inhibition interferes with antigen specific T cell cytokine production or leads to generation of antigen specific Tregs to clinically relevant CMV or influenza A. We believe that a better understanding of the immunologic consequences of mTOR inhibition will result in safer and more successful bone marrow transplantation, allowing expansion of this potentially curative therapy to a wider number of patients with chronic hematologic illnesses. PUBLIC HEALTH RELEVANCE (provided by applicant): Sickle cell anemia and other chronic anemias impose a huge burden of pain and suffering for patients and large health care costs related to hospitalizations and chronic transfusion/chelation therapy. In this proposal we seek to define the operative cellular and biochemical processes that promote T cell tolerance in a novel protocol to cure sickle cell disease with non-myeloablative bone marrow transplantation. It is hoped that the results of this study will allow safer application of this curative therapy to a greater number of patients and aid in improving tolerogenic therapy for autoimmunity and solid organ transplantation as well.

描述（由申请人提供）：非甲状腺骨髓移植提供了安全的，潜在的治疗性治疗，可用于镰状细胞贫血等非机敏性血液学疾病。不幸的是，由于免疫介导的移植物排斥，成功治疗镰状细胞贫血的非乳不公动移植受到限制。我们的研究表明，雷帕霉素可以促进幼稚T细胞的调节性T细胞（TREG）分化，而T细胞激活后Th1细胞的厌食症。我们使用这些观察结果来开发一种新型的制备方案，以抑制通过T细胞耐受性来抑制排斥和移植与宿主疾病（GVHD）。我们的策略用Alemtuzumab降低了同种反应性T细胞的频率，创建了具有低剂量的总体辐照的“空间”，并允许在雷帕霉素治疗的扩展下淋巴细胞恢复。在匹配的兄弟姐妹设置中，这种方法取得了巨大的成功，导致稳定的混合嵌合体纠正其镰状细胞贫血的血液学表型并逆转肺动脉高压。基于这一成功，开发了第二次临床试验，以扩大潜在的供体池，包括与单倍型相关的供体，大大增加了这种疗法对患者的潜在可用性。这项新试验采用相同的基本原理在选择制备方案中，增加了移植后环磷酰胺的剂量升级，以进一步减少可能有助于排斥或GVHD的同种反应性T细胞。该试验中的患者和捐助者的外周血样本将为系统地研究T细胞耐受性在促进稳定的嵌合体中的作用提供独特的机会。我们建议通过检查混合淋巴细胞反应（MLR）和细胞内细胞因子染色（IC）（ICS），该样品在完成雷帕霉素治疗后，在雷帕霉素上获得的样品，雷帕霉素的移植后和移植剂进行后移植。我们将确定雷帕霉素的持续存在是否需要在体外​​抑制同种异反应以及MLR中测得的公差是否取决于Treg的存在。我们将测试雷帕霉素或Tregs的添加是否能够抑制在接受雷帕霉素时产生移植物排斥或GVHD的患者的MLR。我们将确定以排斥反应或GVHD形式对雷帕霉素的临床抗性是否对应于MTOR靶磷酸化水平上对雷帕霉素的生化耐药性，以及新型的MTOR激酶抑制剂是否可以克服体外生物化学耐药性。最终目的是确定延长MTOR抑制作用会干扰特定的T细胞因子的产生或导致产生与临床相关的CMV或流感A的抗原特异性Treg或A. A.我们更好地理解MTOR抑制作用的免疫学后果会导致SAFER和更成功的骨骼疗法，从而可以将这种跨性疗法延伸到这种跨性别术中，从而使骨骼的扩展构成了一定的跨越型骨骼的锻炼。血液学疾病。 公共卫生相关性（由申请人提供）：镰状细胞性贫血和其他慢性贫血对患者造成了巨大的痛苦和痛苦负担，以及与住院和慢性输血/螯合疗法有关的大量医疗保健费用。在此提案中，我们试图定义具有非毛囊骨髓移植的新型方案，以治愈镰状细胞疾病，以促进T细胞耐受性的手术性细胞和生化过程。希望这项研究的结果能够使这种治疗疗法更安全地应用于更多的患者，并有助于改善自身免疫性和固体器官移植的耐受性疗法。