Mechanisms of tolerance in recipients of combined kidney and bone marrow transpla

肾骨髓联合移植受者的耐受机制

• 批准号: 7728635
• 负责人: Megan Sykes
• 金额: $ 23.41万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-11 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7728635
• 关键词: Achievement; Acute; Address; Allograft Tolerance; Allografting; Antibodies; Antigens; Autoantibodies; B-Lymphocytes; Biological Assay; Biopsy Specimen; Bone Marrow; Bone Marrow Transplantation; CD4 Positive T Lymphocytes; Cell Count; Cells; Chronic; Clinical Research; Clinical Trials; Complement; Core Facility; Development; Funding; Grant; Hematopoietic; Housing; Human; Immune Tolerance; Immunoglobulin Class Switching; Immunosuppression; Immunosuppressive Agents; In Vitro; Isoantibodies; Kidney; Kidney Transplantation; Maintenance; Measures; Organ Transplantation; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phenotype; Population; Protocols documentation; Reporting; Role; T-Cell Depletion; T-Lymphocyte; Therapeutic immunosuppression; Time; Toxic effect; Transplantation; Treatment Protocols; Tubular formation; conditioning; in vivo; kidney allograft; peripheral blood; pilot trial; response; success

Induction of allograft tolerance would avoid the need for chronic immunosuppressive therapy with its attendant toxicities. We have recently performed a pilot trial of combined non-myeloabiative bone marrow and kidney transplantation (CKBMT) from related haploidentical donors. Four of 5 patients achieved durable allograft acceptance without maintenance immunosuppression, representing the first successful intentional achievement of tolerance to HLA-mismatched allografts. In vitro studies revealed the development of specific unresponsiveness to the donor in assays that primarily measure direct alloreactivity. Regulatory T cells (Tregs) were enriched in the recovering peripheral blood T cell populations, and suppression of anti-donor reactivity was detected variably within the first year post-transplant. However, early acute humoral rejection episodes occurred in several patients, resulting in the addition of B cell-depleting anti-CD20 mAb to the regimen. Several patients developed autoantibodies and donor-specific alloantibodies in the presence of low T cell counts and/or T cell tolerance in vivo and in vitro. We hypothesize that these antibodies are generated by recovering transitional B cells in the absence of T cell help. However, an alternative hypothesis is that indirectly alloreactive T cells provide help for class-switched Ig responses in these patients, despite the donor unresponsiveness seen in bulk MLR and CML assays. The protocol is now being reopened to include both HLA-haploidentical and more extensively mismatched donors. We propose to address several hypotheses in order to understand the tolerance achieved through CKBMT. We will: 1) Assess tolerance of directly and indirectly donor alloreactive T cells in recipients of HLA-mismatched CKBMT. Indirect responses to both hematopoietic and renal tubular cell-derived antigens will be measured and interpreted in the context of the development of anti-donor antibodies; and 2) Assess the role of regulatory cells, including FoxP3+ Treg and CD127-C025-C04 cells, in the development of donor-specific tolerance in recipients of CKBMT. We will assess the phenotype and function of regulatory cell populations obtained from patient PBMC and expanded from renal biopsy specimens. We hypothesize that donor-specific regulatory cells will be enriched in the renal allograft compared to the PBMC and that donor-specific regulatory capacity will decline over time as deletion of donor-reactive T cells occurs. In combination with studies performed at the ITN core facilities, our studies should promote a comprehensive understanding of the mechanisms involved In tolerance induced by CKBMT.

诱导同种异体移植的耐受性将避免对其随附的毒性进行慢性免疫抑制治疗。我们最近对相关单倍体供体进行了非乳脂骨髓和肾脏移植（CKBMT）的合并试验试验。在没有维持免疫抑制的情况下，有5例患者中有4例获得了持久的同种异体移植，这是对HLA不抗匹配的同种异体移植物的首次成功实现耐受性。体外研究揭示了主要衡量直接同种反应性的测定中对供体的特定无反应性的发展。调节性T细胞（TREG）富含恢复的外周血T细胞群体，并在移植后第一年内可变地检测到抗抑制反应性的抑制。但是，几名患者发生了早期急性体液排斥发作，导致在该方案中添加了B细胞止动抗CD20 MAB。在体内和体外，有几名患者在存在低T细胞计数和/或T细胞耐受性的情况下会产生自身抗体和供体特异性同种抗体。我们假设这些抗体是通过在没有T细胞帮助的情况下恢复过渡B细胞而产生的。但是，另一种假设是，尽管在散装MLR和CML分析中看到供体无反应性，但间接同种反应性T细胞为这些患者的类别开关Ig反应提供了帮助。现在，该协议正在重新开放，以包括HLA-HAPLOIDENITAL和更广泛的不匹配捐助者。我们建议解决几种假设，以了解通过CKBMT实现的公差。我们将：1）评估HLA不匹配的CKBMT受体中直接和间接供体同种异体T细胞的耐受性。在抗抑制抗体的发展中，将测量和解释对造血和肾小管细胞衍生抗原的间接反应；和2）评估调节细胞的作用，包括Foxp3+ Treg和CD127-C025-C04细胞在CKBMT受体中供体特异性公差的发展中。我们将评估从患者PBMC获得的调节细胞种群的表型和功能，并从肾脏活检标本扩展。我们假设与PBMC相比，供体特异性的调节细胞将富集在同种异体移植中，并且随着供体反应性T细胞的缺失，供体特异性的调节能力将随着时间的流逝而下降。结合在ITN核心设施上进行的研究，我们的研究应促进对CKBMT诱导的耐受性机制的全面理解。