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: 7911685
• 负责人: Megan Sykes
• 金额: $ 42.01万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 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 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7911685
• 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; 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; Recovery; Regimen; Regulatory T-Lymphocyte; Reporting; Role; T-Cell Depletion; T-Lymphocyte; Therapeutic immunosuppression; Time; Toxic effect; Transplantation; Tubular formation; autoreactivity; cell type; 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.

同种异体移植耐受的诱导将避免长期免疫抑制治疗及其伴随的毒性的需要。我们最近进行了一项针对相关半相合供体的非清髓性骨髓和肾联合移植（CKBMT）的试点试验。 5 名患者中有 4 名在没有维持免疫抑制的情况下实现了持久的同种异体移植接受，这是首次成功有意实现对 HLA 不匹配同种异体移植的耐受。体外研究揭示了在主要测量直接同种异体反应性的测定中对供体的特异性无反应的发展。调节性 T 细胞 (Treg) 在恢复的外周血 T 细胞群中富集，并且在移植后第一年内检测到不同程度的抗供体反应性抑制。然而，一些患者出现了早期急性体液排斥反应，导致在治疗方案中添加了 B 细胞耗竭型抗 CD20 mAb。一些患者在体内和体外 T 细胞计数和/或 T 细胞耐受性较低的情况下产生了自身抗体和供体特异性同种抗体。我们假设这些抗体是在没有 T 细胞帮助的情况下通过恢复移行 B 细胞而产生的。然而，另一种假设是，尽管在批量 MLR 和 CML 检测中发现供体无反应，但间接同种异体反应性 T 细胞为这些患者的类别转换 Ig 反应提供了帮助。该协议现在正在重新开放，以包括 HLA 单倍体捐献者和更广泛的不匹配捐献者。我们建议解决几个假设，以便了解通过 CKBMT 实现的容忍度。我们将： 1) 评估 HLA 不匹配的 CKBMT 受体对直接和间接供体同种反应性 T 细胞的耐受性。将在抗供体抗体开发的背景下测量和解释对造血细胞和肾小管细胞衍生抗原的间接反应； 2) 评估调节细胞（包括 FoxP3+ Treg 和 CD127-C025-C04 细胞）在 CKBMT 受体发展供体特异性耐受中的作用。我们将评估从患者 PBMC 中获得并从肾活检标本中扩增的调节细胞群的表型和功能。我们假设，与 PBMC 相比，供体特异性调节细胞在同种异体肾移植物中会富集，并且随着供体反应性 T 细胞的缺失，供体特异性调节能力将随着时间的推移而下降。结合在 ITN 核心设施进行的研究，我们的研究应促进对 CKBMT 诱导耐受所涉及的机制的全面理解。

项目成果

Acute renal endothelial injury during marrow recovery in a cohort of combined kidney and bone marrow allografts.

一组肾和骨髓同种异体联合移植物的骨髓恢复过程中的急性肾内皮损伤。

• 发表时间: 2011-07
• 作者: Farris, A B;Taheri, D;Kawai, T;Fazlollahi, L;Wong, W;Tolkoff;Spitzer, T R;Iafrate, A J;Preffer, F I;Locascio, S A;Sprangers, B;Saidman, S;Smith, R N;Cosimi, A B;Sykes, M;Sachs, D H;Colvin, R B
• 通讯作者: Colvin, R B

Mechanisms of donor-specific tolerance in recipients of haploidentical combined bone marrow/kidney transplantation.

单倍相合联合骨髓/肾移植受者的供体特异性耐受机制。

• 发表时间: 2011-06
• 作者: Andreola, G;Chittenden, M;Shaffer, J;Cosimi, A B;Kawai, T;Cotter, P;Locascio, S A;Morokata, T;Dey, B R;Tolkoff;Preffer, F;Bonnefoix, T;Kattleman, K;Spitzer, T R;Sachs, D H;Sykes, M
• 通讯作者: Sykes, M

Long-term results in recipients of combined HLA-mismatched kidney and bone marrow transplantation without maintenance immunosuppression.

HLA 不匹配的肾和骨髓联合移植（无需维持免疫抑制）的受者的长期结果。

• 发表时间: 2014-07
• 作者: Kawai, T;Sachs, D H;Sprangers, B;Spitzer, T R;Saidman, S L;Zorn, E;Tolkoff;Preffer, F;Crisalli, K;Gao, B;Wong, W;Morris, H;LoCascio, S A;Sayre, P;Shonts, B;Williams Jr, W W;Smith, R;Colvin, R B;Sykes, M;Cosimi, A B
• 通讯作者: Cosimi, A B

Mixed chimerism, lymphocyte recovery, and evidence for early donor-specific unresponsiveness in patients receiving combined kidney and bone marrow transplantation to induce tolerance.

混合嵌合现象、淋巴细胞恢复以及接受肾和骨髓联合移植以诱导耐受的患者早期供体特异性无反应的证据。

• 发表时间: 2010-12-27
• 影响因子: 6.2
• 作者: LoCascio SA;Morokata T;Chittenden M;Preffer FI;Dombkowski DM;Andreola G;Crisalli K;Kawai T;Saidman SL;Spitzer TR;Tolkoff-Rubin N;Cosimi AB;Sachs DH;Sykes M
• 通讯作者: Sykes M