MIXED CHIMERISM AND TOLERANCE IN CYNOMOLGUS MONKEYS

食蟹猴的混合嵌合和耐受

• 批准号: 6287590
• 负责人: A BENEDICT COSIMI
• 金额: $ 40.89万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-03-15 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6287590
• 关键词: CD40 molecule; Macaca fascicularis; T lymphocyte; artificial immunosuppression; bone marrow transplantation; cell mediated lymphocytolysis test; cyclophosphamide; disease /disorder model; immune tolerance /unresponsiveness; interleukin 2; kidney function; kidney transplantation; mixed lymphocyte reaction test; mixed tissue /cell culture; monoclonal antibody; nonhuman therapy evaluation; stem cells; technology /technique development; thymus; tissue mosaicism; transplantation immunology; whole body irradiation dosage

The induction of specific transplantation tolerance, which might eliminate both the need for long-term immunosuppressive medications and the persistent problem of chronic rejection, remains a major goal of clinical organ transplantation. Previous studies from our laboratory have demonstrated that the establishment of mixed lymphohematopoietic chimerism provides an effective means for the induction of long-term transplantation tolerance across major histocompatibility barriers in mice. Based on these murine studies, we successfully developed a non- myeloablative preparative regimen that permits the induction of mixed chimerism and renal allograft tolerance following bone marrow transplantation in MHC-mismatched cynomolgus monkeys, without GVHD. However, to apply this regimen to a clinical setting, several modifications will be necessary. Therefore, the major goals of this proposal are to achieve consistent tolerance, to reduce further the morbidity of the preparative regimen, and to extend its clinical application. Specifically, we will: 1) evaluate the addition of costimulatory blockade (with anti-CD40 ligand monoclonal antibody and/or CTLA4-Ig); 2) Attempt to minimize or remove the radiation requirements of the preparative regimen by either utilizing high-dose mobilized peripheral blood stem cell (PBSC) transplantation or the use of cyclophosphamide; and 3) modify the preparative regimen to improve its clinical applicability to cadaver-donor transplantation and to recipients of living donor transplants with good renal function, but who are currently not tolerating standard immunosuppression. In addition, we will investigate and compare the underlying mechanism of tolerance induced by each of these non-myeloablative regimens, with particular emphasis on distinguishing central from peripheral mechanisms. These analyses should provide valuable information for extending this approach to clinical allotransplantation.

诱导特异性移植耐受可能消除对长期免疫抑制药物的需求和持续存在的慢性排斥问题，仍然是临床器官移植的主要目标。我们实验室先前的研究表明，混合淋巴造血嵌合体的建立为诱导小鼠跨越主要组织相容性障碍的长期移植耐受提供了有效手段。基于这些小鼠研究，我们成功开发了一种非清髓性准备方案，该方案允许在 MHC 不匹配的食蟹猴骨髓移植后诱导混合嵌合和肾同种异体移植耐受，而无需 GVHD。然而，为了将该方案应用于临床，需要进行一些修改。因此，该提案的主要目标是实现一致的耐受性，进一步降低预备方案的发病率，并扩大其临床应用。具体来说，我们将：1）评估共刺激阻断的添加（使用抗CD40配体单克隆抗体和/或CTLA4-Ig）； 2) 尝试通过利用高剂量动员外周血干细胞（PBSC）移植或使用环磷酰胺来尽量减少或消除准备方案的辐射需求； 3) 修改准备方案，以提高其对尸体供体移植和肾功能良好但目前不耐受标准免疫抑制的活体供体移植受者的临床适用性。此外，我们将研究和比较每种非清髓性治疗方案诱导的耐受性的潜在机制，特别强调区分中枢机制和外周机制。这些分析应该为将该方法扩展到临床同种异体移植提供有价值的信息。