MIXED CHIMERISM AND TOLERANCE IN CYNOMOLGUS MONKEYS

食蟹猴的混合嵌合和耐受

基本信息

批准号：
6129890
负责人：
TATSUO KAWAI
金额：
$ 23.17万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-03-15 至 2001-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6129890
关键词：
Macaca fascicularis T lymphocyte artificial immunosuppression bone marrow transplantation disease /disorder model immune tolerance /unresponsiveness kidney transplantation mixed lymphocyte reaction test monoclonal antibody nonhuman therapy evaluation technology /technique development thymus tissue mosaicism transplantation immunology whole body irradiation dosage

项目摘要

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 use to the transplantation of cadaveric organs. Specifically, we will: 1) evaluate the addition of costimulatory blockade (with anti-CD40L monoclonal antibody and/or CTLA4-Ig) to the preparative regimen; 2) attempt to minimize the radiation requirements of the preparative regimen by utilizing high-dose mobilized peripheral blood stem cells (PBSC) for the induction of mixed chimerism; and 3) modify the preparative regimen to improve its applicability to cadaver-donor transplantation in humans. 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.

诱导特定的移植耐受性，这可能消除了对长期免疫抑制药物的需求和慢性排斥反应的持续问题，仍然是临床器官移植的主要目标。我们实验室的先前研究表明，建立混合淋巴结虫的嵌合体为诱导小鼠主要组织相容性障碍的长期移植耐受性提供了一种有效的手段。基于这些鼠类研究，我们成功地开发了一种非肌瘤的制备方案，该方案允许在MHC匹配的cynomolgus猴子骨髓移植后诱导混合的嵌合和肾脏同种异体耐受性，而无需GVHD。但是，要将该方案应用于临床环境，将需要进行几种修改。因此，该提案的主要目标是实现一致的耐受性，以进一步降低制备方案的发病率，并将其使用扩展到尸体器官的移植中。具体而言，我们将：1）评估在制备方案中加入共刺激性阻断（用抗CD40L单克隆抗体和/或CTLA4-Ig）； 2）尝试通过利用高剂量的动员外周血干细胞（PBSC）来诱导混合嵌合体，以最大程度地降低制备方案的辐射需求； 3）修改制备方案，以提高其对人类尸体donor移植的适用性。此外，我们将研究和比较这些非毛囊疗法中的每一种诱导的耐受性的潜在机制，尤其强调将中心与外围机制区分开。这些分析应提供有价值的信息，以将这种方法扩展到临床同种异体移植中。