MIXED CHIMERISM AND TOLERANCE IN CYNOMOLGUS MONKEYS

食蟹猴的混合嵌合和耐受

• 批准号: 6881426
• 负责人: TATSUO KAWAI
• 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/6881426
• 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要和慢性排斥的持续问题，仍然是临床器官移植的主要目标。我们实验室之前的研究表明，混合淋巴造血嵌合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，我们成功地开发了一种非清髓制备方案，允许在没有GVHD的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物耐受。然而，要将该方案应用于临床环境，需要进行一些修改。因此，本提案的主要目标是实现一致的耐受性，进一步降低制备方案的发病率，并扩大其临床应用。具体来说，我们将：1)评估添加共刺激阻断（抗cd40配体单克隆抗体和/或CTLA4-Ig）；2)通过使用高剂量动员性外周血干细胞（PBSC）移植或使用环磷酰胺，尽量减少或消除制备方案的辐射要求；3)修改制备方案，提高其在尸体供体移植和肾功能良好但目前免疫抑制不耐受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一种非清髓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。这些分析应该为将这种方法扩展到临床同种异体移植提供有价值的信息。

项目成果

Mixed chimerism to induce tolerance: lessons learned from nonhuman primates.

• DOI: 10.1016/j.trre.2008.08.006
• 发表时间: 2009-01-01
• 期刊: Transplantation reviews (Orlando, Fla.)
• 作者: Murakami, Toru;Cosimi, A Benedict;Kawai, Tatsuo
• 通讯作者: Kawai, Tatsuo

Immunologic tolerance to organ transplants.

对器官移植的免疫耐受。

• DOI: 10.1016/s1091-255x(99)80017-1
• 发表时间: 1999
• 期刊: Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract
• 作者: Sachs,DH

Comparison of horse antithymocyte globulin with other T cell-depleting antibodies for induction of chimerism and renal allograft tolerance in nonhuman primates.

马抗胸腺细胞球蛋白与其他 T 细胞消耗抗体在非人灵长类动物中诱导嵌合和肾同种异体移植耐受的比较。

• DOI: 10.1016/s0041-1345(00)01933-3
• 发表时间: 2001
• 期刊: Transplantation proceedings
• 影响因子: 0.9
• 作者: Sogawa,H;Kawai,T;Wee,SL;Boskovic,S;Nadazdin,O;Phelan,J;Abrahamian,G;Ko,DS;Hong,H;Mauiyyedi,S;Colvin,RB;Sachs,DH;Cosimi,AB
• 通讯作者: Cosimi,AB

Clinical application of tolerance induction in solid organ transplantation.

耐受诱导在实体器官移植中的临床应用

• DOI: 10.1016/s0041-1345(99)00174-8
• 发表时间: 1999
• 期刊: Transplantation proceedings
• 影响因子: 0.9
• 作者: Cosimi,AB

Overcoming memory T-cell responses for induction of delayed tolerance in nonhuman primates.

克服记忆T细胞反应，以诱导非人类灵长类动物的延迟公差。

• DOI: 10.1111/j.1600-6143.2011.03795.x
• 发表时间: 2012-02
• 期刊: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
• 作者: Yamada Y;Boskovic S;Aoyama A;Murakami T;Putheti P;Smith RN;Ochiai T;Nadazdin O;Koyama I;Boenisch O;Najafian N;Bhasin MK;Colvin RB;Madsen JC;Strom TB;Sachs DH;Benichou G;Cosimi AB;Kawai T
• 通讯作者: Kawai T