INDUCTION OF SPECIFIC TOLERANCE TO ORGAN ALLOTRANSPLANTS

诱导对器官同种异体移植的特异性耐受

• 批准号: 2003837
• 负责人: MARK STUART ORLOFF
• 金额: $ 11.11万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-01-01 至 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2003837
• 关键词: T lymphocyte; autologous transplantation; bone marrow transplantation; flow cytometry; gastrointestinal transplantation; graft versus host disease; heart transplantation; histocompatibility; homologous transplantation; immune tolerance /unresponsiveness; immunocytochemistry; immunosuppression; isoantigen; laboratory rat; microspectrophotometry; small intestines; thymectomy; thymus; thymus transplantation; tissue /cell culture; tissue mosaicism; transplant rejection

Donor specific tolerance has the potential to prolong solid organ allograft survival and avoid the complications associated with non- specific immunosuppression. We created mixed allogeneic chimeras through transplantation of allogeneic and syngeneic T cell-depleted (TCD) bone marrows, and demonstrated that this chimerism effectively produces long- term tolerance to vascularized heart allografts across major and minor histocompatibility barriers. This approach has recently been extended to transplantation of the highly immunogenic small bowel allograft across these same barriers. Preliminary studies demonstrate bone marrow cells share sufficient antigens with small bowel grafts to prevent rejection by chimeras. The extent to which this tolerance depends upon peripheral chimerism, its resistance to breakage and graft-versus-host disease (GVHD) will be examined in the experiments of Specific Aim # 1. We will test the hypothesis: central tolerance depends upon an intrathymic persistence and sharing of alloantigens between donor bone marrow-derived thymic cells and the allograft. Specific Aim #2 will examine presence of donor-derived intrathymic alloantigenic cells, the dependence of tolerance upon persistence of this alloantigen, and the ability of tolerant thymuses to transfer tolerance. Initial investigations into deletion-, and suppressor-based mechanisms will be made. Attempts to further separate the role of peripheral alloantigen from central alloantigen in tolerance induction will be made in Specific Aim #3 by looking at the effects on tolerance of chimeric cells maturing in syngeneic thymi, and elimination of chimerism after established tolerance. Tolerance will be stringently defined by the ability to cross highly incompatible full MHC barriers to the highly small bowel allograft. These experiments will lay the necessary groundwork for more detailed cellular and molecular investigations into the mechanisms of tolerance in bone marrow chimeras.

供体特异性公差有可能延长固体器官 同种异体移植生存，并避免与非 - 并发症相关的并发症 特定的免疫抑制。 我们通过 同种异体和同性T细胞缺乏（TCD）骨的移植 骨髓，并证明这种嵌合有效地产生了长期 对主要和次要的血管化同种异体移植的术语耐受性 组织相容性障碍。 这种方法最近已扩展 移植高度免疫原性小肠同种异体移植 这些相同的障碍。 初步研究表明骨髓细胞 与小肠移植物共享足够的抗原，以防止排斥 由嵌合体。 这种公差依赖于周围的程度 嵌合体，其抵抗力的破裂和移植物抗宿主病 （GVHD）将在特定目标1的实验中进行检查。我们将 检验假设：中心公差取决于胸膜 供体骨髓衍生之间的同种抗原的持久性和共享 胸细胞和同种异体移植。特定目标＃2将检查 供体衍生的胸膜同种抗原细胞，依赖性 这种同种抗原的持久性和能力 耐受的胸腔传递耐受性。 初步调查 将制定删除和基于抑制器的机制。 尝试 进一步将外围同种抗原的作用与中部分开 耐受性诱导中的同种剂将在特定的目标＃3中由 查看对成熟嵌合细胞耐受性的影响 建立后的同性百里香和消除嵌合 宽容。 公差将由交叉的能力严格定义 高度不兼容的全MHC屏障高度小肠 同种异体移植。 这些实验将为更多的基础奠定必要的基础 详细的细胞和分子研究 骨髓嵌合体的耐受性。