Activation, Apathy, Anergy and Apoptosis

描述(申请人提供)：移植已成为 多种终末期器官衰竭的首选治疗方法。而当 短期结果有所改善，但长期结果仍然不足。至 保持同种异体，患者必须严格坚持终身治疗 使用昂贵的免疫抑制剂的方案显著增加了 心血管疾病、感染和恶性肿瘤的风险。最新进展 促进接受同种异体组织而不需要的策略 因为铬免疫抑制不仅可以降低这些疾病的风险 危及生命的并发症，也大大扩展了其应用范围 器官、组织和细胞移植治疗疾病，如 血红蛋白疾病和遗传免疫缺陷、I型糖尿病和 可能是其他自身免疫性疾病。 我们已经开发了一种新的非骨髓抑制方案，使用抗CD4OL和 CTLA4-Ig允许诱导可滴定水平的。 在这项提案中，我们将探索替代免疫调节剂的使用 促进嵌合体和宽容发展的战略，研究 常规免疫抑制剂与耐受性的相互作用 归纳方法，探索耐受性维持的机制， 明确耐受诱导对免疫记忆的影响，并研究 使用干细胞作为初级骨髓准备的替代品。

DESCRIPTION (provided by applicant): Transplantation has emerged as the preferred method of treatment for many forms of end-stage organ failure. While short-term results have improved long-term outcomes remain inadequate. To maintain their allogralts, patients must rigidly adhere to life-long treatment regimens using costly immunosuppressive agents that dramatically increase the risks of cardiovascular disease, infections and malignancies. The development of strategies to promote the acceptance of allogeneic tissues without the need for chromic immunosupression could not only reduce the risk of these life-threatening complications, but also greatly expand the application of organ, tissue and cellular transplantation for diseases such as the hemoglobinopathies and genetic irnmunodeficiencies, Type I diabetes, and possibly other autoimmune diseases. We have developed a novel non-myelosuppressive protocol using anti-CD4OL and CTLA4-Ig to permit the induction of titratable levels of. In this proposal we will explore the use of alternative immunomodulatory strategies to facilitate the development of chimerism and tolerance, study the interactions of conventional immunosuppressive agents with the tolerance induction approach, explore the mechanisms involved in tolerance maintenance, define the effects of tolerance induction on immunologic memory and study the use of stem cells as alternatives to primary bone marrow preparation.