Overcoming Barries to Mixed-chimerism Induced Tolerance

请参阅说明)： 该计划项目的目标是通过以下方式改善心脏或肺移植后的结果 阐明供体特异性耐受诱导的机制。之前的研究是由这一项目资助的 计划项目为成功推广耐受性诱导方法提供了基础 活体肾和骨髓联合移植患者的混合嵌合体 捐赠者。我们的假设是，随着进一步的机制研究，通过混合嵌合体诱导的耐受 将被证明适用于已故供体器官的接受者，使心脏和肺可以获得耐受性 同种异体移植受者。该计划的整合主题是：1)针对新认识的障碍 宽容将使我们能够改变同种反应的平衡，从同种侵略转向 缺失/调节导致长期耐受，2)体液反应和促炎状态 尤其不利于耐受诱导，可能是限制持续时间的重要混杂因素 混合嵌合体的状态和持久的混合嵌合体很可能是心脏耐受所必需的 和肺受体，因为与肾脏不同，胸部器官似乎不能维持耐受性 一旦嵌合体消失。在每个项目的具体目标中，异体、自动和自然的贡献 在混合嵌合体诱导后移植物丢失的抗体被识别并在创新的和 互补的方式。同样，促炎分子的有害影响也被考虑在内。 在整个计划中，并以创新和互补的方法加以解决。我们期待着 正在取得的进展将继续有助于减少与固体有关的发病率和死亡率 器官移植。 相关性(请参阅说明)： 心脏和肺移植受者的存活受到排斥反应和并发症的限制。 抗排斥药物。这一建议的目的是在接受者中诱导一种免疫耐受状态， 这“诱骗”免疫系统将异体移植物视为自己的组织，这样器官就不会 不需要药物就被拒绝了。这将大大改善心脏和肺移植的结果。

Seeinstructions): The objective of this Program Project is to improve outcomes following heart or lung transplantation by clarifying the mechanisms involved in donor-specific tolerance induction. Previous studies funded by this Program Project have provided the basis for successfully extending a tolerance induction approach using mixed chimerism to patients who received simultaneous kidney and bone marrow transplants from living donors. Our hypothesis is that with further mechanistic study, tolerance induced through mixed chimerism will prove applicable to recipients of deceased donor organs making tolerance accessible to heart and lung allograft recipients. The integrating themes in this Program are that 1) targeting newly recognized barriers to tolerance will allow us to alter the balance of an alloresponse away from alloaggression and towards deletion/regulation leading to long-term tolerance, 2) humoral responses and proinflammatory states are particularly detrimental to tolerance induction and may be important confounding factors limiting the duration of the state of mixed chimerism and 3) durable mixed chimerism will likely be required for tolerance in heart and lung recipients because, unlike kidneys, thoracic organs do not appear capable of maintaining tolerance once chimerism disappears. In the specific aims of each Project, the contributions of allo-, auto- and natural antibodies to graft loss after mixed chimerism induction are recognized and addressed in an innovative and complementary manner. Likewise, the deleterious effects of proinflammatory molecules are considered throughout the program and addressed with innovative and complementary approaches. We anticipate ongoing progress will continue to contribute to a reduction in the morbidity and mortality associated with solid organ transplantation. RELEVANCE (See instructions): The survival of human recipients of heart and lung transplants is limited by rejection and by complications of anti-rejection drugs. The objective of this proposal is to induce a state of immune tolerance in the recipient, which "tricks" the immune system into seeing the foreign graft as its own tissue, so that the organ is not rejected without the need for drugs. This would greatly improve the outcomes of heart and lung transplants.