Overcoming Barries to Mixed-chimerism Induced Tolerance

克服混合嵌合体诱导耐受的障碍

• 批准号: 8073145
• 负责人: James S. Allan
• 金额: $ 48.7万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8073145
• 关键词: Acute; Address; Affect; Alloantigen; Allogenic; Allograft Tolerance; Allografting; Animal Model; Antibodies; Antibody Formation; Antigens; Attention; Attenuated; B-Lymphocytes; Bone Marrow; Bone Marrow Transplantation; Brain Death; Bronchiolitis; Cell Adhesion Molecules; Cell Maturation; Cell Survival; Cell Therapy; Cells; Chest; Chimera organism; Chimeric Proteins; Chimerism; Chronic; Clinical Protocols; Clinical Research; Collagen; Collagen Type V; Data; Dendritic Cells; Development; Dichloromethylene Diphosphonate; Engraftment; Environment; Equilibrium; Family suidae; Freedom; Funding; Generations; Genes; Graft Tolerance; Heart; Hematopoietic; Histocompatibility Antigens Class II; Human; Immune Tolerance; Immune response; Immune system; Immunity; Immunoglobulin G; Immunoglobulin M; Immunologics; Immunosuppression; Immunosuppressive Agents; Indium; Infection; Inflammation; Inflammatory; Instruction; Intercellular adhesion molecule 1; Interleukin-1 beta; Interleukin-6; Isoantibodies; Kidney; Kidney Failure; Laboratories; Lesion; Leukocytes; Liposomes; Living Donors; Lung; Lung Transplantation; Lymphoid Tissue; Macaca fascicularis; Maintenance; Malignant Neoplasms; Marrow; Mediating; Methods; Minor; Modeling; Monkeys; Morbidity - disease rate; Multiple Myeloma; Mus; NF-kappa B; Organ; Organ Donor; Organ Transplantation; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Plasma Cells; Population Control; Pre-Clinical Model; Principal Investigator; Process; Progress Reports; Proteins; Protocols documentation; Recording of previous events; Refractory; Regimen; Regulation; Regulatory T-Lymphocyte; Reperfusion Injury; Reporting; Rodent; Signal Transduction; Skin; Solid; Sterility; System; T cell regulation; T memory cell; Tissue Donors; Tissues; Transplant Recipients; Transplantation; Transplantation Tolerance; Tumor Necrosis Factor-alpha; Up-Regulation; Work; allograft rejection; base; body system; clinically relevant; cytokine; experience; heart-lung allograft; human TNF protein; immune activation; improved; inhibitor/antagonist; innovation; kidney allograft; lung allograft; mortality; nonhuman primate; novel; prevent; programs; protocol development; reconstitution; response; success; tositumomab; transcription factor

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.

参见说明）： 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所涉及的机制。此前由该项目资助的研究 计划项目为成功扩展耐受诱导方法提供了基础 同时接受活体肾脏和骨髓移植的患者出现混合嵌合现象 捐助者。我们的假设是，通过进一步的机制研究，通过混合嵌合诱导耐受 将被证明适用于已故捐赠器官的接受者，使心脏和肺部能够耐受 同种异体移植受者。该计划的整合主题是 1) 针对新认识到的障碍 宽容将使我们能够改变同种反应的平衡，从同种攻​​击转向同种攻击。 删除/调节导致长期耐受，2）体液反应和促炎状态 特别不利于耐受诱导，并且可能是限制持续时间的重要混杂因素 混合嵌合状态的状态和 3) 持久的混合嵌合状态可能需要心脏的耐受性 和肺受体，因为与肾脏不同，胸部器官似乎无法维持耐受性 一旦嵌合现象消失。在每个项目的具体目标中，异体、自动和自然的贡献 混合嵌合体诱导后移植物丢失的抗体在创新和解决方案中得到认可和解决 互补的方式。同样，促炎分子的有害作用也被认为是 在整个计划中，并通过创新和补充的方法来解决。我们预计 持续取得的进展将继续有助于降低与固体相关的发病率和死亡率 器官移植。 相关性（参见说明）： 接受心脏和肺移植的人类受者的生存受到排斥反应和并发症的限制。 抗排斥药物。该提案的目的是在接受者中诱导免疫耐受状态， 它“欺骗”免疫系统将外来移植物视为自己的组织，这样该器官就不会受到影响。 无需药物即可被拒绝。这将大大改善心脏和肺移植的结果。