Overcoming Barries to Mixed-chimerism Induced Tolerance

克服混合嵌合体诱导耐受的障碍

• 批准号: 8459913
• 负责人: James S. Allan
• 金额: $ 46.13万
• 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/8459913
• 关键词: Acute; Address; Affect; Alloantigen; Allogenic; Allograft Tolerance; Allografting; Animal Model; Antibodies; Antibody Formation; Antigens; Attention; Attenuated; Autoantibodies; B-Lymphocytes; Bone Marrow; Bone Marrow Transplantation; Brain Death; Brain Ischemia; 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; Heart Transplantation; 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; 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; System; T cell regulation; T memory cell; Tissue Donors; Tissues; Transcription Factor AP-1; 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; novel strategies; 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.

see Instructions）： 该计划项目的目的是通过 澄清参与供体特异性耐受性诱导的机制。以前由此资助的研究 计划项目为成功扩展了使用宽容诱导方法的基础 对接受生活的同时肾脏和骨髓移植的患者的混合嵌合体 捐助者。我们的假设是，通过进一步的机械研究，通过混合嵌合诱导的耐受性 证明适用于已故捐赠者器官的接受者，使宽容可容纳在心脏和肺中 同种异体移植者。该程序中的集成主题是1）针对新认识的障碍 宽容将使我们能够改变远离同种异体的平衡 删除/调节导致长期耐受性，2）体液反应和促炎状态是 特别有害耐受性诱导，可能是限制持续时间的重要混杂因素 在混合嵌合的状态和3）可能需要耐用的混合嵌合物才能使心脏耐受性需要 和肺接受者，因为与肾脏不同，胸部器官似乎无法维持耐受性 一旦嵌合主义就消失了。在每个项目的具体目的中，同种，自动和自然的贡献 在创新中识别并解决了混合嵌合诱导后移植物损失的抗体 互补的方式。同样，促炎分子的有害作用也被认为 在整个计划中，并采用了创新和互补的方法来解决。我们期待 持续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（请参阅说明）： 人类心脏和肺移植接受者的生存受到排斥和并发症的限制 抗排斥药。该提案的目的是诱导接受者的免疫耐受状态， 哪个“欺骗”免疫系统将外国移植物视为其自身的组织，因此器官不是 拒绝而无需毒品。这将大大改善心脏和肺移植的结果。