Mechanisms of immune regulation by rapamycin-conditioned dendritic cells

雷帕霉素条件树突状细胞的免疫调节机制

• 批准号: 7492150
• 负责人: Heth R Turnquist
• 金额: $ 5.13万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7492150
• 关键词: Alloantigen; Allogenic; Allografting; Animals; Antigen-Presenting Cells; Area; B-Lymphocytes; Blood Vessels; Bone Marrow; CD40 Antigens; CD80 gene; Cell Maturation; Cells; Chronic; Clinical; Condition; Data; Dendritic Cells; Dependence; Effectiveness; Exposure to; Generations; Graft Survival; Heart Transplantation; Histocompatibility Antigens Class II; IL2RA gene; Immune; Immune response; Immunosuppression; Immunosuppressive Agents; Inflammatory; Infusion procedures; Link; Lymphoid Tissue; Major Histocompatibility Complex; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Mus; Myelogenous; Organ Transplantation; Pathway interactions; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Physiologic pulse; Population; Postoperative Period; Prevention; Protein Overexpression; Proteins; Pulse taking; Regulation; Resistance; Role; Sclerosis; Signal Transduction; Signaling Pathway Gene; Sirolimus; Solid; Stimulus; Surface; T-Cell Proliferation; T-Lymphocyte; Therapeutic; Therapeutic immunosuppression; Transgenic Organisms; Transplant Recipients; Transplantation; Treatment Failure; Work; base; cytokine; day; heart allograft; prevent; response; vector

DESCRIPTION (provided by applicant): We have demonstrated the capacity of allogeneic or alloantigen-presenting immature dendritic cells (iDC), expressing low levels of major histocompatibility complex (MHC) class II and the co-stimulatory molecules, to prolong MHC-mismatched cardiac allograft survival when delivered before transplantation. This effect is potentiated by co-stimulation blockade, and the combination of iDC and co-stimulation blockade also reduced transplant vasculopathy. However, consistent indefinite graft survival via iDC administration is not observed, suggesting that infused iDC may be susceptible to maturation following exposure to endogenous inflammatory factors. Our recent data show that the 'tolerance-sparing' immunosuppressive drug rapamycin (RAPA) results in stably-immature dendritic cells (RAPA-DC) that are markedly impaired in their ability to stimulate T cells via direct and indirect pathways of allorecognition, even following exposure to potent inflammatory stimuli, RAPA-DC infusion, in the absence of any administered immunosuppression, induced indefinite cardiac allograft survival in 40% of animals. Further evidence suggests that RAPA-DC, when contrasted to iDC, selectively expand Foxp3+ CD4+ CD25+ T cells. Thus, based on the stable immature phenotype of RAPA-DC and their propensity to selectively expand Treg, the combination of co-stimulation blockade with RAPADC administration may prove a highly effective therapy to promote tolerance and thus reduce vascular sclerosis. As such, the current application will define whether alloantiqen (alloAq) Aq presentation by recipient-derived RAPA-DC in combination with blockade of the CD40-CD154 pathway results in lonq-term, rejection-free alloqraft survival through the generation of Treq in a murine heart transplant model. Also, the studies proposed are focused on elucidating the molecular mechanisms that underlie the inhibitory action of RAPA on DC maturation and stimulatory abilitv, and on utilizinq RAPA-DC to identify siqnalinq pathway and qene products that are critical for their expansion of Treq cells. Relevance: The morbidity associated with long-term immunosuppressant administration, and the failure of these treatments to prevent allograft loss due to chronic rejection, remain significant obstacles in clinical solid organ transplantation. Dendritic cells, potent natural regulators of immune responses, if properly utilized as tolerogenic vectors may hold the key to consistent induction of operational tolerance reducing the current dependence on chronic immunosuppression and blocking immunological components of chronic rejection.

描述（由申请人提供）：我们已经证明了同种异体或同种抗原的未成熟树突状细胞（IDC）的能力，表达较低水平的主要组织相容性复合物（MHC）II类和共刺激性分子，可延长MHC匹配的心脏抗心Allograpt Allograft在递送之前延长MHC匹配的心脏Allograft存活。这种效果通过共刺激阻滞增强，IDC和联合刺激的结合也减少了移植血管病。但是，未观察到通过IDC给药的一致的无限移植物存活，这表明在暴露于内源性炎症因子后，注入的IDC可能容易受到成熟的影响。我们最近的数据表明，“耐受性”免疫抑制药物雷帕霉素（RAPA）会导致稳定的弱化树突状细胞（RAPA-DC），这些细胞（RAPA-DC）在通过过度识别的直接和脱节途径刺激T细胞的能力上也受到显着损害，即使在强有力的炎症性刺激性刺激性刺激性刺激性刺激下，无效的无效刺激性刺激性，无效，无效地刺激性刺激性刺激性刺激性，无效，无效地刺激性刺激性刺激性，无效。 40％的动物中，不确定的心脏同种异体移植生存。进一步的证据表明，RAPA-DC与IDC形成鲜明对比时，有选择地扩展Foxp3+ CD4+ CD25+ T细胞。因此，基于RAPA-DC的稳定不成熟表型及其选择性扩展Treg的倾向，共同刺激阻断与RAPADC给药的组合可能证明是一种高效的疗法来促进耐受性，从而减少血管硬化。因此，当前的应用将定义受体衍生的RAPA-DC的同具有同类（Alloaq）AQ是否与CD40-CD154途径的封锁相结合，是否会导致LONQ期限，无拒绝的AlloQraft生存，通过鼠心脏移植模型中的TREQ产生。同样，提出的研究集中在阐明RAPA对DC成熟和刺激性ABILITV的抑制作用的基础的分子机制上，以及utilizinq RapA-DC识别SIQNALINQ途径和Qene产品，这些途径和Qene产物对于它们的TREQ细胞扩张至关重要。相关性：与长期免疫抑制剂给药相关的发病率，以及这些治疗因素因慢性排斥而导致同种异体移植的失败，在临床固体器官移植中仍然存在明显的障碍。树突状细胞是免疫反应的有效自然调节剂，如果适当用作耐受性载体，则可能是持续诱导操作耐受的关键，从而降低了当前对慢性免疫抑制的依赖性并阻止了慢性排斥的免疫学成分。