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异体抗原呈递的未成熟树突状细胞（iDC）表达低水平的主要组织相容性复合体（MHC）II类和共刺激分子，在移植前递送时能够延长MHC不匹配的心脏同种异体移植物的存活时间。共刺激阻断可增强这种作用，iDC 和共刺激阻断的组合还可减少移植血管病变。然而，没有观察到通过 iDC 给药一致的无限期移植物存活，这表明输注的 iDC 在暴露于内源性炎症因子后可能容易成熟。我们最近的数据表明，“耐受性保留”免疫抑制药物雷帕霉素 (RAPA) 会导致稳定未成熟的树突状细胞 (RAPA-DC)，即使在暴露于强效炎症刺激、RAPA-DC 输注、没有任何免疫抑制的情况下，其通过直接和间接同种异体识别途径刺激 T 细胞的能力也明显受损。 40% 的动物同种异体心脏移植物无限期存活。进一步的证据表明，与 iDC 相比，RAPA-DC 选择性扩增 Foxp3+ CD4+ CD25+ T 细胞。因此，基于 RAPA-DC 稳定的未成熟表型及其选择性扩增 Treg 的倾向，共刺激阻断与 RAPADC 给药的组合可能被证明是一种促进耐受性并从而减少血管硬化的高效疗法。因此，当前的申请将确定受体源性 RAPA-DC 的同种异体抗原 (alloAq) Aq 呈递与 CD40-CD154 通路阻断相结合是否可以通过在小鼠心脏移植模型中生成 Treq 来实现长期、无排斥反应的同种异体移植物存活。此外，所提出的研究重点是阐明 RAPA 对 DC 成熟和刺激能力的抑制作用的分子机制，并利用 RAPA-DC 来鉴定对于 Treq 细胞扩增至关重要的 siqnalinq 途径和 qene 产物。相关性：与长期使用免疫抑制剂相关的发病率，以及这些治疗未能防止慢性排斥导致的同种异体移植物损失，仍然是临床实体器官移植的重大障碍。树突状细胞是免疫反应的有效天然调节剂，如果正确用作耐受性载体，可能是持续诱导操作耐受性的关键，减少目前对慢性免疫抑制的依赖并阻断慢性排斥的免疫学成分。