The Molecular Biology Of Experimental and Clinical Immune Tolerance

实验和临床免疫耐受的分子生物学

基本信息

批准号：
7734612
负责人：
Jack Ragheb
金额：
$ 10.63万
依托单位：
NATIONAL EYE INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
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/7734612
关键词：
Adverse effects Affinity Allergic Allografting Antigen-Presenting Cells Autoimmune Diseases Autoimmune Process B-Lymphocytes Blocking Antibodies CD28 gene Cell Maturation Cell Surface Receptors Cell division Cells Clinic Clinical Clinical Immunology Clinical Trials Conduct Clinical Trials Daclizumab Disease Drug usage End Point Exhibits Goals Graft Rejection Human Hypersensitivity Immune Immune Tolerance Immunologics Immunology Immunosuppression Immunosuppressive Agents Immunotherapy Inflammatory Interferon Type II Interleukin 2 Receptor Interleukin-12 Interleukin-2 Investigation Laboratories Laboratory Study Life Ligands Maintenance Manuscripts Mission Modality Modeling Molecular Molecular Biology Molecular Immunology Monoclonal Antibodies Mus Pharmaceutical Preparations Phase Primates Production Regulation Reporting Research Role Signal Transduction Sirolimus Surface TNFSF5 gene Therapeutic Therapeutic immunosuppression Time Transplantation Treatment Protocols United States Food and Drug Administration Work autoimmune uveitis base cytokine innovation man memory CD4 T lymphocyte monocyte mouse model partial response receptor

项目摘要

I. Induction of Clinical Immunotolerance. To date, autoimmune disease and transplant graft rejection have been managed using a barrage of immunosuppressive drugs. These medications often require life-long administration and have a plethora of serious side effects. With few exceptions, these same drugs block the induction of immune tolerance, a likely prerequisite for long-term graft acceptance in the absence of continued immunosuppression or for an autoimmune disease cure. A Phase I/II Clinical Trial to induce immune tolerance, 04-EI-0115, will be complete in April 2008. In this study we utilize two pharmacological agents; daclizumab, a monoclonal antibody against the interluekin-2 receptor that can control autoimmune uveitis but does not appear to block the induction of tolerance, and sirolimus (rapamycin), a drug that can induce experimental immune tolerance. To date three subjects have completed the study. Two reached the primary study endpoint and the third had a partial response. Two additional subjects are approaching the primary study endpoint. II. Molecular Consequences of IL-2 Receptor Blockade. Laboratory investigations to understand the mechanism(s) by which blockade of the high affinity IL-2 receptor (a therapeutic modality in transplantation, allergic, and autoimmune disease) inhibits immune activation have demonstrated for the first time that both IFN-gamma production and CD40L expression are biphasic and that the latter, but not the initial phase of expression, is highly dependent on IL-2R signaling. Weve found that nave and memory CD4 T cells exhibit biphasic CD40L expression and in both, the late phase is CD28-dependent and inhibited by daclizumab independently of cell division. In contrast to mouse, human late phase CD40L is a consequence of CD28 signaling and IL-2, not the principal Th1/Th2 polarizing cytokines. This fundamental difference between man and mouse in the regulation of CD40L has profound implications for mouse models of B cell maturation, transplant tolerance, allergy and autoimmune disease. Our findings also have important implications for the choice of immunosuppressive regimen (e.g. anti- IL-2R vs. anti- IL-12) employed in the setting of transplantation or autoimmune disease. Others have shown that blocking CD40L alone can induce long-term tolerance in a primate transplant model, which has never been accomplished by any other means. Unfortunately, CD40L blocking antibodies had serious adverse effects when used in human trials. Our observations suggest IL-2R blockade could represent one component of an alternative strategy to anti-CD40L immunotherapy for the induction of immune tolerance. Collectively, our results also indicate that IL-2 has a broader immunologic role than the expansion and maintenance of CD25+Tregs. In contrast to late CD40L expression, early expression is completely independent of cytokines. However, weve discovered that early CD40L expression, like late expression, is dependent on the presence of antigen presenting cells (APC), but through different and unknown cell surface receptors. The CD40L costimulatory activity of APC is dependent upon cell-cell contact with monocytes and does not require monocyte activation. Our current efforts are focused on identifying the unknown surface ligand on APC that augments the induction of early CD40L expression and the molecular mechanisms underlying its biphasic expression. A manuscript reporting this work has been submitted.

I.诱导临床免疫力耐受性。迄今为止，已经使用一系列免疫抑制药物来管理自身免疫性疾病和移植移植抑制。这些药物通常需要终身管理，并且具有许多严重的副作用。除少数例外，这些相同的药物阻止了免疫耐受性的诱导，这是在没有持续免疫抑制或自身免疫性疾病治疗的情况下长期接受接枝的先决条件。 I/II期临床试验诱导免疫耐受性为04-EI-0115，将于2008年4月完成。在这项研究中，我们使用两种药理剂。 Daclizumab是一种针对Interluekin-2受体的单克隆抗体，可以控制自身免疫性葡萄膜炎，但似乎并不能阻止耐受性的诱导，Sirolimus（Rapamycin）（一种可以诱导实验性免疫耐受性的药物）。迄今为止，三个受试者已经完成了这项研究。两个达到了主要研究终点，第三个有部分响应。另外两个主题正在接近主要研究终点。 ii。 IL-2受体阻滞的分子后果。实验室研究以了解高亲和力IL-2受体阻断的机制（移植，过敏性和自身免疫性疾病的治疗方式）首次证明了IFN-GAMMA的产生和CD40L表达是Biphasic的首次表现出来，并且不是最初的阶段，但最初是表达的，这是最初的表达，这是最初的表达，这是IFN-GAMMA的产生和CD40L的表达均高度依赖，并且是表达的最初阶段。我们发现，中殿和记忆CD4 T细胞表现出双相CD40L的表达，在这两者中，晚期均依赖CD28依赖性，并且由Daclizumab抑制了与细胞分裂无关。与小鼠相反，人类晚期CD40L是CD28信号传导和IL-2的结果，而不是主要TH1/TH2极化细胞因子。在CD40L调节中，人与小鼠之间的这种基本差异对B细胞成熟，移植耐受性，过敏和自身免疫性疾病的小鼠模型具有深远的影响。我们的发现对在移植或自身免疫性疾病的情况下采用的免疫抑制方案（例如抗IL-2R与抗IL-12）的选择也具有重要意义。其他人则表明，仅阻止CD40L可以在灵长类动物移植模型中诱导长期耐受性，这从未通过任何其他方式完成。不幸的是，在人类试验中使用CD40L阻断抗体会产生严重的不利影响。我们的观察结果表明，IL-2R封锁可以代表抗CD40L免疫疗法的替代策略的一个组成部分，以诱导免疫耐受性。总的来说，我们的结果还表明，IL-2比CD25+Treg的扩展和维持具有更广泛的免疫学作用。与晚期CD40L表达相反，早期表达完全独立于细胞因子。但是，我们发现早期的CD40L表达（如晚表达）取决于抗原呈递细胞（APC），但通过不同和未知的细胞表面受体的存在。 APC的CD40L共刺激活性取决于细胞 - 细胞与单核细胞的接触，并且不需要单核细胞激活。我们目前的努力集中在识别APC上未知的表面配体，该配体增强了早期CD40L表达的诱导和其双相表达的分子机制。报告了这项工作的手稿。