Adjuvant Therapies Improving the Anti-Rejection Effects of Costimulation Blockade

辅助疗法提高共刺激阻断的抗排斥作用

• 批准号: 8230754
• 负责人: Allan D. Kirk
• 金额: $ 60.69万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-27 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8230754
• 关键词: Acute; Adjuvant Therapy; Adrenal Cortex Hormones; Affinity; Alloantigen; Allografting; Animals; Antigens; Antiviral Response; Attention; Blood donor; CD28 gene; CD58 Antigens; CD58 gene; CD80 gene; CTLA4-Ig; Calcineurin; Calcineurin inhibitor; Cell Death; Cells; Chimeric Proteins; Chronic; Clinical; Clinical Trials; Complement; Complex; Data; Development; Dose; Drug toxicity; Experimental Models; Exposure to; FDA approved; Fostering; Frequencies; Goals; Graft Rejection; Human; Immune; Immune response; Immunity; Immunosuppression; Immunosuppressive Agents; Infusion procedures; Isoantibodies; Kidney Transplantation; Knowledge; LEA29Y; Life; Maintenance; Measures; Mediating; Memory; Modeling; Modified Vaccinia Virus Ankara; Organ; Organ Transplantation; Outcome; Pathway interactions; Peptides; Peripheral; Pharmaceutical Preparations; Phase III Clinical Trials; Phenotype; Population; Prevention; Primates; Prophylactic treatment; Receptor Signaling; Regimen; Relative (related person); Reliance; Resistance; Rheumatoid Arthritis; Risk; Rodent; Rodent Model; Role; Sirolimus; Source; Stem cells; Steroids; T cell regulation; T cell response; T memory cell; T-Cell Activation; T-Cell Depletion; T-Cell Receptor; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; Tacrolimus; Testing; Therapeutic; Time; Toxic effect; Transfusion; Translations; Transplantation; Up-Regulation; Vaccination; Vaccines; Viral; Viral Antigens; Whole Blood; alefacept; allograft rejection; base; brief intervention; clinically relevant; falls; immunoregulation; improved; isoimmunity; kidney allograft; mTOR Inhibitor; nonhuman primate; novel; pathogen; pre-clinical; prevent; public health relevance; resistance mechanism; sound; success

DESCRIPTION (provided by applicant): Organ transplantation requires the use of immunosuppressive drugs to prevent rejection of the transplanted organ, substantially limiting its benefit and augmenting its risk. Unfortunately, all regimens, regardless of the agents used, are incompletely and transiently effective, and induce some degree of immune incompetence for life. Since its discovery, costimulation blockade (CoB) has been suggested as a means of attaining indefinite, well-tolerated, antigen-specific prophylaxis from allograft rejection. An exemplary approach is blockade of the CD28/B7 pathway. Although exceedingly effective in some rodent models, CD28/B7 blockade is not alone sufficient to prevent rejection in primates, including humans. Several mechanisms of CoB- resistant rejection have been suggested, many related to the relative presence of activated alloreactive memory-phenotype T cells. We now have found that treatment with the CD2 specific fusion protein LFA-3-Ig (alefacept) synergizes with the CD28/B7-targeted fusion protein abatacept successfully preventing renal allograft rejection in primates. We hypothesize that alefacept specifically targets many of the factors fostering CoB resistance, including heterologous alloreactive T cell memory, while avoiding interference with peripheral mechanisms that serve to foster CoB-mediated allograft acceptance, including T cell regulation and donor antigen-specific T cell elimination. We therefore propose to investigate the mechanisms by which alefacept improved CoB and use this information to optimize its use, developing a clinically applicable therapy to prevent allograft rejection without the use of calcineurin inhibitors, steroids, or gross T cell depletion. In developing the regimen, we will specifically test alefacept's ability to eliminate pre-existing and induce memory T cells, evaluating the absolute and relative effects of alefacept on allospecific and memory T cells, and viral specific memory T cells. Throughout the study, we will determine the degree to which this regimen's influence on alloimmunity alters protective viral immunity. Based on preliminary evidence suggesting a salutary role for donor specific antigen infusion, we also will determine the degree to which antigen exposure at transplant improves the durability of the effect of this regimen, augmenting the allospecific effect without altering its effect on protective immunity. As this regimen uses agents that are approved for clinical use, this will provide data in support of an immediately translatable strategy to prevent rejection in humans, and establish generalizable knowledge regarding the role of T cell memory in thwarting CoB-based immune modulation. PUBLIC HEALTH RELEVANCE: Immunosuppressive drugs are required to prevent organ transplant rejection; unfortunately, an optimally effective, non-toxic drug regimen is yet to be developed. Costimulation blockade (CoB) has been shown to prevent rejection in rodents, but is far less effective in primates; however, we have developed a regimen pairing CoB with a fusion protein, alefacept, and have shown that it prevents renal allograft rejection in primates, hypothetically due to alefacept's effects countering CoB-resistant mechanisms of rejection. We propose to determine the mechanisms involved in alefacept's action focusing on its effects on allo- and viral-specific immunity, and in doing so develop this regimen into a well-tolerated, clinically applicable, and mechanistically sound therapy to prevent allograft rejection.

描述（由申请人提供）：器官移植需要使用免疫抑制药物来防止移植器官的排斥反应，这大大限制了其益处并增加了其风险。不幸的是，所有的治疗方案，无论使用何种药物，都是不完全和短暂有效的，并且会导致某种程度的终身免疫功能低下。自发现以来，共刺激阻断（CoB）被认为是一种获得无限期、耐受性良好、抗原特异性的同种异体移植排斥预防的方法。一个典型的方法是阻断CD28/B7通路。虽然CD28/B7阻断在一些啮齿类动物模型中非常有效，但单独阻断并不足以防止包括人类在内的灵长类动物的排斥反应。已经提出了几种CoB耐药排斥反应的机制，其中许多机制与激活的同种反应性记忆表型T细胞的相对存在有关。我们现在已经发现用CD2特异性融合蛋白LFA-3-Ig （alefacept）与CD28/ b7靶向融合蛋白abataccept协同治疗成功地预防了灵长类动物的肾移植排斥反应。我们假设alefacept特异性靶向许多促进CoB耐药的因素，包括异源异体反应性T细胞记忆，同时避免干扰有助于促进CoB介导的异体移植物接受的外周机制，包括T细胞调节和供体抗原特异性T细胞消除。因此，我们建议研究alefacept改善CoB的机制，并利用这些信息优化其使用，开发一种临床适用的治疗方法，以防止同种异体移植排斥，而不使用钙调磷酸酶抑制剂、类固醇或总T细胞消耗。在开发方案中，我们将专门测试alfacept消除预先存在和诱导记忆T细胞的能力，评估alfacept对同种异体和记忆T细胞以及病毒特异性记忆T细胞的绝对和相对影响。在整个研究过程中，我们将确定该方案对同种异体免疫改变保护性病毒免疫的影响程度。基于初步证据表明供体特异性抗原输注的有益作用，我们还将确定移植时抗原暴露在何种程度上提高了该方案效果的持久性，在不改变其对保护性免疫的影响的情况下增强了同种异体特异性效果。由于该方案使用的药物已被批准用于临床使用，这将为支持立即可翻译的策略提供数据，以防止人类排斥反应，并建立关于T细胞记忆在阻碍基于cob的免疫调节中的作用的可推广知识。

项目成果

Fatal SV40-associated pneumonia and nephropathy following renal allotransplantation in rhesus macaque.

• DOI: 10.1111/jmp.12285
• 发表时间: 2018-03
• 期刊: Journal of medical primatology
• 影响因子: 0.7
• 作者: Song M;Mulvihill MS;Williams KD;Collins BH;Kirk AD
• 通讯作者: Kirk AD