The Potential to Immunocloak Renal Allografts

免疫斗篷同种异体肾移植的潜力

• 批准号: 8812766
• 负责人: Lauren Brasile
• 金额: $ 96.11万
• 依托单位: BREONICS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-25 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8812766
• 关键词: Acute; Adverse effects; Affect; Antibodies; Antigen Presentation; Apical; Attention; Biomedical Engineering; Blood Vessels; Blood capillaries; Caring; Chronic; Clinical; Clinical Trials; Collagen Type IV; Data; Development; Development Plans; Devices; Dose; Electron Microscopy; Evaluation; Fibronectins; Foundations; Funding; Future; Goals; Graft Rejection; Graft Survival; Health; Human; Immune; Immune Cell Activation; Immune system; Immunologics; Immunosuppression; Immunosuppressive Agents; Integrins; Kidney; Laminin; Lead; Leukocytes; Malignant Neoplasms; Mass Spectrum Analysis; Membrane; Metabolic; Necrosis; Nephrotoxic; Opportunistic Infections; Organ; Outcome; Perfusion; Pharmaceutical Preparations; Phase; Program Development; Regimen; Renal Tissue; Renal function; Reperfusion Therapy; Reporting; Research; Risk; Severities; Small Business Innovation Research Grant; Structure; Structure of renal vein; Surface; Surgical Replantation; T-Cell Activation; Technology; Therapeutic; Time; Transplantation; Vascular Endothelial Cell; Work; allograft rejection; capillary; clinically relevant; delayed graft function; design; immunogenic; immunogenicity; improved; kidney allograft; nano; new technology; novel; phase 1 study; phase 2 study; pressure; prevent; product development; receptor; response

DESCRIPTION (provided by applicant): The focus of this project is a novel immunomodifying therapy that provides protection from early allograft rejection in the absence of the standard toxic systemic immunosuppressive drug regimens. This novel therapy is a nano-barrier membrane called NB-LVF4 consisting of a matrix made of laminin, vitrogen, fibronectin and type IV collagen. NB-LVF4 is applied to "immunocloak" the luminal surfaces within the renal vasculature by covering the point of contact between donor vascular endothelial cells and the host immune system; without adversely affecting renal function. The result is an apical surface that is non-thrombogenic and non- immunogenic and significantly delays the onset of rejection 5-fold over untreated controls by preventing allo- recognition that normally occurs immediately upon reperfusion. A warm acellular Exsanguinous Metabolic Support (EMS) perfusion technology that is entering clinical trials is the platform used to apply NB-LVF4. The immunocloaking technology will be a follow-on product that can be applied to a kidney allograft during ex vivo EMS perfusion. If the results of our studies support our hypotheses and prove that: 1. the immunogenicity of renal allografts can be further reduced by trapping passenger leukocytes that migrate into the recirculating EMS perfusate to prevent reentry into the kidney, 2. the use of a concordant low-dose immunosuppressive drug monotherapy potentiates long-term graft survival, 3. the mechanisms of protection provided by NB-LVF4 are fully elucidated, along with an understanding of how it degrades over time along the vasculature and 4. a strategy for the organ-specific re-application of NB-LVF4 posttransplant to replace systemic drug regimens can be achieved, the NB-LVF4 technology will mark a new era in transplantation. It is envisioned that the ability to eliminate toxic systemic immunosuppressive drug regimens will lead to a paradigm shift where instead of daily immunosuppressive drug regimens it will become feasible to re-administer NB-LVF4 every three to four weeks. However, even if these goals are not fully achieved, NB-LVF4 will still be clinically relevant. The ability to use NB-LVF4 treatment to eliminate systemic immunosuppression during the early posttransplant period will be important to expanding the cadaveric kidney donor pool with warm ischemically damaged DCD kidneys. The acute tubule necrosis that is the result of ischemic damage leads to delayed graft function that in turn is associated with the risk of developing currently untreatable chronic rejection. By eliminating the need for systemic immunosuppressive drugs, that are in of themselves nephrotoxic, during the early posttransplant period of acute tubule necrosis the severity and duration of delayed graft function would be ameliorated. The consultants and collaborators involved in this project are internationally recognized experts in their respective field and their involvement in this project will significantly increase the likelihood of successfu outcomes.

描述（由申请人提供）：该项目的重点是一种新型免疫调节疗法，在缺乏标准的有毒全身免疫抑制药物治疗方案的情况下，可提供针对早期同种异体移植排斥的保护。这种新颖的疗法是一种名为 NB-LVF4 的纳米屏障膜，由层粘连蛋白、vitrogen、纤连蛋白和 IV 型胶原蛋白制成的基质组成。 NB-LVF4 通过覆盖供体血管内皮细胞和宿主免疫系统之间的接触点来“免疫覆盖”肾脉管系统内的管腔表面；对肾功能无不良影响。其结果是形成一种非血栓形成和非免疫原性的顶端表面，并且通过防止通常在再灌注后立即发生的同种异体识别，使排斥反应的发生比未处理的对照显着延迟5倍。正在进入临床试验的温热无细胞外血代谢支持（EMS）灌注技术是用于应用NB-LVF4的平台。免疫隐匿技术将是后续产品，可在离体 EMS 灌注过程中应用于同种异体肾移植。如果我们的研究结果支持我们的假设并证明： 1. 通过捕获迁移到再循环 EMS 灌注液中的过客白细胞以防止再进入肾脏，可以进一步降低同种异体肾移植物的免疫原性， 2. 使用一致的低剂量免疫抑制药物单一疗法可增强移植物的长期存活， 3. 移植物提供的保护机制 NB-LVF4得到了充分阐明，并且了解了它如何随着时间的推移沿着脉管系统降解，并且4.可以实现移植后器官特异性重新应用NB-LVF4以取代全身药物治疗方案的策略，NB-LVF4技术将标志着移植的新时代。预计消除有毒的全身性免疫抑制药物治疗方案的能力将导致范式转变，取代每日免疫抑制药物治疗方案，每三至四周重新施用 NB-LVF4 将变得可行。然而，即使这些目标没有完全实现，NB-LVF4 仍然具有临床相关性。使用 NB-LVF4 治疗的能力 消除移植后早期的全身免疫抑制对于扩大具有温暖的缺血性损伤的 DCD 肾脏的尸体肾供体库非常重要。缺血性损伤导致的急性肾小管坏死导致移植物功能延迟，进而与发生目前无法治疗的慢性排斥反应的风险相关。通过消除对本身具有肾毒性的全身免疫抑制药物的需求，在急性肾小管坏死的移植后早期，移植物功能延迟的严重程度和持续时间将得到改善。参与该项目的顾问和合作者都是各自领域的国际公认专家，他们参与该项目将大大增加取得成功的可能性。