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的免疫改良疗法，在没有标准有毒的系统性免疫抑制药物方案的情况下，可保护免受早期同种异体移植的抑制。这种新颖的疗法是一种称为NB-LVF4的纳米式膜膜，由层粘连蛋白，玻璃体，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与宿主免疫系统之间的接触点，将NB-LVF4应用于肾脏脉管系统内的腔表面。没有不利影响肾功能。结果是一个具有非控制性和非免疫原性的顶端表面，并通过防止同种识别通常会在再灌注后立即发生，从而明显地延迟了未经处理的对照的排斥反应的发作。进入临床试验的温暖的巨细胞外的代谢支持（EMS）灌注技术是用于应用NB-LVF4的平台。免疫液化技术将是一种后续产品，可以在离体EMS灌注过程中应用于肾脏同种异体移植物。如果我们的研究结果支持我们的假设并证明：1。可以通过捕获乘客白细胞的肾脏同种异体移植物的免疫原性来进一步降低，这些白细胞将迁移到循环的EMS灌注液中，以防止肾脏重新进入肾脏2。 NB-LVF4被充分阐明，并了解了它如何随着时间的流逝而沿脉管系统降解。可以预见的是，消除有毒的系统性免疫抑制药物方案的能力将导致范式转变，在这种情况下，每三到四个星期都可以重新使用每三到四个星期，而不是每天的免疫抑制药物方案。但是，即使没有完全实现这些目标，NB-LVF4仍将在临床上具有重要意义。使用NB-LVF4处理的能力 在移植后期早期消除系统性免疫抑制，对于用温暖的液化性DCD肾脏扩展尸体肾脏供体池非常重要。急性小管坏死是缺血性损伤的结果，导致移植功能延迟，这反过来又与发展当前不可治疗的慢性排斥反应有关。通过消除对肾毒性本身的全身免疫抑制药物的需求，在急性小管坏死后移植时期的早期，延迟接枝功能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是各自领域的国际认可的专家，他们参与该项目将大大增加成功成果的可能性。