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The Potential to Immunocloak Renal Allografts

免疫斗篷同种异体肾移植的潜力

基本信息

批准号：
9010903
负责人：
Lauren Brasile
金额：
$ 96.11万
依托单位：
BREONICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-25 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9010903
关键词：
Acute Adverse effects Affect Antibodies Antigen Presentation Apical Attention Biomedical Engineering Blood Vessels Blood capillaries 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 improved outcome kidney allograft nano new technology novel novel therapeutics phase 1 study phase 2 study pressure prevent product development receptor response standard of care

项目摘要

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，在缺乏标准毒性全身免疫抑制药物方案的情况下，可保护早期同种异体移植物排斥反应。这种新的疗法是一种称为NB-LVF 4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-LVF 4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“免疫封闭”肾血管系统内的管腔表面;而不会对肾功能产生不利影响。其结果是一个非血栓形成和非免疫原性的顶端表面，并通过阻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著延迟5倍。一种正在进入临床试验的温暖的无细胞脱血代谢支持（EMS）灌注技术是用于应用NB-LVF 4的平台。免疫封闭技术将是一种后续产品，可在离体EMS灌注期间应用于肾移植。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，可以进一步降低肾同种异体移植物的免疫原性。使用一致的低剂量免疫抑制药物单一疗法增强了移植物的长期存活率。充分阐明了NB-LVF 4提供的保护机制，沿着理解了它如何随着时间沿着脉管系统和4降解。可以实现移植后器官特异性再应用NB-LVF 4以替代全身性药物方案的策略，NB-LVF 4技术将标志着移植的新时代。设想消除毒性全身性免疫抑制药物方案的能力将导致范式转变，其中代替每日免疫抑制药物方案，每三至四周重新施用NB-LVF 4将变得可行。然而，即使这些目标没有完全实现，NB-LVF 4仍然具有临床意义。使用NB-LVF 4治疗的能力在移植后早期消除全身免疫抑制对于扩大热缺血损伤DCD肾的尸体肾供体库将是重要的。缺血性损伤导致的急性肾小管坏死导致移植物功能延迟，这反过来又与发展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性免疫抑制药物的需要，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。