The Potential to Immunocloak Renal Allografts

描述（由申请人提供）：这个项目的重点是一种新的免疫修饰疗法，在没有标准的毒性全身免疫抑制药物方案的情况下，提供早期同种异体移植排斥反应的保护。这种新疗法是一种名为NB-LVF4的纳米屏障膜，由层粘连蛋白、玻璃体、纤维连接蛋白和IV型胶原蛋白组成。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，用于“免疫覆盖”肾血管内的管腔表面；不影响肾功能。其结果是根尖表面非血栓性和非免疫原性，通过阻止通常在再灌注后立即发生的同种异体识别，显著延迟排斥反应的发生，比未治疗的对照组延迟5倍。NB-LVF4应用的平台是正在进入临床试验的热脱细胞Exsanguinous Metabolic Support （EMS）灌注技术。这种免疫隐形技术将是一种后续产品，可以在体外EMS灌注过程中应用于同种异体肾脏移植。如果我们的研究结果支持我们的假设并证明：同种异体肾移植物的免疫原性可以通过捕获迁移到再循环的EMS灌注液中以防止再进入肾脏的客运白细胞而进一步降低，2。使用一致的低剂量免疫抑制药物单药治疗可增强移植物的长期存活。NB-LVF4提供的保护机制已经完全阐明，同时也了解了它是如何随着时间的推移沿着脉管系统和血管降解的。可以实现移植后器官特异性再应用NB-LVF4替代全身药物方案的策略，NB-LVF4技术将标志着移植的新时代。预计消除毒性全身免疫抑制药物方案的能力将导致范式转变，即每三到四周重新施用NB-LVF4将变得可行，而不是每天使用免疫抑制药物方案。然而，即使这些目标没有完全实现，NB-LVF4仍将具有临床相关性。能否采用NB-LVF4治疗

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.