Role of integrin CD11b in delayed graft function and allorejection

项目摘要/摘要 移植肾功能延迟是移植肾缺血再灌注损伤的一种表现 异体移植。在T细胞或抗体介导的活检证实的急性排斥反应中，DGF是一个重要的危险因素，而 慢性同种异体移植物功能障碍的最大危险因素，甚至超过移植前糖尿病。IRI是一个 受者活化的先天免疫细胞介导的急性炎症反应 再灌流后出现器官缺血。以前限制IRI的努力，主要是在啮齿动物身上进行的，目标是 单独的促炎介质，并在啮齿类动物中显示出希望，但这种方法在 大型动物，在人体试验中失败。我们已经证明了原型先天免疫受体 白细胞整合素CD11b/CD18介导天然非人类灵长类(NHP)肾脏的IRI，而一位First in-in. 抗CD11b类单抗(MAb107)对IRI天然肾脏的保护作用 肾衰竭。此探索性R21的主要目的是评估mAb107限制IRI的效果 在我们研究良好的NHP肾移植模型中关于DGF的研究。我们还证明了接受者天生的 同种异体反应性记忆T细胞在同种异体移植中起关键作用 拒绝。我们的初步数据表明，这些细胞表达CD11b，并在体外被mAb107抑制。 因此，本研究的第二个目的是评价mAb107对促炎作用的影响。 这些同种异体反应细胞在NHP移植受者中的功能。这些研究应该有助于阐明 将先天DGF、排斥反应和同种异体移植结果联系起来的机制，并可能有助于确定一种有效的方法 限制目前临床上观察到的65%的同种异体肾移植的进行性纤维化。

Project Summary/Abstract Delayed graft function (DGF) is a manifestation of ischemia-reperfusion injury (IRI) in the transplanted kidney allograft. DGF is an important risk factor in T-cell or antibody-mediated biopsy-proven acute rejection, and the strongest risk factor for chronic allograft dysfunction, exceeding even that of pre-transplant diabetes. IRI is an acute inflammatory response mediated by the recipient's activated innate immune cells that infiltrate the ischemic organ following reperfusion. Previous efforts to limit IRI, conducted primarily in rodents, have targeted individual proinflammatory mediators and showed promise in rodents, but this approach was less effective in large animals and failed in human trials. We have demonstrated that the archetypal innate immune receptor leukocyte integrin CD11b/CD18 mediates IRI in native nonhuman primate (NHP) kidneys, and that a first-in- class anti-CD11b monoclonal antibody (mAb107) protected IRI native kidneys from otherwise irreversible kidney failure. The main objective of this exploratory R21 is to evaluate the effect of limiting IRI with mAb107 on DGF in our well-studied NHP kidney transplant model. We have also shown that the recipient's innate alloreactive memory T cells present in primates but absent in laboratory mice, play a critical role in allograft rejection. Our preliminary data show that these cells express CD11b, and are inhibited by mAb107 in vitro. Therefore, a second objective of this study is to evaluate the effect of mAb107 on the proinflammatory functions of these alloreactive cells in NHP transplant recipients. These studies should help elucidate the mechanisms linking innate DGF, rejection and allograft outcome, and may help define an effective approach to limiting the progressive fibrosis currently observed clinically in 65% of renal allografts.