Lobb R R, Abraham W M, Burkly L C, Gill A, Ma W, Knight J A, Leone D R, Antognetti G, Pepinsky R B
Biogen, Inc., Cambridge, Massachusetts 02142, USA.
Ann N Y Acad Sci. 1996 Oct 31;796:113-23. doi: 10.1111/j.1749-6632.1996.tb32573.x.
Evidence for a central role for the integrins alpha 4 beta 1 and alpha 4 beta 7 in leukocyte pathophysiology is rapidly accumulating. Five distinct alpha 4 mAbs, each able to block alpha 4-dependent adhesion in vitro, show beneficial effects in vivo in six different species, and in a wide variety of organ systems, including colon, lung, skin, neural tissue, pancreas, peritoneum, and the vessel wall. In particular, a clear role for these integrins in lung pathophysiology is implied on the basis of in vivo studies in four different species. Although several issues remain to be resolved, including the relative importance of alpha 4 beta 1 and alpha 4 beta 7, and the relative roles of their counterligands, VCAM1, fibronectin, and MAdCAM, the data argue that alpha 4 integrins will likely be critical to both the normal physiology and pathology of the lung in man. To this end, we (Adams, Lin, Lobb, and Gill, unpublished data) and others have generated peptidomimetic small molecule antagonists of VLA4 based on the connecting segment 1 (CS1) peptide sequence of fibronectin that are potent blockers of integrin adhesive function in vitro and show efficacy in vivo. We have found that our inhibitors are excellent blockers of both murine contact hypersensitivity, and of the LPR and AHR in the sheep allergic airways model (Abraham, Lobb, Adams, and Gill, unpublished data), and are therefore possible candidates for clinical intervention in human asthma. The use of the VCAM-Ig fusion protein as a probe for high-affinity alpha 4 integrins has further enhanced our understanding of alpha 4 integrin function in the lung. While integrin upregulation in vitro has been observed many times, and high affinity (as opposed to avidity) of integrins seen in vitro in several systems, in vivo proof of integrin upregulation to a high-affinity state has been difficult to obtain in the absence of selective probes. Our data provide key information in this regard and strongly argue not only that integrin upregulation does indeed occur in vivo, but also that it is in fact obligatory for the leukocyte pathologies we have examined to date. Further studies are clearly warranted to further examine mechanisms of action, and to confirm and extend these studies, both with the alpha 4 integrins and with other integrin families. In summary, our studies of alpha 4 integrins continue to provide novel insights into the pathophysiology of integrin function and into future directions for drug discovery.
整合素α4β1和α4β7在白细胞病理生理学中起核心作用的证据正在迅速积累。五种不同的α4单克隆抗体，每种都能在体外阻断α4依赖性黏附，在六种不同物种以及包括结肠、肺、皮肤、神经组织、胰腺、腹膜和血管壁在内的多种器官系统中均显示出体内有益作用。特别是，基于对四种不同物种的体内研究，暗示了这些整合素在肺病理生理学中的明确作用。尽管仍有几个问题有待解决，包括α4β1和α4β7的相对重要性，以及它们的反配体VCAM1、纤连蛋白和黏膜地址素细胞黏附分子（MAdCAM）的相对作用，但数据表明α4整合素可能对人类肺部的正常生理和病理过程都至关重要。为此，我们（亚当斯、林、洛布和吉尔，未发表数据）以及其他人已基于纤连蛋白的连接段1（CS1）肽序列生成了VLA4的拟肽小分子拮抗剂，这些拮抗剂在体外是整合素黏附功能的有效阻断剂，并在体内显示出疗效。我们发现我们的抑制剂对小鼠接触性超敏反应以及绵羊过敏性气道模型中的迟发性相反应（LPR）和气道高反应性（AHR）均有出色的阻断作用（亚伯拉罕、洛布、亚当斯和吉尔，未发表数据），因此有可能成为人类哮喘临床干预的候选药物。使用VCAM-Ig融合蛋白作为高亲和力α4整合素的探针进一步加深了我们对α4整合素在肺中功能的理解。虽然在体外多次观察到整合素上调，并且在几个系统中在体外也看到了整合素的高亲和力（与亲和力相对），但在缺乏选择性探针的情况下，很难在体内获得整合素上调至高亲和力状态的证据。我们的数据在这方面提供了关键信息，并有力地表明不仅整合素上调确实在体内发生，而且实际上对于我们迄今为止所研究的白细胞病理过程来说是必不可少的。显然有必要进行进一步研究以进一步研究作用机制，并确认和扩展这些研究，包括对α4整合素和其他整合素家族的研究。总之，我们对α4整合素的研究继续为整合素功能的病理生理学以及药物发现的未来方向提供新的见解。
