Inhibition of VEGF-receptors 1 and 2 attenuates NK cell and innate immune responses in an experimental model for obliterative bronchiolitis

Am J Pathol. 2021 Nov 10:S0002-9440(21)00475-2. doi: 10.1016/j.ajpath.2021.10.018. Online ahead of print.ABSTRACTObliterative bronchiolitis (OB) after lung transplantation is a non-reversible life-threatening complication. We investigated the role of the main receptors for vascular endothelial growth factor (VEGF), VEGFR -1 and -2, in the development of obliterative airway disease (OAD), an experimental model for OB. The non-immunosuppressed recipients were transplanted with fully MHC-mismatched heterotopic tracheal allografts and received VEGFR-1 and -2 -specific monoclonal antibodies either alone or in combination, or rat IgG as a control. The treatment either with VEGFR-1- or -2 -blocking antibody significantly decreased intragraft mRNA expression of NK cell activation markers early after transplantation. This was followed by reduced infiltration of CD11b+ cells and CD4+ T cells as well as downregulated mRNA expression of proinflammatory chemokines and profibrotic growth factors. However, blocking of both VEGFR-1 and -2 was necessary to reduce luminal occlusion. Furthermore, concomitant inhibition of the calcineurin activation pathway almost totally abolished the development of OAD. We propose that blocking of VEGF receptors blunted NK cell and innate immune responses early after transplantation and attenuated the development of OAD. Our results suggest that further studies on the role of VEGFR-1 and -2 -blocking in development of obliterative airway lesions might be rewar...
Source: The American Journal of Pathology - Category: Pathology Authors: Source Type: research