Baba, Nobuyasu, Van, VuQuang, Wakahara, Keiko, Weckbecker, Gisbert, Kolbinger, Frank, Heusser, Christoph, Huber, Thomas, Welzenbach, Karl and Sarfati, Marika (2013) CD47 fusion protein targets CD172a+ cells in Crohn's disease and dampens the production of IL-1β and TNF. J Exp Med..

Abstract

In mice, the transfer of CD172a(+) (SIRP-α) dendritic cells (DCs) elicits T cell-driven colitis, whereas treatment with CD47-Fc protein, a CD172a-binding agent, confers protection. The aim of this study was to elucidate the nature and functional properties of human CD172a(+) DCs in chronic intestinal inflammation. Here, we show that CD172a(+)CD11c(+) cells accumulate in the mesenteric lymph nodes (mLNs) and inflamed intestinal mucosa in patients with Crohn's disease (CD). These cells are distinct from resident DCs and may coexpress markers typically associated with monocyte-derived inflammatory DCs such as CD14 and/or DC-SIGN, E-Cadherin, and/or CX3CR1. Spontaneous IL-1β and TNF production by HLA-DR(+) cells in CD tissues is restricted to those expressing CD172a. An avidity-improved CD47 fusion protein (CD47-Var1) suppresses the release of a wide array of inflammatory cytokines by CD172a(+) cells, which may include HLA-DR(-)CD172a(+) neutrophils, in inflamed colonic explant cultures and impairs the ability of HLA-DR(+)CD172a(+) cells to activate memory Th17 but not Th1 responses in mLNs. In conclusion, targeting CD172a(+) cells may represent novel therapeutic perspectives for patients with CD.

Item Type:	Article
Additional Information:	First author is postdoc at collaborator M Sarfati
Keywords:	CD47, Dendritic cells; CD47 fusion protein; Crohn`s disease; Colitis; gut inflammation; CD172a; SIRPa
Date Deposited:	07 Jun 2016 23:45
Last Modified:	07 Jun 2016 23:45
URI:	https://oak.novartis.com/id/eprint/7945