Immunomodulation of human intestinal T cells by the synthetic CD80 antagonist RhuDex®. Issue 3 (3rd November 2014)

• Record Type: Journal Article
• Authors: Heninger, Anne‐Kristin; Wentrup, Sabine; Al‐Saeedi, Mohammed; Schiessling, Serin; Giese, Thomas; Wartha, Florian; Meuer, Stefan; Schröder‐Braunstein, Jutta
• Is Part Of: Immunity, inflammation and disease. Volume 2:Issue 3(2014)
• Page Start: 166
• Page End: 180
• Publication Date: 2014-11-03
• Subjects: Immunology -- Periodicals; Immunity -- Periodicals; Inflammation -- Periodicals; 616.079
• DOI: 10.1002/iid3.34
• Languages: English
• ISSNs: 2050-4527

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <sec id="iid334-sec-0001" sec-type="section"> <p>Deregulated activation of mucosal lamina propria T cells plays a central role in the pathogenesis of intestinal inflammation. One of the means to attenuate T cell activation is by blocking the CD28/CD80 co‐stimulatory pathway. Here we investigate RhuDex®, a small molecule that binds to human CD80, for its effects on the activation of lamina propria T cells employing a gut‐culture model of inflammation. To this end, lamina propria leukocytes (LPL) and peripheral blood lymphocytes (PBL) were stimulated either through the CD3/T‐cell‐receptor complex or the CD2‐receptor (CD2) employing agonistic monoclonal antibodies. Co‐stimulatory signals were provided by CD80/CD86 present on lamina propria myeloid cells or LPS‐activated peripheral blood monocytes. Results show that RhuDex® caused a profound reduction of LPL and PBL proliferation, while Abatacept (CTLA‐4‐Ig) inhibited LPL proliferation to a small degree, and had no effect on PBL proliferation. Furthermore, Abatacept significantly inhibited IL‐2, TNF‐α, and IFN‐γ release from LPL, primarily produced by CD4<sup>+</sup> T cells, where IL‐2 blockage was surprisingly strong, suggesting a down‐regulating effect on regulatory T cells. In contrast, in the presence of RhuDex®, secretion of IL‐17, again mostly by CD4<sup>+</sup> T cells, and IFN‐γ was inhibited in LPL and PBL, yet IL‐2 remained unaffected. Thus, RhuDex® efficiently inhibited lamina propria and peripheral blood T‐cell activation in this pre‐clinical study making it a promising drug candidate for the treatment of intestinal inflammation.</p> </sec> </abstract>