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Immunomodulation of human intestinal T cells by the synthetic CD80 antagonist RhuDex®.

ABSTRACT: 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(+) 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(+) 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.

SUBMITTER: Heninger AK

PROVIDER: S-EPMC4257762 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Immunomodulation of human intestinal T cells by the synthetic CD80 antagonist RhuDex®.

Heninger Anne-Kristin AK Wentrup Sabine S Al-Saeedi Mohammed M Schiessling Serin S Giese Thomas T Wartha Florian F Meuer Stefan S Schröder-Braunstein Jutta J

Immunity, inflammation and disease 20141103 3

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 stimu ...[more]

PMID: 25505551

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Dataset Information

Immunomodulation of human intestinal T cells by the synthetic CD80 antagonist RhuDex®.

Publications

Immunomodulation of human intestinal T cells by the synthetic CD80 antagonist RhuDex®.

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