title: 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.
authors.affiliation: Institute for Immunology, University Hospital Heidelberg Im Neuenheimer Feld 305, 69120, Heidelberg, Germany.
authors.forename: Anne-Kristin
authors.initials: AK
authors.lastname: Heninger
authors.affiliation: Institute for Immunology, University Hospital Heidelberg Im Neuenheimer Feld 305, 69120, Heidelberg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Wentrup
authors.affiliation: Department of General, Visceral and Transplant Surgery, University Hospital Heidelberg Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al-Saeedi
authors.affiliation: Institute for Immunology, University Hospital Heidelberg Im Neuenheimer Feld 305, 69120, Heidelberg, Germany ; Department of General, Visceral and Transplant Surgery, University Hospital Heidelberg Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
authors.forename: Serin
authors.initials: S
authors.lastname: Schiessling
authors.affiliation: Institute for Immunology, University Hospital Heidelberg Im Neuenheimer Feld 305, 69120, Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Giese
authors.affiliation: Medigene AG Lochhamer Str. 11, 82152, Planegg/Martinsried, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Wartha
authors.affiliation: Institute for Immunology, University Hospital Heidelberg Im Neuenheimer Feld 305, 69120, Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Meuer
authors.affiliation: Institute for Immunology, University Hospital Heidelberg Im Neuenheimer Feld 305, 69120, Heidelberg, Germany.
authors.forename: Jutta
authors.initials: J
authors.lastname: Schröder-Braunstein
keywords: CD80 blockage; T cells; immunomodulation; inflammatory bowel disease; mucosal immunology