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OP02. Identification of glycoprotein 2 as an immunomodulator of innate and adaptive immune responses

L. Werner1, D. Reinhold2, D. Roggenbuck3, A. Sturm1

1Charité Campus Virchow-Klinikum Humboldt-Universität zu Berlin, Med. Klinik, Abt.Gastroenterologie/Hepatologie, Berlin, Germany; 2Otto-von-Guericke-University, Magdeburg, Germany; 3Medipan GmBH, Dahlewitz, Germany

Background: Pancreatic autoantibodies (PAB) are believed to be Crohn's disease (CD)-specific serological markers. Their antigen, glycoprotein 2 (GP2), has only recently been identified. GP2 is secreted from pancreatic granules and is suggested to support bacterial handling. However, the functional and immunological roles of GP2 are unknown.

We hypothesized that not only GP2 antibodies differentiate CD patients, but also that GP2 itself modulates innate and adaptive immune responses.

Methods and Results: We initially confirmed anti-GP2 levels are significantly elevated in CD, using ELISA. For functional studies, we cultured stimulated peripheral blood, lamina propria, or intraepithelial T lymphocytes; as well as human intestinal epithelial cells or epithelial line T84 with or without GP2 for 48 h. GP2 has an immunosupressive effect on T cells, as observed by decreased cell cycling (flow cytometric PI staining), activation (CD25 expression), pro-inflammatory cytokine secretion (ELISA) and apoptosis (annexinV/PI staining). GP2 also modifies epithelial function as observed by decreased cell cycling and IL8 secretion (ELISA), as well as modulation of TLR4, E‑Cadherin and CD49d expression.

No migratory influence was exerted by GP2 on either PBMCs (Transwell assay) or epithelial cells (wound healing assay). However, T84 stimulated with GP2 potently chemoattracts PBMCs (Transwell co-cultures). Moreover, GP2 increased antigen presentation by T84 as observed by increased expression of HLA-DR, CD40, and MICA. Last, GP2 augments uptake of E. Coli by epithelial cells and even more efficiently by monocytes (Phagocytosis Assay Kit).

Conclusions: We demonstrate, for the first time, a role for GP2 in immune regulation which could be a platform for therapeutic medication for the treatment of IBD. Involvement of the GP2 in bacterial handling could yield great benefit for medical intervention. Last, anti-GP2 antibodies might serve as a diagnostic tool for recognition of CD sub-types.