Significance relative to placebo\treated group was tested with the MannCWhitney and and showed no signs of a superagonistic effect 15, 37

Significance relative to placebo\treated group was tested with the MannCWhitney and and showed no signs of a superagonistic effect 15, 37. alone, FR104, CTLA\4 Ig and CsA (r1 a r2?=?PBMC of rhesus monkey 1 responds to irradiated PBMC of rhesus monkey 2). (b) CII\specific proliferation was measured for two animals that MIHC were immunized with CII (rhesus 1, 2) in Monoammoniumglycyrrhizinate the presence of medium alone, FR104, CTLA\4 Ig and CsA. CEI-183-405-s002.pdf (30K) GUID:?3BFE160B-1D78-44B2-B60B-97A4C9A91326 Fig. S3. FR104 serum levels during the experiment. (a) FR104 levels were measured after the first dosing and (b) during the entire evaluation period through levels of FR104 were measured before dosing. CEI-183-405-s003.pdf (36K) GUID:?2B56EC25-AB83-4484-AD25-39B65B1C6F79 Fig. S4. Dot\plots showing the cell gating strategy for flow cytometry analysis of regulatory T cell population. CEI-183-405-s004.pdf (124K) GUID:?D4CDEEE1-099B-4B56-8E3E-DBE51458204A Table S1. CII\specific proliferation presented as counts per minute and calculated stimulation index. Phorbol myristate Monoammoniumglycyrrhizinate acetate (PMA)/I was taken along as a positive control. CEI-183-405-s005.docx (102K) GUID:?B14C3990-668A-4D25-BDD9-3B44D5FD587C Summary T cells have a central pathogenic role in the aetiopathogenesis of rheumatoid arthritis (RA), and are therefore a favoured target of immunotherapy aiming at physical or functional elimination. Here we report an efficacy test of FR104, a new co\stimulation inhibitor directly targeting CD28 on T cells, in a translationally relevant model, the rhesus monkey model of collagen\induced arthritis (CIA). As a relevant comparator we used abatacept [cytotoxic T lymphocyte antigen immunoglobulin (CTLA Ig)], an antagonist of CTLA\4 binding to CD80/86 clinically approved for treatment of RA. Treatment with either compound was started at the day of CIA induction. Although Monoammoniumglycyrrhizinate FR104 previously demonstrated a higher control of T cell responses than abatacept, both compounds were equally potent in the suppression of CIA symptoms and biomarkers, such as the production of C\reactive protein (CRP) and interleukin (IL)\6 and anti\collagen type II (CII) serum antibody (IgM/IgG). However, in contrast to abatacept, FR104 showed effective suppression of CII\induced peripheral blood mononuclear Monoammoniumglycyrrhizinate cell (PBMC) proliferation. The current study demonstrates a strong potential of the new selective CD28 antagonist FR104 for treatment of RA. Keywords: CD28, CIA, co\stimulation blockade, rhesus monkey, T cell Introduction The central pathogenic role of T cells in rheumatoid arthritis (RA) is illustrated by the presence of T cells in synovial infiltrates 1 and the sensitivity of RA for T cell\targeted therapies [methotrexate 2, cyclosporin A 3, 4, leflunomide 5, 6 and cytotoxic T lymphocyte\4 immunoglobulin (CTLA 4\Ig) 7]. Moreover, susceptibility to RA is linked strongly with certain major histocompatibility complex (MHC) class II alleles 8. A pivotal target that is involved critically in T cell activation is the interaction of CD28 on the T cells with two molecules of the B7 family, CD80 and CD86, on antigen\presenting cells (APC). The interaction relays essential co\stimulation to T cells 9. Activation of T cells requires the binding of the T cell receptor with an MHCCpeptide complex (signal 1) and the additional interaction of CD28 with CD80/86 (signal 2). Specifically in primates, but not in mice, interaction of CD28 with inducible T cell co\stimulator ligand (ICOS\L) has also been described 10. These two activation signals are supplemented with a cytokine\mediated third signal that determines the functional polarization of the newly activated T cells 11. Dysregulation of the T cell response is avoided by shut\down signals from counter\regulatory molecules, such as CTLA\4 interaction with CD80/86 and programmed death\1 (PD\1) interaction with PD\1 ligand 12, 13. In addition, PD\1 ligand can interact with CD80 to regulate T cell responses 14. Conceptually, the ideal approach for controlling autoreactive T cells would be to block T cell activation signals, without affecting shut\down signals. For blockade of CD80/86 interaction with CD28 in the clinic, CTLA\4 Ig (abatacept; Orencia?) has been used. However, binding of soluble CTLA\4 Ig to CD80/86 not only.