Effectiveness of Soluble CTLA-4-Fc in the Inhibition of Bone Marrow T-Cell Activation in Context of Indoleamine 2.3-Dioxygenase (IDO) and CD4+Foxp3+ Treg Induction

Abstract

Background Rheumatoid arthritis (RA) is a chronic autoimmune disease with systemic inflammation finally resulting in damaged joints. One of the RA development models suggests bone marrow (BM) as a place of inflammation development further leading to disease progression. We aimed to investigate the potential of CTLA-4-Fc molecule in inducing tolerogenic milieu in BM measured as indoleamine 2,3-dioxygenase (IDO) expression, CD4 + Foxp3 + Treg induction, and T cell activation control. The expression of IDO-pathway genes was also examined in monocytes to estimate the tolerogenic potential in the periphery. Methods Bone marrow mononuclear cells (BMMC) were stimulated by pro-inflammatory cytokines and CTLA-4-Fc. Next IDO expression, CD4 + CD69 + and CD4 + Foxp3 + percentage were estimated by PCR and FACS staining, respectively. Enzymatic activity of IDO was confirmed by HPLC in BM plasma and blood plasma. Genes expressed in IDO-pathway were analyzed by NGS in peripheral monocytes isolated from RA patients and healthy controls. Results We found that CTLA-4-Fc and IFN-γ stimulation results in IDO production by BMMC. CTLA-4-Fc induced tryptophan catabolism can inhibit mitogen-induced CD4 + T cells activation without influencing CD8 + cells, but did not control CD25 nor Foxp3 expression in BM cells. Significantly higher expression of selected IDO-pathway genes was detected on peripheral monocytes isolated from RA as compared to healthy controls. Conclusion This study sheds light on some immunosuppression aspects present or induced in BM. The potential of IDO-mediated pathways were confirmed in the periphery, what may represent the promising candidates for therapeutic strategies in RA.

The Biologic IRL201805 Alters Immune Tolerance Leading to Prolonged Pharmacodynamics and Efficacy in Rheumatoid Arthritis Patients

“…Abatacept, a CTLA-4-Ig fusion protein, binds to CD80/CD86 and blocks inflammatory pathways in T-cells and is used to treat progressive RA [12]. Mechanistically, evidence suggests soluble CTLA-4-Fc induces tolerogenic conditions via indolamine dioxygenase (IDO) and Tregs, by increasing the production of enzymatically active IDO, but not necessarily increasing the Treg number [13]. In physiologically relevant whole-blood cultures, the addition of IRL201805 induced soluble CTLA-4 (sCTLA-4) production (24 h, range 1-18 pg/mL; 72 h, range 50-72 pg/mL) (Figure 3B) when the control cultures showed no detectable CTLA-4.…”

Immunopotentiating effects of herb-partitioned moxibustion on the spleens of cyclophosphamide-induced immunosuppressed rats

“…CTLA-4, a coinhibitory immune checkpoint, typically exerts inhibitory effects on T cells [ 15 ]. Studies on CTLA-4 and CD28 in nontumor fields other than oncology have mainly concentrated on autoimmune diseases, transplantation, and other domains, with limited research on immunosuppression [ 16 , 17 ].…”

Der Einfluss von Trauma-aktiviertem platelet-rich fibrin auf mesenchymale Stammzellen in vitro

“…Besonders bei der Abwehr von bakteriellen und viralen Infektionen spielt es eine Rolle. 25 Der Einfluss auf regulierende T-Zellen wird bei IDO-1 und auch bei IDO-2, einem dem IDO-1 ähnelnden Protein, beschrieben. 26 Die hier aufgeführten Faktoren stellen nur eine Auswahl an möglichen Einflussfaktoren dar.…”