ANTI‐CD3 therapy expands the numbers of CD4+ and CD8+ treg cells and induces sustained amelioration of collagen‐induced arthritis

Abstract

Objective. To assess the therapeutic potential of anti-CD3 monoclonal antibodies (mAb) for rheumatoid arthritis, using collagen-induced arthritis as an animal model.Methods. Arthritis was induced in DBA/1 mice by immunization with type II collagen. After disease onset, a single injection of anti-CD3 mAb (20 g/mouse) was administered, and arthritis severity was monitored over a 10-day period.Results. Anti-CD3 mAb treatment resulted in a sustained reduction in disease activity, which was associated with an increase in the proportion of naturally occurring CD4؉CD25؉FoxP3؉ regulatory T (Treg) cells and the generation of a population of CD8؉ CD25؉FoxP3؉ Treg cells. Anti-CD3 mAb treatment did not alter the capacity of CD4؉ Treg cells to suppress effector T cell proliferation and interferon-␥ (IFN␥) production in vitro. However, CD4؉ Treg cells from both anti-CD3 mAb-treated and control mice were unable to suppress interleukin-17 (IL-17) production. In contrast, CD8؉ Treg cells induced by anti-CD3 therapy suppressed IL-17 production as well as CD4؉ T cell proliferation and IFN␥ production.Conclusion. These results show that anti-CD3 mAb treatment has important therapeutic potential for rheumatoid arthritis and has the capacity to generate antiarthritic CD8؉ Treg cells and expand the relative numbers of CD4؉ Treg cells.

CD8+Foxp3+ T cells share developmental and phenotypic features with classical CD4+Foxp3+ regulatory T cells but lack potent suppressive activity

“…Importantly, the majority (75.8%) of activated CD8 1 Foxp3 À T cells produced IFN-g, whereas almost no IFN-g production (5.5%) was observed in induced CD8 1 Foxp3 1 cells (Fig. 5A), consistent with a previous study [27]. Similarly, fewer CD8 1 Foxp3 1 T cells produced IFN-g in comparison to their Foxp3 À counterpart ex vivo (Fig.…”

“…Suppressive CD8 1 Foxp3 1 T cells and CD4 1 Foxp3 1 Tregs were recently described to expand in response to aCD3 treatment [27]. However, there is no direct evidence provided that CD8 1 Foxp3 1 T cells contribute significantly to suppression in vivo, and no suppression data of CD8 1 Foxp3 À T cells (which we here show to have comparable suppressive activity) are available.…”

“…In sum, our results suggest that Foxp3 alone is not sufficient to confer strong suppressive activity to CD8 1 T cells. Although transgenic mice with forced overexpression of Foxp3, but not WT mice, were described to harbor suppressive CD8 1 T cells, Foxp3 was similarly considered as implicated but not sufficient to confer suppressive activity in a previous study [41].Suppressive CD8 1 Foxp3 1 T cells and CD4 1 Foxp3 1 Tregs were recently described to expand in response to aCD3 treatment [27]. However, there is no direct evidence provided that CD8 1 Foxp3 1 T cells contribute significantly to suppression in vivo, and no suppression data of CD8 1 Foxp3 À T cells (which we here show to have comparable suppressive activity) are available.…”

OX40L blockade is therapeutic in arthritis, despite promoting osteoclastogenesis

“…Cultures were replenished with fresh media and treatment factors every 3 or 4 d. On day 7 of culture, TRAP histochemical staining of the cultures was then performed as previously described (45), and TRAP positive multinucleated cells (greater than three nuclei) were counted by light microscopy. Functional evidence of osteoclast differentiation and activation was determined by lacunar resorption of dentine discs (n = 3 dentines per treatment).…”

Effect of ultrafine zinc oxide (ZnO) nanoparticles on induction of oral tolerance in mice

“…At least some of compounds that have adjuvant effects have been demonstrated to break immune tolerance, causing autoimmune diseases. For instance, CFA has been widely used as an adjuvant for induction of experimental autoimmune diseases including adjuvant arthritis (Shahrara et al, 2008), collagen-induced arthritis (Notley et al, 2009), and experimental autoimmune encephalomyelitis (Farez et al, 2009). More importantly, DEP is able to block the induction of oral tolerance (Yoshino et al, 1998).…”