Inhibition of Th2-Mediated Allergic Airway Inflammatory Disease by CD137 Costimulation

Abstract

The engagement of CD137 (4-1BB), an inducible T cell costimulatory receptor and member of the TNF receptor superfamily, by agonistic Abs can promote strong tumor and viral immunity mediated by CD8+ T cells and stimulate IFN-γ production. However, its role in Th2-mediated immune responses has not been well defined. To address this issue, we studied the function of CD137 engagement using an allergic airway disease model in which the mice were sensitized with inactivated Schistosoma mansoni eggs followed by S. mansoni egg Ag challenge directly in the airways and Th1/2 cytokine production was monitored. Interestingly, treatment of C57BL/6 mice with agonistic anti-CD137 (2A) during sensitization completely prevents allergic airway inflammation, as shown by a clear inhibition of T cell and eosinophil infiltration into the lung tissue and airways, accompanied by diminished Th2 cytokine production and reduced serum IgE levels, as well as a reduction of airway hyperresponsiveness. At various time points after immunization, restimulated splenocytes from 2A-treated mice displayed reduced proliferation and Th2 cytokine production. In accordance with this, agonistic Ab to CD137 can directly coinhibit Th2 responses in vitro although it costimulates Th1 responses. CD137-mediated suppression of Th2 response is independent of IFN-γ and T regulatory cells. Our study has identified a novel pathway to inhibit Th2 responses in a CD137-dependent fashion.

Immune regulation and control of regulatory T cells by OX40 and 4-1BB

“…Whether any of these activities were due to a direct effect of signaling to the CD4 T cells is not known. Suppression of CD4 T cell reactivity by anti-4-1BB was also shown in mouse models of allergic asthma [53,54] accompanied by prevention of the development of disease as well as reversal of established disease. The protective function in this case was associated with a marked reduction of Th2 cytokines but augmented IFN-γ.…”

4-1BB Ligand-Mediated Imbalance of Helper 17 T Cells and Regulatory T Cells in Patients with Allergic Asthma

“…It is possible that a deficiency in 4-1BBL/4-1BB signalling (including s4-1BBL) may contribute to a shift from a T h 1 response to a T h 2 response in asthma. 32 As such, the decrease in 4-1BBL might promote the development of allergic asthma. A T h 17/T reg imbalance has been shown to be present in patients with asthma, particularly in moderate-to-severe disease.…”

Intervention with costimulatory pathways as a therapeutic approach for graft-versus-host disease

“…Early observations showed that the same agonistic mAb to CD137 that have a potent anti-tumor effect (Melero et al, 1997) can abrogate T celldependent Ab responses (Mittler et al, 1999). Since this phenomenon was reported, an explosion of literature have demonstrated that stimulation of CD137 results in strong suppression of a variety of autoimmune or inflammatory diseases that are believed to be mediated mainly by CD4 + T cells (Sun et al, 2002a(Sun et al, , 2002b(Sun et al, , 2006Foell et al, 2003Foell et al, , 2004Seo et al, 2004;Fukushima et al, 2005;Kim et al, 2005Kim et al, , 2007Shao et al, 2005;Cho et al, 2006;Polte et al, 2006). Mechanisms of action behind anti-CD137-mediated immunosuppression still remain to be fully elucidated but seem to depend upon the context of inflammatory processes involved in the development of diseases.…”

“…For example, agonistic anti-CD137 mAb inhibits autoantibody production almost without exception, subsequently blocking autoantibody-mediated autoimmune diseases such as SLE and rheumatoid arthritis (Sun et al, 2002b;Foell et al, 2003Foell et al, , 2004Seo et al, 2004;Kim et al, 2005). CD137 ligation also serves as a powerful therapeutic mediator for Th2-mediated diseases, including asthma (Fukushima et al, 2005;Cho et al, 2006;Polte et al, 2006;Sun et al, 2006). By contrast, agonistic anti-CD137 mAb exacerbates diseases accompanying acute inflammation (Kim et al, 2009).…”

“…In rheumatoid arthritis, CD8 + T cells have been shown to play such a role by inducing the expression of indoleamine 2,3-dioxyginase (IDO) in APCs in an IFN-γ-dependent manner (Seo et al, 2004). However, this mechanism of action has not been shown to be involved in the immunosuppression by agonistic anti-CD137 mAb in other disease models (Kim et al, 2005;Polte et al, 2006;Sun et al, 2006;Kim et al, 2007). Interestingly, CD137 is constitutively expressed on Treg cells and CD137 signals can promote their proliferation and prosurvival in vitro, especially in the presence of IL-2 (Zheng et al, 2004;Elpek et al, 2007).…”