Involvement of the TNF-α/TGF-β/IDO axis in IVIg-induced immune tolerance.
The immune tolerance induced by IVIg treatment is generally attributed to its capacity to modulate the functions of antigen presenting cells and to induce the expansion of regulatory T cells by mechanisms that are not well-defined. Herein, we investigated the contribution of the TNF-α/TGF-β/IDO axis to IVIg-induced immune tolerance. We show that high dose IVIg is able to markedly increase the expression (>3 fold) of the well-known tolerogenic cytokine TGF-β in monocytes. In addition, the expression of TNF-α, a pleiotropic cytokine that controls TGF-β-induced tolerogenic effects, as well as of its cognate receptors (TNF-R1 and TNF-R2) is also significantly increased following IVIg treatment. Along with TNF-α, the expression of the enzyme and signaling protein IDO, known to mediate TGF-β dependant tolerogenic effect, is similarly increased following IVIg treatment. We thus propose that the complex interplay between plasticity of immune cells and environmental modifications in which the TNF-α/TGF-β/IDO axis may represent a new mechanism contributing to the development of tolerance in IVIg-treated patients.