Tim-3 suppression combined with TLR3 activation enhances antiviral immune response in patients with chronic HCV infection

Abstract

Objective: To investigate the regulation mechanism of T cell immunoglobulin and mucin domain-3 (Tim-3) combined with toll-like receptor 3 (TLR3) or TLR4 on antiviral immune and inflammatory response in patients with chronic hepatitis C virus (HCV) infection.

Methods: Patients with chronic HCV infection and healthy control subjects were recruited. Patients received interferon (IFN)-α based therapy. Plasma galectin-9 (Gal-9) was quantitated. Peripheral blood mononuclear cells (PBMCs) were cultured with TLR3 or TLR4 agonists, alone or in combination with Tim-3 antagonist. Levels of IFN-α, TNF-α, and 2'-5' oligoadenylate synthetase (2'-5'OAS), myxovirus resistance protein A (MxA) and suppressor of cytokine 1 (SOCS1) RNA in PBMC cultures were evaluated.

Results: Plasma Gal-9 levels were increased in patients (n = 52) compared with controls (n = 20) and significantly declined at treatment week 12 and 24 weeks post-treatment. IFN-α, 2'-5'OAS, MxA, TNF-α and SOCS1 were upregulated by TLR3 and TLR4 agonists. TNF-α and SOCS1 levels were suppressed by the addition of Tim-3 antagonist.

Conclusions: Tim-3 blockade in combination with TLR activation induces the expression of antiviral molecules without a significant increase in TNF-α or SOCS1.

Keywords: Galectin-9; Hepatitis C virus; T cell immunoglobulin and mucin domain-3; antiviral immunological response; peripheral blood mononuclear cells; toll-like receptors.

Figure 1.

Flow diagram of the progress through the phases of the study.

Figure 2.

Plasma concentration of Gal-9 in (a) healthy control subjects and patients with chronic hepatitis C virus (HCV) infection at baseline, treatment week 12 and 24 weeks post-treatment with interferon-based therapy. (b) Patients stratified according to attainment of complete early virological response (cEVR). (c) Patients stratified according to attainment of sustained virological response (SVR). *P < 0.01 and **P < 0.001 vs healthy control; ^#P < 0.01 vs baseline; △P < 0.05; one-way analysis of variance with least significant difference-t test for post hoc comparisons.