TH1/TH2 Cytokine profile in relapsing-remitting multiple sclerosis patients treated with Glatiramer acetate or Natalizumab

Abstract

Background: The balance between T helper cells Th2- and Th1-related cytokines plays a key role in multiple sclerosis (MS). A shift from a Th1 towards a Th2 cytokine profile could have a beneficial effect on the clinical course of the disease. The objective of this study was to assess Th2/Th1 cytokine profile in relapsing-remitting MS (RRMS) patients receiving an immunosuppressive treatment with natalizumab (NAT), or an immunomodulatory treatment with glatiramer acetate (GA) after one year of treatment.

Methods: This was an observational cross-sectional study. All consecutive patients diagnosed with RRMS who had received GA or NAT for 12 months were included in the study. We determined serum levels of Th1 and Th2 cytokines (interleukin [IL]-1a, IL-1b, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-13, monocyte chemotactic protein [MCP]-1, tumor-necrosis factor [TNF]-α, interferon [IFN]-γ and granulocyte macrophage colony stimulating factor [GM-CSF]) by flow cytometry. Th2/Th1 bias was defined based on the ratio of IL-4, IL-5, IL-6 or IL-10 Th2 cytokines and proinflammatory INF-γ or TNF-α Th1 cytokines.

Results: Eleven patients under treatment with NAT and 12 patients treated with GA were evaluated. RRMS patients treated with NAT showed significantly higher levels of IL-6 (p < 0.05), MCP-1 (p < 0.01), and GM-CSF (p < 0.05) compared to GA patients after one year of treatment. A trend for increasing of IL-12p70, IL-1b, TNF- α and IFN- γ levels was also found in patients receiving NAT compared to GA patients. IL-4/IFN-γ, IFN-γ/TNF-α and IL-10/IFN-γ ratios as markers of Th2/Th1 ratio were significantly elevated in GA patients compared to those receiving NAT (p < 0.05).

Conclusion: In conclusion, our findings suggest that GA promotes a superior Th2-biased anti-inflammatory response as compared with NAT in the systemic circulation of RRMS patients. Future studies with larger cohorts will determine whether this immune Th2 shift in GA patients is associated with a beneficial effect on disease outcome.

Figure 1

Serum levels of cytokines after one year of treatment with GA or NAT in RRMS patients. Cytokines are grouped as Th1-related (A) or Th2-related (B). Cytokines were determined by Flow cytometry. All concentrations are given in pg/mL and were converted to international WHO/MIBBSC standards. Data are shown as median and interquartile ranges. NAT-treated patients showed significantly higher levels of proinflammatory cytokines MCP-1, and GM-CSF compared to those patients treated with GA. IL-6 Th2-related cytokine was significantly higher in NAT group. *p < 0.05; **p < 0.01. GA = glatiramer acetate; NAT = natalizumab.

Figure 2

Th2/Th1 ratio in GA and NAT patients. Comparative Th2/Th1 ratios considering anti-inflammatory IL-4, IL-5, IL-6, IL-10 cytokines and pro-inflammatory cytokine INF-γ (A) or TNF-α (B). Box and whiskers plots showing median and interquartile ranges are presented. IL-4/IFN-γ, IL-4/TNF-α and IL-10/IFN-γ ratio as markers of Th2/Th1 ratio are significantly higher for GA patients compared to patients receiving NAT. *p < 0.05. GA = glatiramer acetate; NAT = natalizumab.