Kinetics of T Helper Subsets and Associated Cytokines Correlate Well with the Clinical Activity of Graft-Versus-Host Disease

Background: CD4(+) interferon (IFN)-gamma(+) T cell (Th1) and CD4(+) interleukin (IL)-4(+) T cell (Th2) polarizations are crucial in the pathogenesis of graft-versus-host disease (GVHD). However, this hypothesis is largely based on animal experiments of Parent-into-F1 GVHD model. The causal relationship between kinetics of Th1, Th2 and associated cytokines and the clinical activity of GVHD in a real world situation remains unknown. Methodology: Peripheral blood was collected every week prospectively from Day 0 to Day 210 (patients without GVHD) or Day 300 (patients with chronic GVHD) after allogeneic peripheral blood stem cell transplantation in consecutive 27 patients. The frequencies of Th1 and Th2 within CD4(+) T cells were determined by flow cytometry and pplasma IFN-gamma, IL-12, IL-4, and IL-10 were determined by ELISA. Principal Findings: Kinetics of Th1, Th2 frequency, and the plasma IL-10 and IFN-gamma more commonly coincided with, rather than predicted, the activity of GVHD. These markers are significantly higher when acute or chronic GVHD developed. The kinetics of IL-10 is especially correlated well with the activity of GVHD during clinical course of immunosuppressive treatment. For patients with hepatic GVHD, there is a positive correlation between plasma IL-10 levels and the severity of hepatic injury. The frequency of Th2 is also significant higher in acute GVHD and tends to be higher in chronic GVHD. Interestingly, there is a very good positive correlation between the frequency of Th1 and Th2 (r = 0.951, p< 0.001). The plasma level of IL-4 and IL-12 are not associated with the activity of GVHD. Conclusions: The frequency of Th1, Th2 within CD4(+) T cells and plasma IL-10 and IFN-gamma are good biomarkers of GVHD. Plasma IL-10 can also be used to monitor the therapeutic responsiveness. Furthermore, both Th1 and Th2 likely contribute to the pathogenesis of GVHD.