Cytokine Profiles in Various Graft-Versus-Host Disease Target Organs following Hematopoietic Stem Cell Transplantation

Abstract

Previous studies using genetic-deficient murine models suggest that different T-helper subsets may contribute to different types of tissue damages in graft-versus-host disease (GvHD). However, there is limited information available on the distribution of T-helper cytokines in the various GvHD target tissues. In the current study, an acute GvHD murine model was set up to directly assess the in situ cytokine profiles in various GvHD tissue lesions; in addition, we also studied GvHD tissues from patients who had undergone bone marrow transplantation procedures. We observed that interferon-γ (IFN-γ was dominant in murine liver and gastrointestinal tissue lesions, whereas IFN-γ and interleukin 17 (IL-17) were abundant in murine skin lesions. Furthermore, in human GvHD tissues, interleukin 4 (IL-4) and IFN-γ were predominant in liver lesions and colon lesions, respectively, while no specific cytokine was prevalent in human GvHD skin lesions. In addition, a low ratio of CD4+ T helper (Th) versus CD8+ T cytotoxic (Tc) cells in human GvHD tissue lesions, especially in the liver, was detected, and this contrasts with the situation in murine GvHD tissues where CD4+ Th cells were predominant. Dual staining for CD markers and cytokine expression showed that IFN-γ-secreting T cells were enriched in all murine GvHD target tissue lesions, and Tc1 and Tc2 cells were predominant in human GvHD colon and liver sections, respectively. However, IFN-γ+ Th1, IL-17+ Th17, IFN-γ+ Tc1, and IL-17+ Tc17 cells were slightly more frequent in human skin lesions compared to IL-4+ Th2 and IL-4+ Tc2 cells. To sum up, these results suggest that differences in cytokine imbalances may significantly contribute to tissue-specific pathogenesis in GvHD target organs, and CD8+ Tc cells may play an important role in human GvHD induction.