LBH589 Enhances T Cell Activation In Vivo and Accelerates Graft-versus-Host Disease in Mice

Histone deacetylase inhibitors (HDACis) are a new class of compounds that induce acetylation of histone lysine tails in chromatin and modify gene expression. The Food & Drug Administration approved HDACi, Vorinostat, or suberoylanilide hydroxamic acid (SAHA), has been shown to inhibit tumor cell growth and the production of proinflammatory cytokines. In preclinical allogeneic transplant models, SAHA induces graft-versus-host disease (GVHD) amelioration in treated mice without impairing graft-versus-leukemia. LBH589 (Panobinostat), a structurally novel cinnamic hydroxamic acid class, is an HDACi more potent than SAHA. In the current work, we tested the hypothesis that LBH589 would be highly effective in the prevention of GVHD. Using mouse model of allogeneic bone marrow transplant (BMT), we unexpectedly found that treatment with LBH589 accelerated GVHD, in contrast to the treatment with SAHA that alleviated GVHD. Accelerated GVHD in the recipients treated with LBH589 was associated with elevated Th1 cytokines in recipient serum, enhanced CXCR3 expression on donor T cells, and T cell infiltration in the liver. The current study highlights the distinct effects of pan HDACi on allogeneic BMT and alerts that LBH589 (Panobinostat) could have an adverse effect on GVHD, and possibly on other inflammatory diseases

Interleukin-17 in Various Ocular Surface Inflammatory Diseases

Recently, the association of Th-17 cells or IL-17 with ocular inflammatory diseases such as uveitis, scleritis and dry eye syndrome was discovered. We assessed whether interleukin (IL)-17 was present in the tears of various ocular surface inflammatory diseases and the tear IL-17 concentrations were clinically correlated with various ocular surface inflammatory diseases. We measured concentrations of IL-17 in tears of normal subjects (n = 28) and patients (n = 141) with meibomian gland dysfunction (MGD), dry eye syndrome (DES), Sjögren syndrome (SS), Stevens-Johnson syndrome (SJS), graft-versus-host disease (GVHD), filamentary keratitis, and autoimmune keratitis associated with rheumatoid arthritis or systemic lupus erythematosus. Clinical epitheliopathy scores were based on the surface area of corneal and conjunctival fluorescein staining. The mean concentrations of IL-17 in tears of patients with filamentary keratitis, GVHD, autoimmune keratitis, SS, DES, MGD, SJS were significantly higher in order than that in normal subjects. Tear IL-17 concentration was significantly correlated with clinical epitheilopathy scores in the patients with systemic inflammatory disease, while tear IL-17 was not correlated with clinical severity of the cornea and conjunctiva in the dry eye patients without any systemic inflammatory disease. Tear IL-17 is likely to correlate clinically with corneal disease severity only in the patients with systemic inflammatory disease

Synthetic retinoid Am80 ameliorates chronic graft-versus-host disease by down-regulating Th1 and Th17.

Chronic GVHD (cGVHD) is a main cause of late death and morbidity after allogeneic hematopoietic cell transplantation, but its pathogenesis remains unclear. We investigated the roles of Th subsets in cGVHD with the use of a well-defined mouse model of cGVHD. In this model, development of cGVHD was associated with up-regulated Th1, Th2, and Th17 responses. Th1 and Th2 responses were up-regulated early after BM transplantation, followed by a subsequent up-regulation of Th17 cells. Significantly greater numbers of Th17 cells were infiltrated in the lung and liver from allogeneic recipients than those from syngeneic recipients. We then evaluated the roles of Th1 and Th17 in cGVHD with the use of IFN-γ-deficient and IL-17-deficient mice as donors. Infusion of IFN-γ(-/-) or IL-17(-/-) T cells attenuated cGVHD in the skin and salivary glands. Am80, a potent synthetic retinoid, regulated both Th1 and Th17 responses as well as TGF-β expression in the skin, resulting in an attenuation of cutaneous cGVHD. These results suggest that Th1 and Th17 contribute to the development of cGVHD and that targeting Th1 and Th17 may therefore represent a promising therapeutic strategy for preventing and treating cGVHD

Myeloid-Derived Suppressor Cells in Hematologic Diseases: Promising Biomarkers and Treatment Targets

Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of immature myeloid cells that exist at very low numbers in healthy subjects but can expand significantly in malignant, infectious, and chronic inflammatory diseases. These cells are characterized as early-MDSCs, monocytic-MDSCs, and polymorphonuclear-MDSCs and can be studied on the basis of their immunophenotypic characteristics and their functional properties to suppress T-cell activation and proliferation. MDSCs have emerged as important contributors to tumor expansion and chronic inflammation progression by inducing immunosuppressive mechanisms, angiogenesis and drug resistance. Most experimental and clinical studies concerning MDSCs have been mainly focused on solid tumors. In recent years, however, the implication of MDSCs in the immune dysregulation associated with hematologic malignancies, immune-mediated cytopenias and allogeneic hemopoietic stem cell transplantation has been documented and the potential role of these cells as biomarkers and therapeutic targets has started to attract a particular interest in hematology. The elucidation of the molecular and signaling pathways associated with the generation, expansion and function of MDSCs in malignant and immune-mediated hematologic diseases and the clarification of mechanisms related to the circulation and the crosstalk of MDSCs with malignant cells and other components of the immune system are anticipated to lead to novel therapeutic strategies. This review summarizes all available evidence on the implication of MDSCs in hematologic diseases highlighting the challenges and perspectives arising from this novel field of research