Enhanced immune‐modulatory effects of thalidomide and dexamethasone co‐treatment on T cell subsets

• Published in: Immunology 2017-12, Vol.152 (4), p.628-637
• Main Authors: Kim, Eun Jee, Lee, Jae Geun, Kim, Joon Ye, Song, Seung Hwan, Joo, Dong Jin, Huh, Kyu Ha, Kim, Myoung Soo, Kim, Beom Seok, Kim, Yu Seun
• Format: Article
• Language: English
• Subjects: 4-1BB Ligand - immunology; 4‐1BB; Animals; Anti-inflammatory agents; Anticancer properties; Autoimmune diseases; Cancer; CD4 antigen; Cell growth; Cell proliferation; Cell Proliferation - drug effects; Combinatorial analysis; Cytokines; Cytometry; Dexamethasone; Dexamethasone - pharmacology; Drugs; Effector cells; Flow cytometry; Glucocorticoid-Induced TNFR-Related Protein - immunology; Glucocorticoids; glucocorticoid‐induced tumour necrosis factor receptor‐related protein; Immunologic Factors - pharmacokinetics; Immunomodulation; Immunosuppressive agents; Incubation; Inflammation; Lupus nephritis; Lymphocytes; Lymphocytes T; Male; Mice; Multiple myeloma; Nephritis; Original; OX40; Populations; Receptors, OX40 - immunology; Rodents; Spleen; T lymphocyte; T-Lymphocyte Subsets - cytology; T-Lymphocyte Subsets - immunology; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - immunology; Thalidomide; Thalidomide - pharmacology; Tumor necrosis factor; Tumors
• ISSN: 0019-2805; 1365-2567
• DOI: 10.1111/imm.12804

Summary Thalidomide (TM) has been reported to have anti‐cancer and anti‐inflammatory properties, and dexamethasone (DX) is known to reduce inflammation and inhibit production of inflammatory cytokines. Many studies have reported that combinatorial therapy with TM and DX is clinically used to treat multiple myeloma and lupus nephritis, but the mechanism responsible for its effects has not been elucidated. In this study, we determined that TM and DX co‐treatment had an enhanced immune‐modulatory effect on T cells through regulating the expression of co‐stimulatory molecules. Splenic naive T cells from C57BL/6 mice were sort‐purified and cultured for CD4+ T cell proliferation and regulatory T (Treg) cell conversion in the presence of TM and/or DX. Following incubation with the drugs, cells were collected and OX40, 4‐1BB, and glucocorticoid‐induced tumour necrosis factor receptor‐related protein (GITR) expression was quantified by flow cytometry. TM (1 or 10 μm) decreased CD4+ T cell proliferation in a dose‐dependent manner, whereas TM/DX (0·1 or 1 nm) co‐treatment further decreased proliferation. Treg cell populations were preserved following drug treatment. Furthermore, expression of co‐stimulatory molecules decreased upon TM/DX co‐treatment in effector T (Teff) cells and was preserved in Treg cells. Splenic CD4+ T cells isolated from TM‐ and DX‐treated mice exhibited the same patterns of Teff and Treg cell populations as observed in vitro. Considering the selective effect of TM on different T cell subsets, we suggest that TM may play an immunomodulatory role and that TM/DX combinatorial treatment could further enhance these immunomodulatory effects by regulating GITR, OX40, and 4‐1BB expression in CD4+ T cells. Thalidomide/dexamethasone (TM/DX) combinatorial treatment significantly down‐regulates the population of effector T cells (CD4+ CD44hi T cells). TM/DX combinatorial treatment appears to preserve the population of regulatory T cells (CD4+ FOXP3+ T cells). TM may play an immunomodulatory role and TM/DX combinatorial treatment could further enhance the immunomodulatory effects by regulating GITR, OX40, and 4‐1BB expression in CD4+ T cells.