tretinoin and squaric-acid-dibutyl-ester

Mild but efficient treatments of autoimmune diseases are urgently required. One such therapy, long-term maintenance of chronic delayed type hypersensitivity, has been described for alopecia areata (AA), a hair follicle-affecting autoimmune disease. The molecular mechanisms underlying the therapeutic efficacy are unknown, but may involve myeloid-derived suppressor cells (MDSCs). AA-affected mice were treated with squaric acid dibutyl ester (SADBE). The immunoreactivity of SADBE-treated AA lymphocytes and of AA lymphocytes co-cultured with SADBE-induced MDSCs was analyzed. The curative effect of SADBE was abolished by all-transretinoic acid, which drives MDSCs into differentiation, confirming a central role for MDSCs in therapeutic SADBE treatment. SADBE and SADBE-induced MDSCs strongly interfered with sustained autoreactive T-cell proliferation in response to AA skin lysate (autoantigen), which was accompanied by weak ζ-chain down-regulation and strongly impaired Lck activation. In contrast, activation of the mitochondrial apoptosis pathway and blockade of the anti-apoptotic PI3K/Akt pathway by SADBE-induced MDSCs did not require T-cell receptor engagement. Apoptosis induction correlated with high TNF-α expression in SADBE-induced MDSCs and elevated TNFRI levels in AA lymphocytes. SADBE-induced MDSCs interfere with persisting autoreactive T-cell proliferation and promote apoptosis of these T cells, which qualifies MDSCs induced and maintained by chronic delayed type hypersensitivity reactions as promising therapeutics in organ-related autoimmune diseases.

Topics: Adaptor Proteins, Signal Transducing; Alopecia Areata; Animals; Apoptosis; Autoimmune Diseases; Autoimmunity; CD4-CD8 Ratio; Cell Differentiation; Cell Proliferation; Cells, Cultured; Cyclobutanes; Hypersensitivity, Delayed; Lymphocyte Activation; Mice; Mice, Inbred C3H; Mitochondria; Myeloid Cells; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Receptors, Antigen, T-Cell; Receptors, Tumor Necrosis Factor; Signal Transduction; T-Lymphocytes; Tretinoin; Tumor Necrosis Factor-alpha