ABSTRACT
De novo expression of B7-1 impaired tumorigenicity of TRAMP-C2 mouse prostate adenocarcinoma (TRAMP-C2/B7), but it did not elicit a protective response against TRAMP-C2 parental tumor, unless after in vitro treatment with IFN-gamma. TRAMP-C2 cells secrete TGF-beta and show low MHC-I expression. Treatment with IFN-gamma increased MHC-I expression by induction of some APM components and antagonizing the immunosuppressant activity of TGF-beta. Thus, immunization with TRAMP-C2/B7 conferred protection against TRAMP-C2-derived tumors in function of the IFN-gamma-mediated fine-tuned modulation of either APM expression or TGF-beta signaling. To explore possible clinical translation, we delivered IFN-gamma to TRAMP-C2 tumor site by means of genetically engineered MSCs secreting IFN-gamma.
Subject(s)
Adenocarcinoma/immunology , Histocompatibility Antigens Class I/immunology , Interferon-gamma/immunology , Prostatic Neoplasms/immunology , Adenocarcinoma/genetics , Animals , B7-1 Antigen/genetics , B7-1 Antigen/immunology , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Genes, MHC Class I , Histocompatibility Antigens Class I/genetics , Male , Mesenchymal Stem Cells/immunology , Mice , Mice, Inbred C57BL , Neoplasms, Experimental/genetics , Neoplasms, Experimental/immunology , Prostatic Neoplasms/genetics , Spleen/cytology , Spleen/immunology , Transfection , Transforming Growth Factor beta/immunology , Up-RegulationABSTRACT
Myasthenia gravis (MG) is an autoimmune disease of neuromuscular junctions where thymus plays a pathogenetic role. Thymectomy benefits patients, and thymic hyperplasia, a lymphoid infiltration of perivascular spaces becoming site of autoantibody production, is recurrently observed. Cytokines and chemokines, produced by thymic epithelium and supporting survival and migration of T and B cells, are likely to be of great relevance in pathogenesis of thymic hyperplasia. In thymic epithelial cell (TEC) cultures derived "in vitro" from normal or hyperplastic age-matched MG thymuses, we demonstrate by gene profiling analysis that MG-TEC basally overexpress genes coding for p38 and ERK1/2 MAPKs and for components of their signaling pathways. Immunoblotting experiments confirmed that p38 and ERK1/2 proteins were overexpressed in MG-TEC and, in addition, constitutively activated. Pharmacological blockage with specific inhibitors confirmed their role in the control of IL-6 and RANTES gene expression. According to our results, IL-6 and RANTES levels were abnormally augmented in MG-TEC, either basally or upon induction by adhesion-related stimuli. The finding that IL-6 and RANTES modulate, respectively, survival and migration of peripheral lymphocytes of myasthenic patients point to MAPK transcriptional and posttranscriptional abnormalities of MG-TEC as a key step in the pathological remodelling of myasthenic thymus.
Subject(s)
B-Lymphocytes/enzymology , B-Lymphocytes/immunology , Chemokine CCL5/biosynthesis , Extracellular Signal-Regulated MAP Kinases/metabolism , Interleukin-6/biosynthesis , Myasthenia Gravis/enzymology , Myasthenia Gravis/immunology , T-Lymphocytes/enzymology , T-Lymphocytes/immunology , Adolescent , Adult , B-Lymphocytes/pathology , Case-Control Studies , Cell Movement , Cell Survival , Child , Enzyme Activation , Epithelial Cells/enzymology , Epithelial Cells/immunology , Extracellular Signal-Regulated MAP Kinases/genetics , Female , Gene Expression , Humans , MAP Kinase Signaling System , Male , Middle Aged , Mitogen-Activated Protein Kinase 1/genetics , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/genetics , Mitogen-Activated Protein Kinase 3/metabolism , Myasthenia Gravis/pathology , T-Lymphocytes/pathology , Thymus Gland/enzymology , Thymus Gland/immunology , Thymus Gland/pathology , p38 Mitogen-Activated Protein Kinases/genetics , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
Bioactive molecules that can gain access to body tissues through the gastrointestinal tract may interact with immune regulatory circuits and effector functions. Among these are plant lectins, such as wheat germ (WG) agglutinin, which constitute common components of the human diet and target the immune system on a daily basis. Dietary bioactive molecules might be considered as immunomodulatory signals. To investigate the possible effects on the immune system of the long-term absence of such signals, two groups of rats were fed on a diet containing or deprived of WG. The WG-deprived diet induced a state of functional unresponsiveness in lymphocytes from primary and secondary lymphoid organs, as evaluated by in vitro stimulation with T cell mitogen phytohemoagglutinin (PHA) and B cell mitogen lypopolysaccarides (LPS). The unresponsive state of the immune cells could be reversed by injection of antigen emulsified in oil with inactivated mycobacteria (complete Freund's adjuvant, CFA) Dietary signals can thus interact with the immune system possibly influencing its shaping during ontogenesis.
