The overall goal of this application is to identify the mechanisms by which immunosuppression occurs in the mother during pregnancy, in fetus and neonate. A.
Specific Aims 1. Extend ongoing studies of the factor(s) in murine amniotic fluid (MAF) which mediates in the in vitro and in vivo suppression of the immune response. a) isolate and characterize the TGF-Beta2-like immunosuppressor in MAF, determine its sequence and structural relation to other members of the TGF-Beta family; b) identify the ontogeny and sites of synthesis of membranes of the TGF-Beta family in fetal and maternal tissues by in situ hybridization and Northern analyses.2. Evaluate the role of MAF and the purified TGF-Beta2 like suppressive factor in the immune deficiencies of the fetus, neonate, pregnant, and lymphoid irradiated animal: a) evaluate the role of the MAF suppressive factor in generation and activity of suppressor cells; b) determine if the cytokines present in MAF (TGF-Beta, CSF-1) produced by the fetus and/or pregnant uterus, modulate MHC antigens and influence persistence of the fetal allograft. 3. Delineate the molecular mechanisms of immunosuppression by MAF and its cytokine components using normal macrophages, and macrophage and B-cell lines. a) examine modulation of cell surface Ia and Ia gene expression by MAF, CSF-1 and TGF-Beta and their interactions with other cytokines known to induce Ia expression (GM-CSF, IL-4, IFN-gamma); b) study the molecular mechanisms (transcriptional regulation, DNA binding proteins and 5' sequences) involved in the response of macrophages to cytokines that positively (IFN-gamma, GM-CSF, IL-4) or negatively (CSF-1, TGF-Beta) regulate Ia gene expression. 4. To evaluate MAF, TGF-Beta and CSF-1 as immunosuppressive agents capable of inhibiting rodent transplant rejection (cardiac and renal) and murine GVH disease.
| Tomasi, Thomas B; Magner, William J; Wiesen, Jennifer L et al. (2010) MHC class II regulation by epigenetic agents and microRNAs. Immunol Res 46:45-58 |
| Wiesen, Jennifer L; Tomasi, Thomas B (2009) Dicer is regulated by cellular stresses and interferons. Mol Immunol 46:1222-8 |
| Gregorie, Christopher J; Wiesen, Jennifer L; Magner, William J et al. (2009) Restoration of immune response gene induction in trophoblast tumor cells associated with cellular senescence. J Reprod Immunol 81:25-33 |
| Asirvatham, Ananthi J; Magner, William J; Tomasi, Thomas B (2009) miRNA regulation of cytokine genes. Cytokine 45:58-69 |
| Khan, A Nazmul H; Gregorie, Christopher J; Tomasi, Thomas B (2008) Histone deacetylase inhibitors induce TAP, LMP, Tapasin genes and MHC class I antigen presentation by melanoma cells. Cancer Immunol Immunother 57:647-54 |
| Chou, Shiuh-Dih; Tomasi, Thomas B (2008) Spatial distribution of histone methylation during MHC class II expression. Mol Immunol 45:971-80 |
| Asirvatham, Ananthi J; Gregorie, Christopher J; Hu, Zihua et al. (2008) MicroRNA targets in immune genes and the Dicer/Argonaute and ARE machinery components. Mol Immunol 45:1995-2006 |
| Khan, A Nazmul H; Tomasi, Thomas B (2008) Histone deacetylase regulation of immune gene expression in tumor cells. Immunol Res 40:164-78 |
| Khan, A Nazmul H; Magner, William J; Tomasi, Thomas B (2007) An epigenetic vaccine model active in the prevention and treatment of melanoma. J Transl Med 5:64 |
| Shang, Limin; Tomasi, Thomas B (2006) The heat shock protein 90-CDC37 chaperone complex is required for signaling by types I and II interferons. J Biol Chem 281:1876-84 |
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