The overall goal of this proposal is to study the mechanisms underlying the immunologic immaturity of the murine neonate. A variety of physical and serological techniques will be employed to isolate neonate cell pupulations. From this panel of cells, we will then attempt to characterize the cells responsible for accessory and natural killer (NK) activities, as well as other cell types that inhibit these activities. These methods to be employed include adherence, density gradient centrifugation cell sorting and in vitro culture with various growth factors (IL-2, IL-3, M0 growth factor) including a stimulatory factor(s) from mouse amniotic fluid (MAF). We propose to study whether suppressor cells which have already been identified in the eneonate, inhibit via a prostaglandin (PGE) mediated effect on Ia expression and/or via other soluble factors. The relationship, if any between M0 suppressors, T suppressors (Ts) and the accessory cell deficiency will be explored. Whether M0, dendritic cells, and/or epithelial cells are the predominant accessory cells found in the neonate thymus will be examined. These latter experiments bear on the role of the thymus in selecting the T-cell repertoire. Neonatal suppression has also been attributed to circulating soluble factors such as alphafetoprotein (AFP). We propose to isolate the suppressive components from MAF and determine whether their activity is mediated via M0 and/or Ts. The phenotypic characteristics of the cells induced by MAF will be compared (using MAb's and flow cytometry) with those isolated from the neonate. The role of PCE as well as non PGE suppressors will also be explored in this system. Recently, we observed that Cu++ modulates suppression by AFP and a series of experiments are outlined on the role of Cu++ in neonate immunosuppression. In addition, factors which stimulate the growth of neonate and a small subpopulation of adult spleen cells have been identified in MAF. Experiments are planned to isolate the stimulatory factor(s) by HPLC and to determine the spectrum of cells affected (particularly whether suppressor M0 and/or Ts are stimulated). The work outlined is pertinent to the hypothesis that the decline of circulating inhibitory factors in the postnatal period is responsible for the acquisition of positive immunity in the young adults. These studies are also relevant to immunosuppression in pregnancy and disease states where high circulating levels of AFP are found.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Immunological Sciences Study Section (IMS)
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University of New Mexico
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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
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; 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
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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