Dendritic cells (DCs) help to coordinate and bridge innate and adaptive immune responses. DCs for the most part are short lived;how long they live and where may influence whether they induce immunity, tolerance or autoimmune disease. DC fate and cytokine production are regulated in part by RANK (receptor activator ofNF-IcB ligand), receptors for TRAIL (tumor necrosis factor-alpha-related papooses-inducing ligand) and the soluble 'decoy'receptor osteoprotegerin (OPG), which binds RANK ligand (RANKL) and TRAIL. Our data suggest that DC cytokine production and survival are dysregulated in the absence of OPG. We plan to define the role the RANKL/RANK/OPG system plays in regulating DCs. We wiU test the hypothesis that OPG regulates dendritic cell survival by modulating the RANKL/RANK and TRAIL/TRAIL receptor pathways. We will test whether OPG -/- or RANK -/- DCs differ from wildtype DCs in their survival in vitro or in vivo. The effect of overexpressing the survival protein Bcl-2 on the DC- restricted CD1 lc promoter will be evaluated in OPG -/- and RANK -/- mice. We predict that by altering the lifespan of DCs in vivo, that underlying defects in disease, bone homeostasis and peripheral lymphoid development will be altered. We will also test the hypothesis that human immature DCs (iDCs) and mature DCs (mDCs) differ in how they are regulated by the RANK/OPG/TRAIL receptor pathways and by caspases. Next we will test the hypothesis that OPG regulates the profile and levels of cytoldnes produced by DC subsets. We will define how the absence of OPG or RANK affects cytokine production in vitro and test whether the cytokine dysregulation in OPG -/- and RANK -/- mice influences in vivo responses to lipopolysaccharide (LPS) and peptide-induced experimental autoimmune encephalomyelitis (EAE). The expression of OPG, RANKL and TRAIL receptors is regulated by 17-13-estradiol (E2). Therefore, we will test the hypotheses that E2 modulates peptide-induced EAE, DC survival and cytokine production via an OPG-

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Gondre-Lewis, Timothy A
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University of Washington
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Clark, Edward A; Giltiay, Natalia V (2018) CD22: A Regulator of Innate and Adaptive B Cell Responses and Autoimmunity. Front Immunol 9:2235
Giltiay, Natalia V; Shu, Geraldine L; Shock, Anthony et al. (2017) Targeting CD22 with the monoclonal antibody epratuzumab modulates human B-cell maturation and cytokine production in response to Toll-like receptor 7 (TLR7) and B-cell receptor (BCR) signaling. Arthritis Res Ther 19:91
Chappell, Craig P; Giltiay, Natalia V; Draves, Kevin E et al. (2014) Targeting antigens through blood dendritic cell antigen 2 on plasmacytoid dendritic cells promotes immunologic tolerance. J Immunol 192:5789-5801
Giordano, Daniela; Draves, Kevin E; Li, Chang et al. (2014) Nitric oxide regulates BAFF expression and T cell-independent antibody responses. J Immunol 193:1110-20
Chappell, Craig P; Giltiay, Natalia V; Dresch, Christiane et al. (2014) Controlling immune responses by targeting antigens to dendritic cell subsets and B cells. Int Immunol 26:3-11
Chaplin, Jay W; Chappell, Craig P; Clark, Edward A (2013) Targeting antigens to CD180 rapidly induces antigen-specific IgG, affinity maturation, and immunological memory. J Exp Med 210:2135-46
Hughes, Grant C; Clark, Edward A; Wong, Alan H (2013) The intracellular progesterone receptor regulates CD4+ T cells and T cell-dependent antibody responses. J Leukoc Biol 93:369-75
Giltiay, Natalia V; Chappell, Craig P; Sun, Xizhang et al. (2013) Overexpression of TLR7 promotes cell-intrinsic expansion and autoantibody production by transitional T1 B cells. J Exp Med 210:2773-89
Giltiay, Natalia V; Chappell, Craig P; Clark, Edward A (2012) B-cell selection and the development of autoantibodies. Arthritis Res Ther 14 Suppl 4:S1
Chappell, Craig P; Draves, Kevin E; Giltiay, Natalia V et al. (2012) Extrafollicular B cell activation by marginal zone dendritic cells drives T cell-dependent antibody responses. J Exp Med 209:1825-40

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