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-

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI044257-15
Application #
8493970
Study Section
Special Emphasis Panel (NSS)
Program Officer
Gondre-Lewis, Timothy A
Project Start
1998-12-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
15
Fiscal Year
2013
Total Cost
$424,029
Indirect Cost
$178,672
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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
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 192:5789-801
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
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
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
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
Kasahara, Shinji; Clark, Edward A (2012) Dendritic cell-associated lectin 2 (DCAL2) defines a distinct CD8ýý- dendritic cell subset. J Leukoc Biol 91:437-48
Giordano, Daniela; Li, Chang; Suthar, Mehul S et al. (2011) Nitric oxide controls an inflammatory-like Ly6C(hi)PDCA1+ DC subset that regulates Th1 immune responses. J Leukoc Biol 89:443-55
Chaplin, Jay W; Kasahara, Shinji; Clark, Edward A et al. (2011) Anti-CD180 (RP105) activates B cells to rapidly produce polyclonal Ig via a T cell and MyD88-independent pathway. J Immunol 187:4199-209
Yurchenko, Mariya Y; Kovalevska, Larysa M; Shlapatska, Larysa M et al. (2010) CD150 regulates JNK1/2 activation in normal and Hodgkin's lymphoma B cells. Immunol Cell Biol 88:565-74

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