During the last grant period we investigated several antigen (Ag) targeting strategies, where Ags are efficiently delivered into the immune system by coupling to antibodies (Abs) that bind receptors on Ag presenting cells (APCs). Depending on what APCs are targeted, different kinds of immune responses are induced. Ag is usually coupled to an Ab specific for a receptor expressed on dendritic cells (DCs), and then the Ag-anti- receptor is inoculated with an adjuvant. We found that when Ag is targeted to both B cells and DCs by coupling it to a monoclonal Ab (mAb) specific for the CD180 receptor, which is related to members of the Toll-like receptor (TLR) family, strong Ab and T cell responses are induced. Ag coupled to anti-CD180 mAb, when injected into wildtype (WT) mice rapidly induced high levels of Ag-specific IgG responses, and higher and more sustained than those induced by Ag in alum. Ag conjugated to CD180 (Ag-?CD180) rapidly induces IgG Ab responses not only in WT mice but also in mice immunodeficient in T cell, B cell and type I interferon (IFN) innate immune responses. These findings suggest that targeting Ag to CD180 may be a safe and effective means for vaccinating even the immune-compromised. A major Aim of this proposal is to define how CD180- based Ag targeting programs rapid B cell and T cells responses.
A second Aim will be to define how best to induced long-lasting protective immune responses using a CD180- based vaccine and a mouse model for lethal West Nile virus (WNV) infection. Ag- ?CD180 immunization induces IgG Ab responses in a number of immunodeficient mice and can induce protective immunity to WNV even in BAFFR-deficient mice that are deficient in mature B cells. Thus, a third Aim will be to define a CD180-based vaccine that can induce strong protective immunity in immunocompromised mice including B cell or T cell help deficient mice and aged mice. A major goal will be to define a one shot vaccine that can induce protective immunity in an immunodeficient mouse model. These studies could lead to identification of a novel and safe vaccine platform useful for immunizing immunodeficient, neonatal or elderly individuals and potentially for use as a therapeutic vaccine.

Public Health Relevance

New ways to vaccinate individuals are needed, particularly for vaccinating people with compromised immune systems. This proposal will investigate how novel vaccine method works and how best to develop an effective one-shot vaccine against viruses. New information on how best to develop safe, effective vaccines to viruses in immunodeficient individuals may stem from this work.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI052203-11
Application #
8979329
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2003-05-01
Project End
2020-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
11
Fiscal Year
2015
Total Cost
Indirect Cost
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
Chappell, Craig P; Clark, Edward A (2013) STALing B cell responses with CD22. J Clin Invest 123:2778-80
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
Ma, Daphne Y; Suthar, Mehul S; Kasahara, Shinji et al. (2013) CD22 is required for protection against West Nile virus Infection. J Virol 87:3361-75
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
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
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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