The importance of new methods to regulate immune responses is underscored by the difficulty of generating effective vaccines for diseases like HIV, tuberculosis, or cancer. To exploit the full potential of the immune system, the antigen features that lead ultimately to tolerance or immunity must be defined. To expedite the generation of antigens that elicit desired immune responses, a fundamental knowledge is needed of how antigen processing cells (APCs) and the downstream responses that result are influenced by antigen structure. Chemical synthesis provides access to well-defined antigens that vary in valency, elasticity, the identity and number of immune receptors they target, and the proteases that can process them. The four Specific Aims have been devised to leverage synthetic methods from chemistry and chemical biology to generate tailored synthetic antigens to dissect critical steps in immune system function. In the previous grant period, we developed strategies to assemble chemically defined epitopes that target receptors on B cells or the lectins on dendritic cells. We demonstrated that by displaying specific epitopes on a polymer backbone, we could devise antigens that bind the B cell receptor to activate or tolerize B cells. We shall leverage the synthetic methods and building blocks that resulted from those investigations to synthesize chemically defined antigens to pinpoint attributes critical for immunity. A key element of our approach is the use of state-of-art polymer chemistry to vary antigen features, such that the requisite properties can be identified.
In Aim 1, we shall use defined antigens to address how valency influences antigen signaling and trafficking in B cells and dendritic cells (DCs) but also how antigen valency influences the ability of these APCs to activate T cells.
In Aim 2, we shall synthesize nanoparticles to test the hypothesis that increases in antigen stiffness will augment B cell and dendritic cell activation, facilitate antigen uptake and processing, and therefore promote immunity.
In Aim 3, we shall produce antigens to exploit the vacuolar pathway to elicit cross presentation and thereby augment immunity by activating cytotoxic T cell responses.
In Aim 4, we shall use the blueprints that emerge from Aims 1-3 to generate antigens that induce potent in vivo immune responses. We anticipate that progress on the proposed Aims will yield new strategies to recruit the immune system to treat human disease.

Public Health Relevance

Understanding the molecular principles that render a substance immunogenic is critical for harnessing the immune system to fight disease. A powerful means to dissect how properties of a material (e.g., the binding groups it displays, its size, its elasticity) influence its ability to activate the immune system is to use chemical synthesis to vary each property individually. The proposed research takes this tack, and we anticipate it will lead to new principles for designing next-generation vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI055258-10A1
Application #
8964435
Study Section
Special Emphasis Panel (ZRG1-SBCA-D (02))
Program Officer
Gondre-Lewis, Timothy A
Project Start
2003-04-15
Project End
2020-04-30
Budget Start
2015-05-01
Budget End
2016-04-30
Support Year
10
Fiscal Year
2015
Total Cost
$410,597
Indirect Cost
$134,209
Name
University of Wisconsin Madison
Department
Biochemistry
Type
Schools of Earth Sciences/Natur
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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