Vitamin A and its active metabolite, retinoic acid (RA), affect the immune system in multiple ways. Our research is focused on the ability of retinoids to work together with co-stimulatory molecules, of both endogenous and exogenous origin, to promote strong and long-lasting immunity in adults and neonates. Using mice, we have recently shown that a nutritional-immunological combination of RA and a cytokine inducer, poly-l:C (PIC), can act together to stimulate much stronger primary and memory antibody responses in both adult and neonatal mice. Our long-term goal is to understand how RA and co-stimuli can augment antigen-specific antibody responses, especially in the very young and in individuals whose immune system is weakened by vitamin A deficiency or disease. The central hypothesis of this proposal is """"""""Retinoic acid, an active metabolite of VA, cooperates with immunological co-stimuli - especially the Toll-like Receptor (TLR)-3 ligand, poly-l:C (PIC), the signaling co-receptor CD38, and tumor necrosis factor family members - to significantly regulate antibody production at both the neonatal and adult stages of life."""""""" We will use a combination of cell and molecular analysis, flow cytometry, confocal microscopy, and immunoassays to better understand how RA and co-stimuli promote the activation of B-cells and the antibody response to immunization in vivo. Our 3 aims are: 1) To determine how RA and costimulatory molecules activate B cells isolated from adult and neonatal mice;2) To establish how RA and co-stimulation regulate the formation of germinal centers (GC), a specialized microenvironment where antibody-producing cells mature;3) To test whether a special population of T-cells, referred to as iNKT cells, are responsive to RA plus costimuli, and whether a combined nutritional-immunological treatment can balance the production of cytokines that are needed for an optimal immune response. Relevance: Vaccination is a life-saving strategy for infants and children. Vitamin A's active metabolite, retinoic acid, together with immune stimuli of endogenous and exogenous origin, may be an effective combination for promoting B-lymphocyte activation and the production of a strong, durable antibody response in vivo, as is necessary for protection against infectious disease. Our studies will use biochemical and microscopic techniques to test whether nutritional-immunological combinations of RA plus several immune stimuli, given with immunization, can promote B-cell activation, induce microarchitectural changes needed for strong antibody production, and increase the plasma antibody levels in adult and neonatal mice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK041479-21
Application #
7880699
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Maruvada, Padma
Project Start
1989-04-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
21
Fiscal Year
2010
Total Cost
$280,893
Indirect Cost
Name
Pennsylvania State University
Department
Nutrition
Type
Schools of Allied Health Profes
DUNS #
003403953
City
University Park
State
PA
Country
United States
Zip Code
16802
Rubin, Lewis P; Ross, A Catharine; Stephensen, Charles B et al. (2017) Metabolic Effects of Inflammation on Vitamin A and Carotenoids in Humans and Animal Models. Adv Nutr 8:197-212
Chen, Q; Ross, A C (2015) ?-Galactosylceramide stimulates splenic lymphocyte proliferation in vitro and increases antibody production in vivo in late neonatal-age mice. Clin Exp Immunol 179:188-96
Chen, Qiuyan; Ross, A Catharine (2015) All-trans-retinoic acid and CD38 ligation differentially regulate CD1d expression and ?-galactosylceramide-induced immune responses. Immunobiology 220:32-41
Liao, Xiaofeng; Ren, Jingjing; Wei, Cheng-Hsin et al. (2015) Paradoxical effects of all-trans-retinoic acid on lupus-like disease in the MRL/lpr mouse model. PLoS One 10:e0118176
McDaniel, Kaitlin L; Restori, Katherine H; Dodds, Jeffery W et al. (2015) Vitamin A-Deficient Hosts Become Nonsymptomatic Reservoirs of Escherichia coli-Like Enteric Infections. Infect Immun 83:2984-91
Restori, Katherine H; McDaniel, Kaitlin L; Wray, Amanda E et al. (2014) Streptococcus pneumoniae-induced pneumonia and Citrobacter rodentium-induced gut infection differentially alter vitamin A concentrations in the lung and liver of mice. J Nutr 144:392-8
Zhang, Yao; Ross, A Catharine (2013) Retinoic acid and the transcription factor MafB act together and differentially to regulate aggrecan and matrix metalloproteinase gene expression in neonatal chondrocytes. J Cell Biochem 114:471-9
Wu, Lili; Ross, A Catharine (2013) Inflammation induced by lipopolysaccharide does not prevent the vitamin A and retinoic acid-induced increase in retinyl ester formation in neonatal rat lungs. Br J Nutr 109:1739-45
Chen, Qiuyan; Mosovsky, Kara L; Ross, A Catharine (2013) Retinoic acid and ?-galactosylceramide regulate the expression of costimulatory receptors and transcription factors responsible for B cell activation and differentiation. Immunobiology 218:1477-87
Restori, Katherine H; Kennett, Mary J; Ross, A Catharine (2013) Immunization with pneumococcal polysaccharide serotype 3 and lipopolysaccharide modulates lung and liver inflammation during a virulent Streptococcus pneumoniae infection in mice. Clin Vaccine Immunol 20:639-50

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