Significance of the research. Vaccination with recombinant proteins is the safest way to immunize people against biological weapons and infectious diseases. However, the use of mild adjuvants with low levels of inflammatory side effects that make subunit vaccines desirable for immunization may also be responsible for their relatively poor efficacies. This is true because inflamed environments help promote the survival of activated T cells, which in turn promote long-term immunity. It is proposed that identification and description of adjuvant mechanisms that promote T cell survival will improve biodefensive vaccine design by favoring ways to maximize antigen-specific T cell yield while limiting inflammation. Research goals. This K02 application is organized around two research goals to be pursued in tandem over the next five years. The award will make possible Dr. Mitchell's scientific direction of experiments designed to determine i) the mechanisms by which Toll-like receptor (TLR) adjuvants promote T cell immunity via interactions with antigen-presenting cells, and ii) the signaling pathways in T cells that result from upstream interactions and that cause prolonged cellular survival. The hypothesis that TLR adjuvants boost the numbers of antigenspecific T cells by improving their survival through activities of the NF-kappaB/IkappaB factor Bcl-3 will be tested. Multiple aspects of this hypothesis will be tested using mouse models of T cell responses and infectious disease, microarray analyses, retroviral gene transfer, and biochemical analyses of experimentally modified T cells, in order to rationally enhance the establishment of immunity. Career development. Dr. Mitchell was first trained as a virologist and then as a T cell immunologist. He has an eight year history of studying the effects of adjuvants on T cells, and is poised to make significant advances in this subdiscipline. Career development will occur at the University of Louisville's Department of Microbiology, and at the Institute for Cellular Therapeutics, a center of excellence where the Mitchell laboratory is housed. The University of Louisville is a state-supported institution with a rapidly expanding basic research program. External salary support will lessen the load of non-research duties, such that conceptual advances in vaccine design for biodefense can be made.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02AI059023-04
Application #
7197982
Study Section
Allergy & Clinical Immunology-1 (AITC)
Program Officer
Prograis, Lawrence J
Project Start
2004-03-01
Project End
2009-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
4
Fiscal Year
2007
Total Cost
$99,037
Indirect Cost
Name
University of Louisville
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
Cekic, Caglar; Casella, Carolyn R; Eaves, Chelsea A et al. (2009) Selective activation of the p38 MAPK pathway by synthetic monophosphoryl lipid A. J Biol Chem 284:31982-91
Casella, C R; Mitchell, T C (2008) Putting endotoxin to work for us: monophosphoryl lipid A as a safe and effective vaccine adjuvant. Cell Mol Life Sci 65:3231-40
Mata-Haro, Veronica; Cekic, Caglar; Martin, Michael et al. (2007) The vaccine adjuvant monophosphoryl lipid A as a TRIF-biased agonist of TLR4. Science 316:1628-32
Sengupta, Sadhak; Jayaraman, Padmini; Chilton, Paula M et al. (2007) Unrestrained glycogen synthase kinase-3 beta activity leads to activated T cell death and can be inhibited by natural adjuvant. J Immunol 178:6083-91
Chilton, Paula M; Mitchell, Thomas C (2006) CD8 T cells require Bcl-3 for maximal gamma interferon production upon secondary exposure to antigen. Infect Immun 74:4180-9
Thompson, Bruce S; Chilton, Paula M; Ward, Jon R et al. (2005) The low-toxicity versions of LPS, MPL adjuvant and RC529, are efficient adjuvants for CD4+ T cells. J Leukoc Biol 78:1273-80
Sengupta, Sadhak; Chilton, Paula M; Mitchell, Thomas C (2005) Adjuvant-induced survival signaling in clonally expanded T cells is associated with transient increases in pAkt levels and sustained uptake of glucose. Immunobiology 210:647-59
Thompson, Bruce S; Mata-Haro, Veronica; Casella, Carolyn R et al. (2005) Peptide-stimulated DO11.10 T cells divide well but accumulate poorly in the absence of TLR agonist treatment. Eur J Immunol 35:3196-208
Thompson, Bruce S; Mitchell, Thomas C (2004) Measurement of daughter cell accumulation during lymphocyte proliferation in vivo. J Immunol Methods 295:79-87