Under the aegis of an R21 grant (AI49771: Transgenic B cell immunogens), we developed an antigen-presenting cell (APC)-based vaccine using the influenza A virus as a model system. Studies focused on CD8 T cell memory responses revealed that protection is mediated by CD8 T cells with high CD62L expression. These are referred to as central memory T cells. This finding on the correlate of protection in vivo is now proposed as the basis for a new experiment to understand the requirements to induce protective memory CD8 T cells by vaccination. The hypothesis we wish to test is that successful programming by a genetic APC vaccine of central memory CD8 T cell induction may be subject to a series of considerations of general nature such as dose and interval between priming and encounter with the pathogen, the interaction with the environment such as dendritic cells and IL-15, and the presence of CD62L as a key phenotypic feature of the signature gene. Our objective is to further use the newly developed APC vaccination system as a proof of principle to understand the requirements for the generation of protective central memory CD8 T cells against a category 3 viral pathogen. The importance of our studies is also that the new vaccination approach while built on the cardinal axiom Vaccination--> Immunity--> Protection is intended at inducing protection against disease, hence setting a new target for vaccine-directed control of old or emerging infectious diseases. We believe that our studies will have implications in the development of an alternative approach to effectively vaccinate against influenza A virus using novel APC vaccine approach.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI062894-02
Application #
7008599
Study Section
Special Emphasis Panel (ZRG1-VMD (01))
Program Officer
Rathbun, Gary
Project Start
2005-02-01
Project End
2008-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
2
Fiscal Year
2006
Total Cost
$301,332
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Zanetti, Maurizio; Castiglioni, Paola; Ingulli, Elizabeth (2010) Principles of memory CD8 T-cells generation in relation to protective immunity. Adv Exp Med Biol 684:108-25
Almanza, Gonzalo; Fernandez, Antonio; Volinia, Stefano et al. (2010) Selected microRNAs define cell fate determination of murine central memory CD8 T cells. PLoS One 5:e11243
Ingulli, Elizabeth; Funatake, Castle; Jacovetty, Erica L et al. (2009) Cutting edge: antigen presentation to CD8 T cells after influenza A virus infection. J Immunol 182:29-33
Castiglioni, Paola; Hall, De Shon; Jacovetty, Erica L et al. (2008) Protection against influenza A virus by memory CD8 T cells requires reactivation by bone marrow-derived dendritic cells. J Immunol 180:4956-64
Zanetti, Maurizio (2007) Immunity and protection, the unfolding of a tale. Immunol Res 38:305-18
Zanetti, Maurizio; Franchini, Genoveffa (2006) T cell memory and protective immunity by vaccination: is more better? Trends Immunol 27:511-7
Wheeler, Matthew; Cortez-Gonzalez, Xotchil; Frazzi, Raffaele et al. (2006) Ex vivo programming of antigen-presenting B lymphocytes: considerations on DNA uptake and cell activation. Int Rev Immunol 25:83-97