Development of a Therapeutic to Preserve Vaccine Memory Following Ionizing Radiation Exposure

Abstract

Abstract We have demonstrated that in a mouse model of Listeria monocytogenes (LM) infection, revaccination within 3 days after exposure to sub-lethal ionizing radiation prevents the death of memory effector T lymphocytes and preserves vaccine memory. Although revaccination immediately after radiation exposure circumvents an increased risk of infection, it is impractical to revaccinate victims of radiation exposure to the innumerable agents to which they have developed immunity. Thus, we are seeking to develop a single therapeutic or a combination that mimic the effects of T cell activation via revaccination. We have selected our array of potential therapeutics based on their differential targets within T cell survival pathways. Broad spectrum therapeutics, stimulating numerous cell types such as Nicotine, Cimetidine, and Valproic Acid activate AKT and inhibit GSK3-beta to prevent subsequent apoptotic signals. Common gamma chain cytokines such as IL-15 and IL-21 are also candidates because of their ability to potently and specifically promote lymphocyte activation and survival. In addition, we have included Lovastatin to increase levels of P21 by proteasome inhibition. P21 may improve survival through temporary cycle arrest and enhanced DNA repair in activated T cells. We also utilized supplements to our therapeutics such as the FOXP3 inhibiting peptide- P60 and the checkpoint inhibitors anti-CTLA4 and anti-CD25 since regulatory T cells are a radio-resistant population that hinder the immune response to infection. We show, through comparisons of Listeria burden in spleens, that these candidates, either alone or in combination, are able to preserve vaccine memory following radiation exposure.