Modeling human anti-viral humoral responses in the young and elderly

Univ Of Massachusetts Med Sch Worcester, Worcester MA

Investigators

Abstract

? DESCRIPTION (provided by applicant): The very young and the elderly are particularly susceptible to respiratory infections induced by streptococcus, influenza and respiratory syncytial virus (RSV) making these populations high priority targets for effective vaccines. Much of our understanding of immunity in the elderly has been acquired through studies on mice, which do not always translate to humans. Our incomplete knowledge of the fundamental immunology of aged human populations impedes our ability to design effective vaccines t a r g e t i n g t h i s population. What would greatly enhance our current knowledge is an effective in vivo model for a g e d human immune responses that could be experimentally manipulated. A humanized mouse model has been developed in which the fully functionally mature B, T and dendritic cells found in null peripheral blood (PBL) are transferred into immunodeficient NOD.scid.IL2rgc (NSG) mice. Although immune reconstitution is immediate B cells are not maintained. Our laboratory has found providing PBL reconstituted NSG mice with the critical B cell growth and survival factor, B lymphocyte stimulator (BLyS), either by injection of recombinant protein or production from an AAV delivered huBLyS transgene, supports the survival and function of human B cells and allows robust responses to both T cell dependent and independent immunogens. In this submission we propose to extend our model to the study of the immune responses of elderly humans. We hypothesize that NSG mice reconstituted with PBL from elderly adults will retain the immune response characteristics of the individuals from which they where obtained. We have been able to elicit, in humanized mice prepared using the PBL from healthy young to middle aged donors, humoral immune responses to RSV and to RSV based virus-like particles (VLPs) that are isotype-switched, affinity matured and virus neutralizing and to produce a collection of human monoclonal antibodies specific for RSV-F and Ga envelope proteins. RSV infection does not produce durable humoral immunity or B memory cells specific for RSV making development of an effective vaccine challenging. We posit age disparate immunologically humanized surrogates will allow us to model and define the cellular mechanisms that effect responses to pathogens and vaccines. Experimentally, we propose to use young and elderly humanized surrogates t o compare and contrast immune responsiveness, immunoglobulin repertoire, and the induction of protective anti-RSV antibody as induced by either RSV infection or immunization with an RSV-VLP demonstrated to induce durable protective immunity in mice. The proposed studies should facilitate attempts to develop immunization strategies effective for the young and elderly.