Project 4: Vaccines and antibiotics help prevent or ameliorate many infectious diseases. Yet, naturalevolution and engineering for bioterrorism purposes create novel biothreats for which novel countermeasuresare necessary including i) development of novel chemotherapeutic agents, and ii) utilization of naturaldefense mechanisms, i.e., the immune system. The latter one may include non-specific activation of theinnate immune system and manipulation of the adaptive immunity through vaccines. We now know thatvaccines act through dendritic cells (DCs), the initiators and controllers of immune effectors (T and Blymphocytes) differentiation. Just as lymphocytes are composed of different subsets, DCs comprise severalsubsets that differentially control lymphocyte function. It is therefore important to understand how distinct DCsubsets modulate vaccine immunity in vivo. Such knowledge will permit us to design targeted vaccines thatwill induce a desired type of immunity.This project is designed to i) construct novel human vaccines comprised of antibodies targeting distinctsubsets of human DCs coupled to an antigen of choice, either as chemical conjugates or as antibody-antigenfusion proteins, and ii) determine the quality and magnitude of antigen-specific immune responses elicited invitro and in vivo by targeting distinct subsets of human DCs. We will evaluate, in the mice with a humanimmune system (Humouse), the induction of specific cellular and humoral immune responses using Influenzavirus as a model pathogen.
AIM 1 will determine whether anti-DC mAb/Flu conjugates can induce Flu-specific secondaryresponses in vitro.
AIM 2 will determine whether anti-DC mAb/Flu conjugates that target different DC subsetsprime immune responses in vitro.
AIM 3 will determine the in vivo targeting of human DC subsets by selectedanti-DC mAb/Flu conjugates.
AIM 4 will determine whether specific anti-DC mAb/Flu conjugates targeted todistinct human DC subsets in vivo permit the priming of Flu-specific protective immune responses. Theultimate parameter of vaccine potency will be the protection of Humouse from virus rechallenge.This study will lead to generation of novel vaccines targeted to human DC subsets in vivo.
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