The overarching goal of this project is to understand the mechanisms by which transepidermal inoculation ofhuman skin with vaccinia (scarification) leads to a protective immune response to smallpox, and to use thisknowledge to help develop vaccination strategies that are both safe and effective, particularly for patientswho currently are not vaccination candidates (e.g., patients with atopic dermatitis). Studies will be performedusing both human and murine model systems. The potential for vaccinia to productively infect both normaland atopic skin tissue, cells, and artificial skin constructs, will be assessed by vanous techniques. Incollaboration with investigators from Project 1, both skin and blood will be sampled at various time pointsfrom vaccinated normal volunteers. We will test the validity of our paradigm of cutaneous immune response,wherein Langerhans cells containing virus fragments from infected epidermis migrate to draining lymphnodes and differentiate into potent mature dendritic cells and activate naTve T cells. These T cells expandclonally and differentiate into central memory and skin-homing effector memory T cells. Effector memory Tcells extravasate from dermal vessels at the vaccine site and enter the papillary dermis and epidermis.Central memory cells traffic into secondary lymphoid tissues and provide long-term immunolog ic memory.We will characterize key cellular and humoral elements of the protective immune response to variolagenerated as a result of these events. We will test the extent to which atopic dermatitis patients and normalvolunteers vaccinated with MVA develop similar key elements of this protective response. In murine models,we will manipulate the cutaneous microenvironment with biological response modifiers and determinewhether these maneuvers improve the immune response to vaccinia. Transgenlc mice with targetedepidermal expression of cytokines and chemokines that influence dendritic cell migration and function willalso be studied. The efficacy of vaccination will be assessed by testing resistance to vaccinia challenge inthese mice after prior vaccination with MVA or vaccinia, with a major goal being to enhance vaccinationefficiency. The Harvard Skin Disease Research Center has studied both innate and acquired immuneresponse mechanisms in skin for more than 15 years. The resources of the HSDRC will provide a richenvironment for these studies and will enhance collaborative interactions with investigators leading projects1, 2, and 4.
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