The research efforts of my laboratory are focused on understanding the molecular processes that collectively serve to regulate various cellular components of the mammalian immune system.  Specifically, we research the roles played by a number of steroid hormones and their cellular receptors in controlling the initiation, types, magnitude and duration of innate and adaptive immune responses in vivo.

1. Immune Modulatory Influences of calcitriol on mucosal immunity

    A vast majority of disease-causing infectious agents gain entry into susceptible hosts at a mucosal membrane surface of the respiratory, urogenital, nasal or gastrointestinal tracts. Consequently, a major goal to prevent infectious diseases is to develop vaccines capable of effectively inducing protective mucosal immunity. These responses would serve to reduce the transmission of pathogenic microorganisms that utilize the mucosa as their primary portal of entry. Traditionally, vaccine antigen application directly to mucosal sites has been needed to induce protective mucosal immunity. This route of immunization is quite ineffective, and presently requires the co-administration of noxious bacterial enterotoxins as mucosal adjuvants. Conventional systemic routes of vaccine administration, while capable of stimulating robust systemic immune responses, induce only minimal mucosal protection.
    We have discovered that vaccines containing calcitriol, the natural active form of vitamin D3, are able to co-stimulate the generation of both systemic and mucosal immunity following a subcutaneous route of delivery. Calcitriol addition to vaccines allows the myeloid dendritic cells (DCs) that incorporate antigens at the site of vaccination to bypass sequestration in the draining lymph node, enter the bloodstream, and ultimately localize into the classical sites for mucosal immunity induction (Peyers patches, mesenteric lymph nodes). The altered migration of antigen-containing DCs to the Peyers patch allows common mucosal immune responses to be effectively initiated. We are currently investigating the molecular processes affected by calcitriol that are involved in altering the normal trafficking patterns of DCs. We now appreciate that the mechanisms involved are physiological, and manifest themselves when 1α-hydroxylase, an activation-inducible enzyme in DCs and macrophages, converts the inactive circulating vitamin D3 precursor into the bioactive hormone.

2. Glucocorticoid control of macrophage activities

We recently discovered that glucocorticoids (GCs), in addition to their well-researched suppressive effects on inflammatory processes, also play an important role during development in regulating macrophage sensitivity to stimulators of inflammation. The suppressive effects of exogenously added GCs on inflammatory processes generally require high levels of added hormone and activation of the glucocorticoid receptor. Basal levels of GCs, possibly through their capacity to also activate the mineralocorticoid receptor, seem to affect the set-point control of responsiveness that occurs during myeloid cell development. Our long term objectives are to fully characterize the molecular mechanisms responsible for this modulatory process. Our recent findings implicate the phosphatase SHIP-1 and its ability to negatively regulate the phosphatidylinositol-3-kinase-AKT pathway in this process.

3. Molecular mechanisms responsible for immunosenescence

    We previously established that abnormalities in the regulation of inflammatory responses accompanies, and may be responsible for, many of the adverse events that occur during the aging process. Observed depressions in immune function, and the increased incidence of osteoporosis, cardiovascular and rheumatic diseases, diabetes, and many forms of cancer all share linkages to biochemical and cellular processes resulting from abnormal control over inflammation and inflammatory processes. The molecular mechanisms responsible for such dysregulations are under active investigation, and appear to involve alterations in the activities of certain transcription factors and signaling systems, especially those whose activities are redox regulated like nuclear factor kappa B (NFκB) and the mitogen activated protein (MAP) kinase cascade. The age-associated overproduction of inflammatory cytokines and mediators that occur in the elderly subsequent to infection or trauma appear to be linked to a breakdown in control over NFκB activation and other essential signal transduction processes. We are presently evaluating a number of therapeutic interventions for their capacity to reduce cellular oxidative stress, and influence immune competence.