Education:
1987 B.S., Microbiology, University of Notre Dame
1992 Ph.D., Microbiology and Immunology

Professional Experience:
04/97-04/01 Assistant Member, Trudeau Institute
04/01-06/06 Associate Member, Trudeau Institute
06/06-present Member, Trudeau Institute
05/98-present Adjunct Assoc. Prof. of Microbiol. Immunol. and Mol. Genetics, Albany Med. College
07/02-present Adjunct Associate Professor of Medicine, University of Vermont

My laboratory has two major research projects. First, we are interested in understanding, at a molecular level, how the ecto-enzyme CD38 regulates innate and adaptive immune responses. In the last four years we have shown that one of the enzymatic products generated by CD38 (cyclic ADP-ribose) modulates calcium responses in leukocytes that have been activated by a subset of chemokines and chemoattractants. Briefly, we demonstrated that CD38 and cADPR regulate calcium influx in monocytes, neutrophils and dendritic cells stimulated with ligands for several chemoattractant receptors including CCR1, CCR2, CCR5, CCR7, CXCR4 and FPRL1. Importantly, the chemoattractant induced calcium influx response regulated by CD38 and cADPR is required for chemotaxis and cells that lack CD38 or have been treated with CD38/cADPR antagonists are unable to migrate in response to these chemokines. We further showed that trafficking of monocytes, neutrophils and dendritic cells in vivo in response to inflammation and infection is regulated by CD38 and that mice lacking CD38 make impaired innate and adaptive immune responses. Finally, we showed that CD38/cADPR antagonists can be used to block the chemotaxis of human neutrophils and monocytes. Taken all together, our data demonstrate that CD38 regulates signaling through a diverse array of chemokine and chemoattractant receptors in multiple hematopoietic cell types. Since many of the chemoattractant receptors regulated by cADPR bind to ligands that are associated with clinical pathology, we have hypothesized that cADPR and CD38 represent novel drug targets that could be used to suppress infiltration of inflammatory cells to sites of tissue damage as well as to attenuate the accompanying adaptive immune response. Our current experiments are directed toward addressing this hypothesis using whole animal models. For example, we have shown that CD38 deficient mice are more resistant to multi-low dose STZ induced diabetes and to allergen-induced inflammation and airway hyperresponsiveness. We showed that the reduction in airway inflammation in the allergen model is due to reduced T cell priming in the CD38 deficient mice as well as to defective trafficking of CD38 deficient allergen-specific T cell effectors to the lung. Furthermore, in collaboration with the Kannan laboratory at U. Minn., we showed that the reduced airway responsiveness to bronco-constrictors observed in the CD38 deficient mice is due to altered calcium responses in muscarinic receptors expressed by airway smooth muscle cells. Therefore, we predict that CD38 antagonists could be used to block both the inflammation and airway constriction associated with asthma. To test that directly, we have now established collaborations with chemists at UCSF to develop and then test small molecule CD38 inhibitors in our asthma and diabetes models. Finally, we are using CD38 enzyme antagonists and CD38 deficient cells to map the CD38 and cADPR dependent signaling pathway in chemoattractant stimulated leukocytes and have shown that Gαq coupled chemoattractant receptors are regulated by CD38 and cADPR. Using this information, we have now begun studies to test the relative importance of Gαq and Gαi in regulating the development and migration of the different dendritic cell subsets to the various secondary lymphoid tissues. Interestingly, we have found that the migration of DCs under homeostatic and inflammatory conditions are regulated by very distinct sets of signals. In the future, we will better define these signals and then use our arrays of inhibitors and antagonists to alter DC migration in vivo and thereby alter the initiation of immune responses or the induction of peripheral T cell tolerance.

The second major project that we have undertaken is to determine how B cells regulate immune responses to pathogens and autoantigens. We have shown that B cells can produce different arrays of cytokines, depending on the microenvironment in which the B cells were initially primed. We have determined the molecular mechanism(s) that control IFNγ production by B cells activated by T cells and antigen and showed that signaling through the IFNγR on B cells leads to T-bet upregulation and the initiation of an autocrine IFNγ-driven positive feedback loop. Likewise, IFNγ production by B cells activated in the presence of IL-12 and IL-18 is controlled by the IFNγR/T-bet/IFNγ feedback loop. In a related set of experiments we showed that the development of IL-4 producing effector B cells (Be2 cells) is controlled both in vitro and in vivo by IL-4 producing Th2 cells and that while IL-4/IL-4R dependent signals are necessary for the development of Be2 cells, Th2 cells provide additional factors. In collaboration with the Marshak-Rothstein lab, we have begun an analysis to identify the cytokines produced by autoimmune B cells and to determine the signals that regulate the production of these cytokines. Interestingly, we have found that autoimmune B cells activated through TLRs and the BCR produce IL-2 in significant amounts. We are currently testing whether the IL-2 produced by the autoimmune B cells enhances their survival and expansion. In other experiments we are testing whether B cell-derived cytokines regulate the expansion differentiation of B cells in vivo and have found that TNFα production by B cells regulates the differentiation of B cells into IgG1-producing plasma cells. Taken together, our data demonstrates that cytokine producing B cells have the potential to regulate immune responses. We are now extending these data by examining the regulatory role(s) for B cells in influenza and nematode infections. We have now found that B cells play a critical role in activating and maintaining effector T cell responses to H. polygyrus and have shown that a cognate interaction between H. polygyrus specific class II-expressing B cells and T cells is required for the expansion of antigen-specific Th2 cells and the development or maintenance of Th2 memory cells. In our ongoing experiments, we are determining which co-stimulatory signals provided by B cells are necessary for the expansion and maintenance of antigen-specific Th2 cells and are determining whether B cells are also required for the expansion and maintenance of influenza-specific IFNγ-producing CD4 T cells. In the future, we hope to use these data to design vaccination strategies that harness the regulatory properties of B cells to enhance immunity to pathogens.