Our Science – Udey Website

Mark C. Udey, M.D., Ph.D.

Dermatology Branch Branch Chief Building 10, Room 12N238 NCI-Bethesda Bethesda, MD 20892 Phone:   301-496-1741 Fax:   301-496-5370 E-Mail:   udey@helix.nih.gov

Biography

Dr. Udey majored in chemistry at the University of Wisconsin-Madison and received his M.D. and Ph.D. degrees from Washington University. He completed a medical internship and dermatology residency at Barnes Hospital and was a faculty member in dermatology at Washington University prior to coming to the NIH. Dr. Udey is Chief of the Dermatology Branch, a Senior Investigator and an editor of several journals. His research has focused on elucidating important aspects of epidermal Langerhans cell and dendritic cell biology. Recently, he has also become interested in developing vaccines for cancer.

Research

Langerhans cells belong to a family of cells that exhibits similar dendritic morphologies and functional activities. These immature epidermal dendritic cells are responsible for the initiation and propagation of immune responses directed towards antigens encountered in skin. Because they can ingest and process complex antigens, Langerhans cells are well situated to function as sentinels at interfaces between organism and environment. After antigen capture, Langerhans cells migrate from skin to regional lymph nodes where, as mature dendritic cells, they initiate and shape primary immune responses in naive T cells. Thus, Langerhans cells (and other dendritic cells) represent cellular bridges between innate and adaptive immune responses.

Two major initiatives are ongoing in the laboratory. The first involves identification and characterization of gene products that are preferentially expressed by dendritic cells to gain insight into specialized functions of these potent accessory cells. We have utilized representational difference analysis to identify genes that are expressed by dendritic cells but not by closely related cells such as macrophages. These kinds of studies are possible only because we previously defined culture conditions that allow expansion of Langerhans cell-like cells from mouse skin in vitro.

After an initial screening period, we have focused on two genes of interest. One gene (MFG-E8) was chosen because the primary sequence of its protein product suggests that it plays an important role in recognition and acquisition of particulate antigen by dendritic cells for presentation to cytotoxic lymphocytes. This protein is anticipated to play an important role in the initiation of antitumor immunity. The second gene (Langerin) was chosen because it encodes the mouse homolog of a previously described human protein that is expressed only in Langerhans cells and related cells and that is thought to function as a receptor for antigen uptake. Studies of Langerin will focus on identification of physiologic ligands and elucidation of function of the protein.

The second major initiative is an attempt to develop vaccines for cancer. One approach relies on the ability of HIV TAT protein transduction domain (PTD)-containing proteins to translocate across cell membranes and to augment dendritic cell immunogenicity. This pretranslational project is designed to develop methodology that may facilitate the exploitation of the antigen-presenting power of dendritic cells for patient benefit. We predicted that PTD-containing recombinant proteins would be internalized and presented by dendritic cells to helper T cells as expected for exogenous antigens. We also predicted that PTD-containing proteins would selectively accumulate in the cytoplasm of dendritic cells and be metabolized for presentation to cytotoxic lymphocytes. We have demonstrated that PTD antigen-treated dendritic cells are potent stimulators of both helper and cytotoxic lymphocytes, that they prime antigen-specific cytotoxic lymphocyte responses in vivo, and that they efficiently vaccinate against tumors expressing model tumor and tissue-restricted self antigens. Future studies will determine the general applicability of this approach, attempt to improve its efficacy and/or practicality, and assess the impact of this strategy on other serious diseases (e.g., chronic infections such as cutaneous leishmaniasis).

DNA-based vaccines represent another area of interest, and we are also actively trying to develop a strategy that will elicit potent immune responses against T cell lymphomas.

Our collaborators are Drs. David Sacks, NIAID, NIH; and Esther von Stebut, Johannes Gutenberg University, Germany.

This page was last updated on 6/12/2008.