Faculty

Dorothy E. Lewis, Ph.D.

Professor
dolewis@utmb.edu
Mary Moody North Pavillion, Route 0435
Departments of INternal Medicine-Infectious Diseases and Microbiology & Immunology
Phone: (409)747-0236
Fax:

Education:	Ph.D. | 1978 | University of Arizona, Tucson, AZ
	M.S. | 1975 | University of Arizona, Tucson, AZ
	B.S. | 1972 | University of Arizona, Tucson, AZ

Overview

Apoptosis in HIV and Pre-eclampsia

Research Interests

The main focus of research in Dr. Lewis's lab involves study of the roles of cell death in various immune mediated diseases, especially HIV. Cell death is also involved in another major interest in the lab, that of diagnostic and prognostic indicators of pathological pregnancies.

In the case of HIV, Dr. Lewis has studied the natural history of HIV pathogenesis and finds that T cell death continues even though viral replication is eliminated with antiretroviral drugs. The cause of the increased cell death in vivo remains unknown, but is likely associated with chronic activation of the immune system, which is a major factor in the pathogenesis of HIV. Dr. Lewis has shown that CD8 T cells in HIV die by an unique mechanism involved monocytes and ligation of the CD28 molecule on the CD8 T cells by CD80 and CD86 on the monocytes. FAS or TNF-alpha do not appear to be involved. To study the mechanism, Dr. Lewis has found an antibody to CD28 which causes T cell activation and cell death in human T cell lines and in primary T cells. The death seems to involve the production and release of Granzyme B, which can act as a caspase and enters cells without perforin to kill susceptible cells that do not express an inhibitor of Granzyme B--PI-9.

Interest in this type of CD28 antibody, called mitogenic, has increased due to the devastating clinical trial in 2006 where 6 volunteers were given humanized mitogenic CD28 ab and all developed massive cytokine release and multi-organ failure. Although cytokines were detected in these patients, granzyme B release was not examined. Future studies will examine the role of granzyme B in the chronic activation and death of immune cells seen in HIV infected patients by analysis of cells and tissues.

A key reason this antibody was being tested in humans was because of the potential to induce T reg cells that might be useful in regulating autoimmune diseases. Indeed, our in vitro work shows that mitogenic CD28 selectively expands CD4 memory T cells to express Foxp3 and exhibit T regulatory function, involving cell to cell contact. The role of Granzyme B in the function of the T regs will be analyzed in future experiments, as well as signaling mechanisms leading to differential outcomes in response to the mitogenic CD28 signal.

Another major interest of Dr. Lewis stems from her work with fetal cells in the maternal circulation, which were touted to be used in genetic diagnosis in a non-invasive way. However, isolation of the cells proved difficult and the much more abundant fetal DNA in the maternal circulation has been characterized and ways for isolation from maternal DNA developed. This fetal DNA likely comes from apoptotic placental cells so that microparticles still expressing fetal specific markers can be isolated using a magnetic bead approach. Future goals are to use the developed flow cytometric assay to prospectively study the course of pregnancies, especially those involving pathologies. The most frequent pathology involving pregnancy is pre-eclampsia, which is life threatening in up to 10% of pregnant women. The detection and quantification of the cell free fetal DNA could be used to monitor abnormal pregnancies and to study mechanisms involved in pathogenesis.

Recent Publications

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