Annual Report 2011 - Center for Advanced Biotechnology and ...

Dr. Arnold Rabson
Director
Child Health Institute of New Jersey
Professor
Department of Molecular Genetics,
Microbiology and Immunology
Department of Pathology and
Laboratory Medicine
Department of Pediatrics
UMDNJ-Robert Wood Johnson
Medical School
Dr. Celine Granier
Postdoctoral Fellow
Dr. Hsin-Ching Lin
Research Scientist
Viral Pathogenesis Laboratory
Dr. Rabson’s laboratory studies the molecular basis of cancer and human
retroviral infections. His recent research activities are focused in two major
areas: 1) the mechanisms responsible for the pathogenesis of retroviral
infections, particularly infection with the human T-cell leukemia virus
(HTLV-1), and 2) the roles of cellular transcriptional regulation in
development and in human cancer.
It is estimated that over 20 million people are infected by HTLV-1, the first
identified human retrovirus, and 2-5% of them are likely to develop a serious
HTLV-1-associated disease. Dr. Rabson is studying the differential mechanisms
by which HTLV-1 causes an aggressive and fatal T cell leukemia/lymphoma
(Adult T-Cell Leukemia, ATL) in some infected individuals and a series of
immunological disorders including a neurological disease of the spinal cord
(HTLV-associated Myelopathy, HAM/TSP) in other infected people. These
disorders occur in only a minority of patients, years after initial infection. This
suggests that there are important interactions between the virus and the host that
determine its pathogenicity. Furthermore, a strong host immune response against
HTLV-1 gene products favors the establishment of latent infection in vivo.
Nonetheless, expression of HTLV-1 gene products, particularly the Tax
transactivator, is required for disease development. The Rabson laboratory has
identified and characterized the mechanisms by which the expression of HTLV-1
can be activated in infected human T-lymphocytes leading ultimately to disease
pathogenesis. They have shown that stimulation through the T-cell receptor can
potently induce HTLV-1 gene expression, including the expression of Tax,
leading to T cell immortalization. They have recently confirmed this in a mouse
model of HTLV-1 latency and gene expression. T cell receptor stimulation of
CD4+ cells in a Tax transgenic mouse leads to increased T cell proliferation and
long-lived survival (>13 months). Thus, activation of latently infected T cells in
HTLV-1-infected individuals may induce expression of Tax, ultimately leading to
proliferation of subsets of cells, based on specific T cell receptor-ligand
interactions. This could explain the progressive polyclonal to oligoclonal
proliferation to ultimately monoclonal proliferation of infected T-cells that
characterizes HTLV-1-associated diseases.
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