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Office: 803 733 3180
Fax: 803 733 3192
E-mail:
pnagark
@med.sc.edu
Department of Pathology and Microbiology, University
of South Carolina School of Medicine, Columbia, SC 29208 |
Recent Publications
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Research Interests
Immunotoxicity of TCDD and other endocrine disruptors: (Supported by NIH
grant R01 ES 09098)
There is growing concern that environmental chemicals can alter the
functions of the immune system and make an individual more susceptible to
development of cancer, infections, autoimmunity and allergies. This has led
to the emergence of a new field, imunotoxicology. Our lab has demonstrated
for the first time that TCDD (dioxin), a highly toxic environmental
pollutant and carcinogen, triggers apoptosis (programmed cell death) in T
cells, and causes thymic atrophy as well as peripheral immunosuppression.
The apoptosis was based on Fas-FasL interactions because Fas deficient (lpr/lpr)
and FasL defective (gld/gld) mice were resistant to TCDD-mediated apoptosis
and immunosuppression. Currently, we are studying the mechanism by which Fas
and FasL are upregulated following TCDD treatment. We are also studying
other apoptotic genes induced by TCDD using cDNA microarray. Furthermore, we
are elucidating whether TCDD-induced apoptosis through the death receptor
also involves cross-talk with the mitochondrial pathway.
Cannabinoid-induced immunosuppression and use of cannabinoids in cancer
therapy: (Supported by NIH grants R01 DA016545 and R21 DA014885)
Cannabinoids are compounds derived from Cannabis sativa plants, as well as
produced endogenously in the brain and by immune cells. Recently, two
cannabinoid receptors designated CB1 and CB2 have been identified and
cloned. CB1 receptors are expressed at high levels in central nervous
system, where they mediate psychotropic effects. In contrast, the CB2
receptors are solely expressed on immune cells and do not contribute to the
psychoactivity. Recently, we demonstrated that cancers of immune origin also
express CB1 and CB2 receptors. Furthermore, we showed that ligation of CB2
receptors can induce apoptosis in a wide range of murine and human tumors of
immune origin. These studies raise the exciting possibility that molecular
targeting of CB2 receptors on tumor cells may provide a novel approach to
induce apoptosis and thereby treat cancers of the immune system without
inducing psychoactivity. We have also shown that cannabinoids can suppress
immune functions by inducing apoptosis and promote metastasis of certain
types of tumors. Thus, cannabinods may serve as double-edged swords and
studies are in progress to delineate the mechanisms of differential activity
of cannabinoids against immune cells and cancer.
Role of CD44 in endothelial cell injury and antitumor immunity:
(Supported by NIH grants R01 AI053703 and R01 HL058641)
Our lab has also been interested in developing novel approaches to treat
cancer using immune cells or their products, a procedure called
"immunotherapy". We are studying the role of CD44 in IL-2 mediated rejection
of melanomas. IL-2 is extensively used in the treatment of renal cell
carcinomas and melanomas. However, this treatment is extremely toxic
resulting in endothelial cell (EC) injury and vasular leak syndrome. Using
CD44 knockout mice, we have shown that CD44 plays a critical role in the EC
damage caused by cytotoxic lymphocytes. Currently, we are using CD44 isoform
knockout mice to identify the CD44 isoforms involved in EC injury and
developing therapeutic modalities to prevent vascular damage and increase
the efficacy of IL-2 therapy against cancer. |
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