Mitzi Nagarkatti
Professor and Chair
Pathology, Microbiology & Immunology
USC School of Medicine
Columbia, SC 29208
B.S.-- 1970, Bangalore University, India
M.S. -- 1974, Karnatak University, Dharwar, India
Ph.D. -- 1981, Defense R. & D. Establishment, Gwalior, India
Postdoc -- 1981-1983, McMaster University Med. Ctr., Hamilton, Canada
Research Associate 1983-1986, University of Kentucky Med. Ctr., Lexington, KY

Research Interests

The primary research interests of my lab include Cancer Immunology and Immunotherapy, Biodefense, Immunopharmacology, Immunotoxicology, and Complementary and Alternative Medicine. Currently, we are pursuing research in the following specific areas.

• Cancer Immunology and Immunotherapy:
  Interleukin-2 (IL-2) has been shown to be effective in the treatment of certain types of cancer including human melanomas and renal cell carcinomas. However, IL-2 therapy is accompanied by severe life-threatening toxicity characterized by endothelial cell injury leading to vascular leak syndrome (VLS). We are interested in reducing the toxicity associated with such therapy by preventing the interaction of a molecule known as CD44 present on cytotoxic lymphocytes with their ligands found on endothelial cells. Our studies are aimed at addressing the role of various CD44 isoforms present on the lymphocytes that may be involved in endothelial cell injury and tumor rejection. (Supported by NIH grants R01 AI053703 and R01 HL058641).
  

We are also working on another project which involves studying the cellular and molecular mechanisms by which bryostatin-1, a pharmacological agent used in the treatment of cancer, can induce immunomodulation and thereby cause rejection of tumors. Our initial studies have demonstrated that bryostatin-1 induces dendritic cell maturation by serving as a TLR4 ligand. Further studies are underway to examine the downstream signaling pathway following bryostatin ligation.

• Biodefense:
  Yet another area of our research is to examine the role of immune cells including NK, NKT and T cells involved in acute lung injury induced by staphylococcal enterotoxin which is a select agent designated by the Centers for Disease Control and US Department of Agriculture. Furthermore, studies will be carried out to develop strategies to block the toxicity. (Supported by NIH grant R01 058300)

• Immunopharmacology:
  In a collaborative study, we also wish to address the downstream signaling mechanisms involved in induction of apoptosis of T cells and dendritic cells by delta9-tetrahydrocannabinol (THC), the active ingredient in marijuana. We are specifically determining whether the death-receptor pathway or the mitochondrial pathway or both are involved in apoptosis. Attempts are also underway to determine whether other natural or synthetic selective cannabinoid receptor agonists could be used in the treatment of diseases such as cancer and autoimmunity. (Supported by NIH grant R01 DA016545).

• Immunotoxicology:
  Studies from our lab are also aimed at delineating the mechanism by which environmental pollutants such as TCDD (dioxin) and other endocrine disruptors cause immunotoxic effects. We have demonstrated that Fas+ mice are more sensitive than Fas- mice in their susceptibility to TCDD-mediated thymic atrophy suggesting that Fas may be a molecule involved in TCDD-induced apoptosis of thymocytes. Studies are in progress to determine the role of AhR in dioxin-induced upregulation of Fas and Fas ligand. We are also addressing the immunotoxic effects induced by exposure to TCDD during pregnancy in both the mothers and the fetuses. Such alterations in the immune system could lead to susceptibility to infections as well as development of autoimmunity, allergies and cancer (Supported by NIH grant R01 ES009098).

• Complementary and Alternative Medicine:

Lastly, we are pursuing research on one of the 3 projects of an NIH-funded Center for Complementary and Alternative Medicine on Autimmune and Inflammatory Diseases (P01 AT003961) grant awarded to Dr. Prakash Nagarkatti.  We are studying the mode of action of cannabidiol, which is a nonpsychotropic ingredient found in hemp seed and oil, in the treatment of an experimental model of autoimmune hepatitis.  The other 2 projects deal with studies on the effect of resveratrol, an ingredient found in red grape seed and skin in the treatment of experimental multiple sclerosis and the mechanisms underlying the role of American ginseng in the prevention and treatment of colitis.

Recent Publications

  Search PubMed for publications by Dr Mitzi Nagarkatti

• McKallip, R.J., Nagarkatti, P.S. and Nagarkatti, M. Delta-9-tetrahydrocannabinol exposure leads to increased breast cancer growth and metastasis mediated by suppression of the anti-tumor immune response. J. Immunol. 174:3281-9, 2005
• Camacho, I.A., Hegde, V.L., Nagarkatti, M., and Nagarkatti, P.S. Treatment of mice with 2,3,7,8-tetrachlorodibenzo-p-dioxin leads to AhR-dependent nuclear translocation of NF-?B and expression of FasL in thymic stromal cells and consequent apoptosis in T cells. J. Immunol. 175:90-103, 2005.
• Brown, N., Nagarkatti, M. and Nagarkatti, P.S. Diethylstilbestrol alters positive and negative selection of T cells in the thymus and modulates T-cell repertoire in the periphery. Toxicol Appl Pharmacol. 2005 Aug 23 [Epub ahead of print]
• McKallip, R. J., Nagarkatti, M. and Nagarkatti, P.S. Delta-9-tetrahydorcannabinol enhances breast cancer growth and metastasis by suppression of the antitumor immune response. J. Immunol. 174:3281-3289, 2005.
• McKallip,R.J., Szakal, A.K., Nagarkatti, P.S. and Nagarkatti, M. The role of CD44 in SEB-induced hepatitis: CD44 deficiency leads to reduced lymphocyte apoptosis resulting in increased liver damage. Infection and Immunity 73:50-61, 2005.
• Fisher, M.T., Nagarkatti, M., and Nagarkatti, P. S. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) enhances negative selection of T cells in the thymus while allowing auto-reactive T cells to escape deletion and migrate to the periphery. Mol. Pharmacol. 67:327-35, 2005.
• Do, Y., Hegde, V.L., Nagarkatti, P. S. and Nagarkatti, M. Bryostatin-1 enhances the maturation and antigen-presenting ability of murine and human dendritic cells. Cancer Research 64:6756-6765, 2004.
• Do,Y., McKallip, R.J., Nagarkatti, M. and Nagarkatti, P.S. Activation through cannabinoid receptors 1 and 2 on dendritic cells triggers nuclear factor-kB-dependent apoptosis: Novel role for endogenous and exogenous cannabinoids in immunoregulation. J. Immunol. 173:2373-2382, 2004.
• Fisher, M.T., Nagarkatti, M. and Nagarkatti, P. S. Combined screening of thymocytes using apoptosis-specific cDNA array and promoter analysis yields novel gene targets mediating TCDD-induced toxicity. Toxicol. Sci. 78:116-124, 2004.
• Do, Y., Nagarkatti, P.S. and Nagarkatti, M. Role of CD44 and hyaluronic acid (HA) in activation of alloreactive and antigen-specific T cells by bone marrow-derived dendritic cells. J Immunother. 27:1-12, 2004.
• McKallip, R.J., Fisher, M., Szakal, A.K., Gunthert, U., Nagarkatti, P. S. and Nagarkatti, M. Targeted deletion of CD44v7 exon leads to decreased endothelial cell injury and vascular leak syndrome induced by IL-2 activated cytolytic lymphocytes. J. Biol. Chem 278:43818-30, 2003.
• Do, Y., Mckallip, R., Nagarkatti, P. and Nagarkatti, M. Combined deficiency of CD44 and Fas leads to early onset and more severe form of lymphoproliferative disease in the murine host. Int. Immunol. 15:1327-40, 2003.
• Mckallip, R., Do,Y., Nagarkatti, P. and Nagarkatti, M. Role of CD44 in activation-induced cell death: CD44 deficient mice exhibit enhanced T cell response to conventional and superantigens. Int. Immunol. 14:1015-1026, 2002
• Mustafa, A., McKallip, R.J., Fisher, M., Duncan, R., Nagarkatti, P.S., Nagarkatti, M. Regulation of IL-2-induced vascular leak syndrome by targeting CD44 using HA and anti-CD44 antibodies. J. Immunotherapy 25:476-488, 2002
• McKallip, R.J., Lombard, C., Fisher, M., Martin, B.R., Nagarkatti, M. and Nagarkatti, P.S.. Delta-9-tetrahydrocannabinol-induced apoptosis in the thymus and spleen as a mechanism of immunosuppression in vivo. J. Pharmacol. Exp. Therap. 302:451-465, 2002
• McKallip, R.J., Lombard, C., Fisher, M., Martin, B.R., Ryu, S., Nagarkatti, P.S. and Nagarkatti, M. Targeting CB2 cannabinoid receptors as a novel therapy to treat malignancies of the immune system. Blood 100:627-634, 2002.
• Do, Y., Ryu, S., Nagarkatti, M. and Nagarkatti, P. S. Role of death receptor pathway in estradiol-induced T-cell apoptosis in vivo Toxicol. Sci. 70:63-72, 2002
• Chen, D., McKallip, R.J., Zeytun, A., Do, Y., Lombard, C., Robertson, J.L., Mak, T.W., Nagarkatti, P.S. and Nagarkatti, M. CD44-deficient mice exhibit enhanced hepatitis after concanavalin A injection: evidence for involvement of CD44 in activation-induced cell death. J. Immunol 166:5889-5897, 2001
• Zeytun, A., Nagarkatti, M. and Nagarkatti, P. S. Growth of FasL-bearing tumor cells in syngeneic murine host induces apoptosis and toxicity in Fas+ organs. Blood 95:2111-2117, 2000
• Rafi-Janajreh, A., Chen, D., Schmits, R., Mak, T. W., Grayson, R. L., Sponenberg, D. P., Nagarkatti, M. and Nagarkatti, P. S. Evidence For the Involvement of CD44 in Endothelial Cell Injury and Induction of Vascular Leak Syndrome by Interleukin-2. J. Immunol. 163:1619-1627, 1999.
• Kamath, A. B., Camacho, I., Nagarkatti, P. S. and Nagarkatti, M. Role of Fas-Fas ligand interactions in 2, 3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced immunotoxicity. Toxicol. Appl. Pharmacol. 160:141-155, 1999.
• Bradley, M. J., Zeytun, A., Rafi-Janajreh, A., Nagarkatti, P.S. and Nagarkatti, M. Role of spontaneous and IL-2 induced NK activity in the cytotoxicity and rejection of Fas+ and Fas- tumor cells. Blood 92:4248-4255, 1998.
• Rafi, A. Q., Zeytun, A., Bradley M. J., Sponenberg, D.P., Grayson, R. L., Nagarkatti, M. and Nagarkatti, P. S. Evidence for the involvement of Fas ligand and perforin in the induction of vascular leak syndrome. J. Immunol. 161:3077-3086, 1998.
• Kamath, A. B., Nagarkatti, P. S. and Nagarkatti, M. Characterization of phenotypic alterations induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin on thymocytes in vivo and its effect on apoptosis. Toxicol. Appl. Pharmacol. 149: 117-124, 1998.
• Zeytun, A., Hassuneh, M., Nagarkatti, M. and Nagarkatti, P. S. Fas-Fas ligand based interactions between tumor cells and tumor-specific CTL: A lethal two-way street. Blood 90:1952-1959, 1997.
• Kamath, A. B., Xu, H., Nagarkatti, P. S. and Nagarkatti, M. Evidence for the induction of apoptosis in thymocytes by 2,3,7,8-tetrachlorodibenzo-p-dioxin in vivo. Toxicol. Appl. Pharmacol. 142:367-377, 1997.
• Rafi, A., Nagarkatti, M. and Nagarkatti, P. S. Hyaluronate-CD44 interactions can induce murine B cell activation. Blood 89:2901-2908, 1997.
• Hassuneh, M. R., Nagarkatti, P. S. and Nagarkatti, M. Evidence for the participation of IL-2 and IL-4 in the regulation of autonomous growth and tumorigenesis of transformed cells of lymphoid origin. Blood 89:610-620, 1997.
• Hammond McKibben D., Seth, A., Nagarkatti, P. S. and Nagarkatti, M. Characterization of factors regulating successful immunotherapy using tumor specific cytotoxic T lymphocyte clone: Role of interleukin 2, cycling pattern of lytic activity and adhesion molecules. Int. J. Cancer 60:828-836, 1995.
• McKallip, R., Nagarkatti, M. and Nagarkatti, P. S. Immunotoxicity of AZT: Inhibitory effect on thymocyte differentiation and peripheral T cell responsiveness to gp120 of HIV. Tox. Appl. Pharmacol.131: 53-62, 1995.
• Nagarkatti, M., Hassuneh, M., Seth, A., Manickasundari, K. and Nagarkatti, P. S. Constitutive activation of IL 2 gene in the induction of spontaneous in vitro transformation and tumorigenicity of a T cell line. Proc. Natl. Acad. Sci. USA 91:7638-7642, 1994.
• Hammond, D., Nagarkatti, P. S., Gote, L., Seth, A., Hassuneh, M. and Nagarkatti, M. Double negative T cells from MRL lpr/lpr mice mediate cytolytic activity when triggered through adhesion molecules and constitutively express perforin gene. J. Exp.Med. 178:2225 2230, 1993.
• Seth, A., Gote, L., Nagarkatti, M. and Nagarkatti, P. S. T cell receptor independent activation of cytolytic activity of cytotoxic T lymphocytes mediated through CD44 and gp90MEL-14. Proc. Natl. Acad. Sci. USA 88:7877 7881, 1991.
• Dean, T., Kakkanaiah, V.N., Nagarkatti, M. and Nagarkatti, P.S. Immunosuppression by aldicarb of T cell responses to antigen specific and polyclonal stimuli results from defective IL 1 production by macrophages. Toxicol. Appl. Pharmacol. 106:408 417, 1990.
• Nagarkatti, M., Clary, S.R. and Nagarkatti, P. S. Characterization of tumor infiltrating CD4+ T cells as Th1 cells based on lymphokine secretion and functional properties. J. Immunol. 144:4898 4905, 1990.
• Selvan, R. S., Nagarkatti, P. S. and Nagarkatti, M. Role of IL 2, IL 4 and IL 6 in the growth and differentiation of tumor specific CD4+ T helper and CD8+ T cytotoxic cells. Int. J. Cancer 45:1096 1104, 1990.
• Nagarkatti, M. Toney D. and Nagarkatti, P. S. Immunomodulation by various nitrosoureas and its effect on the survival of the host bearing a syngeneic tumor. Cancer Research 49:6587 6592, 1989.
• Seth, A. Pyle, R. H., Nagarkatti, M. and Nagarkatti, P. S. Expression of the J11d marker on L3T4+Lyt2- peripheral T lymphocytes of MRL lpr/lpr mice. J. Immunol. 141:1120 1126, 1988.
• Nagarkatti, M. and Kaplan, A.M. The role of suppressor T cells in BCNU mediated rejection of a syngeneic tumor. J. Immunol. 135:1510 1516, 1985.
• Nagarkatti, P. S., Nagarkatti, M. and Kaplan, A. M. Normal Lyt 1+2- T cells have the unique capacity to respond to syngeneic autoreactivity T cells: Demonstration of a T cell network. J. Exp. Medicine. 162:375, 1985.
• Nagarkatti, P. S. and Nagarkatti, M. Effect of experimental dengue virus infection on immune response of the host. I. Nature of changes in T suppressor cell activity regulating the B and T cell responses to heterologous antigens. J. Gen. Virology 64:1441, 1983.