Dr. Venkatesh L Hegde
Research Assistant Professor
Postdoctoral Fellow: Virginia Commonwealth University (2003-05), University of South Carolina (2005-09)
Ph.D. (2003), University of Mysore, India
B.S. & M.S. (1995, 1997), Karnatak University, India
Office: (803) 216-3412
Fax: (803) 216-3428
Mechanisms of autoimmune hepatitis and Use of immunomodulatory compounds to treat AIH: Major interest of our lab is to investigate the cellular and molecular mechanisms of inflammatory diseases such as autoimmune hepatitis (AIH) and to develop novel treatment strategies using complimentary and alternative medicine (CAM) approach. AIH is a T cell-mediated liver disease in which the body's immune system attacks the cells of the liver, causing hepatocellular inflammation and cell death. AIH is a major health problem worldwide. The frequency of AIH among patients with chronic liver disease is as high as 23% and the disease accounts for about 6% of liver transplantations in the United States. Untreated AIH can lead to liver cirrhosis and eventually liver failure needing liver transplantation. AIH is often treated by drugs such as corticosteroids that suppress the immune system. These medications, which often must be taken long term, carry a number of risks and aren't always effective. Therefore, there is a need to find better, more effective and safer alternatives. Natural cannabinoids such as Delta(9)-tetrahydrocannabinol (THC) and Cannabidiol (CBD) effectively modulate immune cell function and have shown great therapeutic potential in treating inflammatory diseases. We have recently shown that a single dose of THC can effectively suppress liver inflammation in a well-established mouse model of hepatitis in a cannabinoid receptor (CB1 &CB2)-dependent manner. We showed for the first time that THC not only acts by inducing apoptosis in activated T cells, but also by inducing regulatory T cells (Tregs) in liver. We also tested other cannabinoids and have shown that synthetic cannabinoid compounds which bind to both CB1 and CB2 receptors (WIN55212 & CP55940) and endogenous cannabinoids (Anandamide) were as effective as THC. In addition, we observed that transgenic mice deficient in endocannabinoid hydrolyzing enzyme fatty acid amide hydrolase (FAAH) were resistant to experimental hepatitis. Administration of pharmacological inhibitors of FAAH had a similar effect. Our data demonstrate that targeting cannabinoid receptors using exogenous or endogenous cannabinoids and use of FAAH inhibitors may constitute a novel therapeutic approach to treat immune-mediated liver inflammation. Our current studies focus on the role of T regulatory cells and CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs) in the induction of natural tolerance in autoimmune hepatitis and the mechanisms involved. MDSCs are a newly-identified population of potent immune-suppressors which express arginase-1, nitric oxide synthase (NOS) and IL-10. Depletion of L-arginine, an essential amino acid required for T cell function, is the major mechanism by which they produce immune suppression. We are investigating the induction of MDSCs as a mechanism of immunosuppression by cannabinoids and its use in treating inflammatory diseases.
Role of CD44 in T cell-APC interactions and formation of Immunological Synapse: Another interest of our lab is to understand the role of CD44, an important cell adhesion and signaling molecule, in T cell-dendritic cell (DC) interactions with a special reference to immunological synapse. Immunological synapse is a unique structure formed by the clustering of various receptors, cytoskeleton, and intracellular signaling complexes at the contact between T cell and antigen presenting cell such as DC. A mature immunological synapse is characterized by TCR/MHC-peptide complex with associated molecules such as CD3 at the center, called the central supramolecular activation cluster (cSMAC) and molecules such as talin, LFA-1, and ICAM in the periphery (pSMAC) surrounding cSMAC. We have shown recently that CD44 gets localized within lipid rafts at the contact between T cells with mature but not immature DCs. Using cells derived from CD44-deficient mice, we could show that deficiency of CD44 on DCs but not T cells affected the formation of functional immunological synapse as indicated by decreased phosphotyrosine and protein kinase C-theta enrichment at the synapse. Furthermore, CD44 on DCs was crucial for the proliferation of T cells as well as IL-2 and IFN-g production from T cells. Our results show for the first time that CD44 is recruited to the immunological synapse and plays an important role in subsequent T cell activation. Using primary cells derived CD44-sufficient and CD44-deficient mice, we are currently studying the pattern and kinetics of CD44 mobilization at the T cell-endothelial cell (EC) contact, its role in the signaling at the T cell-EC contact as well as subsequent activating or inhibiting signals in T cells.
Search PubMed for Publications by Dr.Venkatesh Hegde
- Nagarkatti P, Pandey R, Rieder SA, Hegde VL, Nagarkatti M. Cannabinoids as novel anti-inflammatory drugs. Future Medicinal Chemistry 2009; 1:1333-1349.
- Pandey R, Hegde VL, Singh NP, Hofseth L, Singh U, Ray S, Nagarkatti M, Nagarkatti PS. Use of cannabinoids as a novel therapeutic modality against autoimmune hepatitis. Vitamins and Hormones 2009; 81:487-504.
- Hegde VL, Singh NP, Nagarklatti PS, Nagarkatti M. CD44 mobilization in allogeneic dendritic cell-T cell immunological synapse plays a key role in T cell activation. Journal of Leukocyte Biology 2008; 84:134-42.
- Hegde VL, Hegde S, Cravatt BF, Hofseth LJ, Nagarkatti M, Nagarkatti PS. Attenuation of experimental autoimmune hepatitis by exogenous and endogenous cannabinoids: involvement of regulatory T cells. Molecular Pharmacology 2008; 74:20-33 (One of the Top Ten downloaded articles on MolPharm website when it was published).
- Singh NP, Hegde VL, Hofseth LJ, Nagarkatti M, Nagarkatti P. Resveratrol (trans-3,5,4'-trihydroxystilbene) ameliorates experimental allergic encephalomyelitis, primarily via induction of apoptosis in T cells involving activation of aryl hydrocarbon receptor and estrogen receptor. Molecular Pharmacology 2007; 72:1508-21.
- Hegde VL, Venkatesh YP. Anaphylaxis following ingestion of mango fruit. Journal of Investigative Allergology & Clinical Immunology 2007; 17:341-4.
- Jia W, Hegde VL, Singh NP, Sisco D, Grant S, Nagarkatti M, Nagarkatti PS. Delta 9-tetrahydrocannabinol-induced Apoptosis in Jurkat leukemia T Cells is Regulated by Translocation of Bad to Mitochondria Through Disruption of RAF/MEK/ERK/RSK Pathway. Molecular Cancer Research 2006; 4:549-62.
- Camacho IA, Singh N, Hegde VL, Nagarkatti M, Nagarkatti PS. Treatment of mice with 2,3,7,8-tetrachlorodibenzo-p-dioxin leads to aryl hydrocarbon receptor-dependent nuclear translocation of NF-kappaB and expression of Fas ligand in thymic stromal cells and consequent apoptosis in T cells. Journal of Immunology 2005; 175:90-103.
- Do Y, Hegde VL, Nagarkatti PS, Nagarkatti M. Bryostatin-1 enhances the maturation and antigen-presenting ability of murine and human dendritic cells. Cancer Research 2004; 64:6756-65.
- Hegde VL, Venkatesh YP. Anaphylaxis to excipient mannitol: evidence for an immunoglobulin E-mediated mechanism. Clinical and Experimental Allergy 2004; 34:1602-9.
- Venkatesh YP, Hegde VL. A hypothesis for the mechanism of immediate hypersensitivity to mannitol. Allergology International 2003; 52:65-70.
- Hegde VL, Venkatesh YP. Oral allergy syndrome to sapodilla (Achras zapota). Journal of Allergy and Clinical Immunology 2002; 110:533-534.
- Hegde VL, Das JR, Venkatesh YP. Anaphylaxis caused by the ingestion of cultivated mushroom (Agaricus bisporus): Identification of allergen as mannitol. Allergology International 2002; 51:121-130.
- Hegde VL, Mahesh PA, Venkatesh YP. Anaphylaxis Caused by Mannitol in Pomegranate (Punica granatum). Allergy and Clinical Immunology International 2002; 14:37-39.