Smoking elicit drugs such as marijuana causes immunosuppression and increases the risk of contracting infections particularly in HIV-seropositive individuals. Delta9-tetrahydrocannabinol (THC), the major psychoactive principle marijuana has been identified as a critical immunosuppressive agent, although the mechanism by which it induces toxicity is not clear. Moreover, recreational use of marijuana during pregnancy remains a major health problem and very little is known about the consequences of prenatal exposure to THC on the immune system. Interest in cannabinoid research has increased tremendously in recent years since the discovery of cannabinoid receptors and the endogenous ligands for these receptors. The fact that cannabinoid CB2 receptors are almost exclusively expressed on immune cells raises exciting questions on the role and significance of such receptors and their endogenous ligands in immunoregulation. Recent studies from our laboratory demonstrated that cannabinoids induce apoptosis in lymphoid organs and suppress lymphocyte functions. In the current study, we will investigate the role of apoptosis in cannabinoid-induced immunomodulation following prenatal and postnatal exposure.
In aim1, we will test the hypothesis that THC triggers apoptosis and immunornodulation by binding to CB1 and/or CB2 receptors on immune cells using mice deficient in CB1, CB2, or both CB1/CB2 receptors.
In aim 2, we will test the hypothesis that THC-induced apoptosis is responsible for decreased T cell response to bacterial antigens by using the superantigen model and analyzing antigen-specific Vbeta3+ and Vbetal 1+ T cells.
In aim 3, the mechanism by which THC induces apoptosis in T cells via the death receptor pathway and/or the mitochondrial pathway will be studied using cDNA array and mutant cell lines that are deficient in FADD, caspases and members of bcl-2 gene family.
In aim 4, we will test whether prenatal exposure to THC alters positive and negative selection of T cells in the thymus and thereby affects the T cell repertoire postnatally. Lastly, in aim 5, the hypothesis that endogenous cannabinoids such as an and amide regulate the immune functions by triggering apoptosis using FAAH knockout mice will be tested. In summary, the aims listed above form the basis for understanding the mechanism of induction of apoptosis in immune cells by exogenous and endogenous cannabinoids. These studies are particularly important in understanding how substance abuse by individuals who are at a higher risk for contracting HIV infection, HIV-infected individuals, and HIV-infected pregnant mothers, will influence the course of infection.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA016545-05
Application #
7025924
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Sharp, Charles
Project Start
2003-04-15
Project End
2008-02-29
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
5
Fiscal Year
2006
Total Cost
$236,202
Indirect Cost
Name
University of South Carolina at Columbia
Department
Pathology
Type
Schools of Medicine
DUNS #
041387846
City
Columbia
State
SC
Country
United States
Zip Code
29208
Nagarkatti, Mitzi; Rieder, Sadiye Amcaoglu; Nagarkatti, Prakash S (2018) Evaluation of Cell Proliferation and Apoptosis in Immunotoxicity Testing. Methods Mol Biol 1803:209-230
Ginwala, Rashida; McTish, Emily; Raman, Chander et al. (2016) Apigenin, a Natural Flavonoid, Attenuates EAE Severity Through the Modulation of Dendritic Cell and Other Immune Cell Functions. J Neuroimmune Pharmacol 11:36-47
Singh, Narendra P; Singh, Ugra S; Nagarkatti, Mitzi et al. (2011) Resveratrol (3,5,4'-trihydroxystilbene) protects pregnant mother and fetus from the immunotoxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Mol Nutr Food Res 55:209-19
Ariza, Maria Eugenia; Ramakrishnan, Rupal; Singh, Narendra P et al. (2011) Bryostatin-1, a naturally occurring antineoplastic agent, acts as a Toll-like receptor 4 (TLR-4) ligand and induces unique cytokines and chemokines in dendritic cells. J Biol Chem 286:24-34
Pandey, Rupal; Hegde, Venkatesh L; Nagarkatti, Mitzi et al. (2011) Targeting cannabinoid receptors as a novel approach in the treatment of graft-versus-host disease: evidence from an experimental murine model. J Pharmacol Exp Ther 338:819-28
Lombard, Catherine; Hegde, Venkatesh L; Nagarkatti, Mitzi et al. (2011) Perinatal exposure to ?9-tetrahydrocannabinol triggers profound defects in T cell differentiation and function in fetal and postnatal stages of life, including decreased responsiveness to HIV antigens. J Pharmacol Exp Ther 339:607-17
Zhou, Juhua; Nagarkatti, Prakash S; Zhong, Yin et al. (2011) Implications of single nucleotide polymorphisms in CD44 exon 2 for risk of breast cancer. Eur J Cancer Prev 20:396-402
Hegde, Venkatesh L; Nagarkatti, Prakash S; Nagarkatti, Mitzi (2011) Role of myeloid-derived suppressor cells in amelioration of experimental autoimmune hepatitis following activation of TRPV1 receptors by cannabidiol. PLoS One 6:e18281
Singh, Narendra P; Singh, Udai P; Singh, Balwan et al. (2011) Activation of aryl hydrocarbon receptor (AhR) leads to reciprocal epigenetic regulation of FoxP3 and IL-17 expression and amelioration of experimental colitis. PLoS One 6:e23522
Rieder, Sadiye Amcaoglu; Nagarkatti, Prakash; Nagarkatti, Mitzi (2011) CD1d-independent activation of invariant natural killer T cells by staphylococcal enterotoxin B through major histocompatibility complex class II/T cell receptor interaction results in acute lung injury. Infect Immun 79:3141-8

Showing the most recent 10 out of 46 publications