The overall goal of our research is to define the function of cannabinoid receptors (CBR) on immune cells in human health and diseases such as AIDS. The goal of the current project, however, is more limited and will define the CBR phenotype of the major immune cell subsets and determine in a limited way the potential of these receptors to function in immunomodulation. Limited data currently suggest that CBR subtypes are expressed and functional on immune cells. However, these seminal findings must be confirmed and extended.
In aim 1, we will define the expression pattern of CB1 and CB2 receptor mRNA in purified immune subsets of T cells, B cells, NK cells, and macrophages isolated from mouse spleen. To examine the relationship between cell activity and CBR mRNA expression, mRNA will be measured in either freshly isolated cells (basal activity) or in cells activated by mitogens.
In aim 2, we will extend the aim 1 data by using radioligand binding studies and flow cytometry to probe for cannabinoid binding sites and receptor proteins on the surface of immune cell subsets under basal and stimulated conditions of cell activity. The studies in aims 1 and 2 will test the hypothesis that immune cell subsets have a distinct CB1/CB2 phenotype which is subject to change following cell activation.
In aim 3, we will determine the potential of CBR to mediate cannabinoid-induced immunomodulation or normal immune homeostasis. This will be done by testing if CBR positive immune cells are modulated in a receptor selective manner using either cannabinoid agonists or antagonists. Mitogen-induced T cell, B cell, and NK cell proliferation and TNF production by macrophages will be analyzed in the presence of cannabinoid agonists and antagonists and the structure/activity relationship and agonist potencies will be determined and related to the CBR phenotype. Mitogen-induced immune cell responses will also be tested in the presence of CBR antagonists only to determine the involvement of the receptors in immune cell responses.
Aim 3 experiments will test the hypothesis that CBR on immune cells mediate cannabinoid-induced immunomodulation as well as normal immune homeostasis. The experiments proposed in this application will increase our understanding of CBR immunobiology and the biology of the brain/immune axis, both of which are new and important issues in human health and disease. These studies will also shed light on the health consequences of marijuana use and on the potential use of CBR agonists and antagonists as immunomodulators and regulators of immunity and inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA010683-01A2
Application #
2542568
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Sharp, Charles
Project Start
1998-02-15
Project End
2001-01-31
Budget Start
1998-02-15
Budget End
1999-01-31
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of South Florida
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Tampa
State
FL
Country
United States
Zip Code
33612
Newton, Catherine A; Chou, Ping-Jen; Perkins, Izabella et al. (2009) CB(1) and CB(2) cannabinoid receptors mediate different aspects of delta-9-tetrahydrocannabinol (THC)-induced T helper cell shift following immune activation by Legionella pneumophila infection. J Neuroimmune Pharmacol 4:92-102
Mamata, Yukimitsu; Hakki, Amal; Newton, Catherine et al. (2007) Differential effects of Chlamydia pneumoniae infection on cytokine levels in human T lymphocyte- and monocyte-derived cell cultures. Int J Med Microbiol 297:109-15
Lu, Tangying; Newton, Cathy; Perkins, Izabella et al. (2006) Cannabinoid treatment suppresses the T-helper cell-polarizing function of mouse dendritic cells stimulated with Legionella pneumophila infection. J Pharmacol Exp Ther 319:269-76
Lu, Tangying; Newton, Cathy; Perkins, Izabella et al. (2006) Role of cannabinoid receptors in Delta-9-tetrahydrocannabinol suppression of IL-12p40 in mouse bone marrow-derived dendritic cells infected with Legionella pneumophila. Eur J Pharmacol 532:170-7
Medveczky, Maria M; Sherwood, Tracy A; Klein, Thomas W et al. (2004) Delta-9 tetrahydrocannabinol (THC) inhibits lytic replication of gamma oncogenic herpesviruses in vitro. BMC Med 2:34
Klein, Thomas W; Newton, Cathy; Larsen, Kellie et al. (2004) Cannabinoid receptors and T helper cells. J Neuroimmunol 147:91-4
Friedman, Herman; Newton, Catherine; Klein, Thomas W (2003) Microbial infections, immunomodulation, and drugs of abuse. Clin Microbiol Rev 16:209-19
Nong, Liang; Newton, Catherine; Cheng, Qingwen et al. (2002) Altered cannabinoid receptor mRNA expression in peripheral blood mononuclear cells from marijuana smokers. J Neuroimmunol 127:169-76
Lee, S F; Newton, C; Widen, R et al. (2001) Differential expression of cannabinoid CB(2) receptor mRNA in mouse immune cell subpopulations and following B cell stimulation. Eur J Pharmacol 423:235-41
Noe, S N; Newton, C; Widen, R et al. (2001) Modulation of CB1 mRNA upon activation of murine splenocytes. Adv Exp Med Biol 493:215-21

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