This is a revised renewal application to study cannabinoid effects on immune responses first funded in this laboratory by NIDA in 1982. We have observed and reported two major findings: (1) THC treatment of mice suppresses resistance to primary and secondary infection with Legionella pneumophila (Lp); (2) the immune changes are associated with drug-induced changes in cytokine mobilization. We propose to study the nature and mechanisms of cannabinoid suppression of host resistance to bacterial infection as well as study the role of cannabinoid receptors in these events.
Aim 1. Using cannabimimetic agents and eicosanoid cascade inhibitors define the role of cannabinoid receptor activity in the THC- induced shift from Th1 protective immunity to Lp infection Th2 nonprotective immunity. In addition, establish by R-PCR and in situ hybridization, if the cannabinoid-induced Th shift is due to changes in lymphoid organ and cellular production of IFNgamma, IL4, IL10, and IL12; also, establish by these methods as well as flow cytometry if tissue cannabinoid receptors are modulated by drug treatment and infection.
Aim 2. Establish the role of TNFalpha, IL6 and IL1alpha hyperproduction in the drug-induced exacerbation of the acute phase inflammatory response to primary Lp infection. In addition, define the relative involvement of cannabinoid receptors and eicosanoid metabolites in the hyperproduction as well as the expression of cannabinoid receptors during the primary infection. We have shown that THC attenuates development of secondary immunity to infection of mice, but amplifies the acute inflammatory response to primary infection with this organism. We hypothesize that THC induces an imbalance in the activity of Th1 versus Th2 helper cells and also results in hyperproduction of acute-phase cytokines IL6, TNFalpha, and IL1. We will examine the imbalance of Th1/Th2 cells which occurs in the infected mice treated with THC by examining the cytokines involved. We further hypothesize that THC effects on immunity are receptor-mediated events. This continuation study of our in vivo infection model using the opportunistic pathogen Legionella and the mechanisms involved will provide new information concerning how marijuana modulates cell-mediated host resistance to a bacterial infection.
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