R Widen

The Effect of Delta-9-Tetrahydrocannabinol and 11-Hydroxy-Delta-9-Tetrahydrocannabinol on T-Lymphocyte and B-Lymphocyte Mitogen Responses

Previous studies have shown that delta-9-tetrahydrocannabinol (THC) suppresses T-lymphocyte proliferation when added to human cell cultures. We report that THC when added to mouse splenocyte cultures suppressed T-lymphocyte (Con A, PHA) and B-lymphocyte (LPS) mitogen-induced proliferation. Although the ED50 concentrations (5 micrograms/ml; 1.6 X 10(-5)M) of THC were similar for suppressing all three mitogen responses, higher threshold concentrations of drug were required to effect suppression of the T-lymphocyte mitogen responses. Complete suppression of T- and B-lymphocyte responses was achieved with THC concentrations (8 micrograms/ml or 2.6 X 10(-5)M) which were not directly toxic as judged by vital dye exclusion. The hydroxylated metabolite of THC, 11-hydroxy-THC, was observed to be much less potent in the inhibition of lymphocyte proliferation. However, as with the parent compound, B-lymphocyte responses appeared to be the most affected by the drug. Additional studies demonstrated that both T- and B-lymphocyte proliferation is rapidly suppressed following THC treatment, not affected by a 24 hr. pretreatment with THC, and not as readily suppressed by THC in cultures containing 20% serum. Thus, THC appears to inhibit both T- and B-lymphocyte proliferation with B-lymphocyte responses displaying greater inhibition at lower drug concentration. The 11-hydroxy metabolite is much less suppressive in this system than the parent compound.

Cocaine suppresses proliferation of phytohemagglutinin-activated human peripheral blood T-cells.

Cocaine has been reported to modulate the immune system of experimental animals. Also, we observed that the drug suppresses the phytohemagglutinin (PHA)-induced proliferation of human peripheral blood mononuclear cells (PBMCs) but at concentrations extremely high relative to those seen in the blood of drug abusers. This suggested that cocaine had a relatively weak effect when tested under conditions of optimum proliferation. We, therefore, decided to examine the effect of lower concentrations of cocaine on suboptimum PHA-induced proliferation. At 0.09-12 microM, cocaine had no effect on the proliferation of PBMC in response to 0.2 micrograms/ml PHA. However, depleting the population of B-cells and monocytes resulted in a drug-induced suppression of the residual T-cells. Maximum suppression by cocaine was observed at 3 microM with both higher and lower concentrations of the drug causing less suppression. Suppression of proliferation was not influenced by either the age or sex of the peripheral blood lymphocytes (PBL) donors. The suppression of T-cell-enriched PBLs induced by cocaine could be eliminated by increasing the dose of the mitogen but was enhanced by preincubating the cells with the drug for 24 h. Also, the drug suppressed cytosolic free calcium mobilization in Fura 2/AM loaded enriched T-cell populations. These results show that cocaine moderately but consistently suppresses PHA-induced proliferation of T-cells from random blood donors at drug concentrations observed in drug abusers. The suppression is only evident under conditions of suboptimum proliferation and is accompanied by a corresponding decrease in the mobilization of cytosolic free calcium. It is suggested that the weak suppressive effect of cocaine is reversed by either helper factors produced by accessory cells or increasing concentrations of mitogen. These factors when present possibly overcome a drug-induced reduction in calcium mobilization and lymphocyte activation.

Delta-9-Tetrahydrocannabiol (THC) decreases the number of high and intermediate affinity IL-2 receptors of the IL-2 dependent cell line NKB61A2

Treatment of the cloned NK-cell line (NKB61A2) with the major psychoactive marijuana component, delta-9-tetrahydrocannabinol (THC), for 24 h suppressed IL-2-induced proliferation of these cells in the cytokine concentration range of 0.25-10 pM suggesting that the drug inhibits the functional activity of the high affinity IL-2R. The proliferation inhibitory effect of THC was accompanied by a decrease in the number of high and intermediate affinity IL-2 binding sites as measured by equilibrium binding studies. However, the expression of Tac protein on the surface of these cells was increased as determined by flow cytometry analysis. THC was also shown to decrease proliferation and the number of IL-2 binding sites of cells previously pulsed with IL-2 and then treated with the drug in the absence of IL-2. These results suggest that THC inhibits IL-2-induced proliferation by modulating the expression of high affinity IL-2 receptors (alpha/beta) required for cell activation and also suppresses the ongoing process of functional receptor expression and clonal expansion of cells previously activated by IL-2. Because the number of intermediate binding sites is decreased following drug treatment along with an increase in the expression of Tac protein (alpha chain), the lowering of high affinity sites possibly results from a drug-induced depression of beta chain expression.