Klein T W, Kawakami Y, Newton C, Friedman H
University of South Florida College of Medicine, Tampa 33612.
J Toxicol Environ Health. 1991 Apr;32(4):465-77. doi: 10.1080/15287399109531496.
Killer lymphocytes play a major role in host defense against tumors and infectious diseases. Previously, we reported that delta-9-tetrahydrocannabinol (THC) and II-hydroxy-delta-9-tetrahydrocannabinol (II-hydroxy-THC) suppressed the cytolytic activity of cultured natural killer (NK) cells. Also, we showed that the drugs appeared to be affecting a stage in the killing process subsequent to the binding of the killer cell to the target cell. In the present report, we have extended these studies to an examination of the effect of cannabinoids on the activity of cytotoxic T lymphocytes (CTLs). The cytolytic activity of CTLs generated by cocultivation with either allospecific stimulators or TNP-modified-self stimulators were suppressed by both THC and II-hydroxy-THC treatment. Allospecific CTLs generated in vivo were also inhibited by an in vitro exposure to either THC or II-hydroxy-THC, and the sensitivity of these cells to drug effects appeared to be greater than the sensitivity of the in vitro generated CTLs. Suppression of cytolytic function by THC and II-hydroxy-THC was maximal after a 4-h drug treatment, suggesting that the drug effects were inducible and therefore required a finite period of time to develop maximally. As seen in previous studies involving NK cells, drug treatment of mature CTLs appears to have little effect on the binding capacity of these cells for the target. However, the maximal killing capacity of the cells and the frequency of CTLs were significantly reduced by drug treatment. In addition to suppressing the cytolytic activity of mature effector CTLs, we also show that drug treatment inhibits both the proliferation of lymphocytes responding to an allogeneic stimulus and the maturation of these lymphocytes to mature CTLs. Similarly, CTL activity developing in vivo could be inhibited by THC injection. These results suggest that CTLs are inhibited by cannabinoids by at least two mechanisms. First, the cytolytic activity of mature killers is suppressed at some point beyond the binding to the target cell. Second, the cannabinoids appear to suppress the normal development of these mature effector cells from less mature precursor cells.
杀伤性淋巴细胞在宿主抵御肿瘤和传染病中发挥着重要作用。此前，我们报道过δ-9-四氢大麻酚（THC）和11-羟基-δ-9-四氢大麻酚（11-羟基-THC）会抑制培养的自然杀伤（NK）细胞的细胞溶解活性。此外，我们还表明这些药物似乎影响杀伤细胞与靶细胞结合后的杀伤过程中的一个阶段。在本报告中，我们将这些研究扩展至考察大麻素对细胞毒性T淋巴细胞（CTL）活性的影响。与同种异体特异性刺激物或三硝基苯修饰的自身刺激物共培养产生的CTL的细胞溶解活性，在经THC和11-羟基-THC处理后均受到抑制。体内产生的同种异体特异性CTL在体外暴露于THC或11-羟基-THC时也会受到抑制，并且这些细胞对药物作用的敏感性似乎高于体外产生的CTL的敏感性。THC和11-羟基-THC对细胞溶解功能的抑制在4小时药物处理后达到最大，这表明药物作用是可诱导的，因此需要一段有限的时间才能达到最大程度的发展。正如在先前涉及NK细胞的研究中所见，对成熟CTL进行药物处理似乎对这些细胞与靶标的结合能力影响很小。然而，药物处理显著降低了细胞的最大杀伤能力和CTL的频率。除了抑制成熟效应CTL的细胞溶解活性外，我们还表明药物处理会抑制对同种异体刺激作出反应的淋巴细胞的增殖以及这些淋巴细胞向成熟CTL的成熟过程。同样，体内发育的CTL活性可被注射THC抑制。这些结果表明，CTL受到大麻素的抑制至少有两种机制。首先，成熟杀伤细胞的细胞溶解活性在与靶细胞结合后的某个点受到抑制。其次，大麻素似乎抑制了这些成熟效应细胞从较不成熟的前体细胞的正常发育。
