Strategies using the immune system for therapy of brain tumors.

Phase II immunotherapy and gene therapy studies should be pursued because of encouraging results in many phase I studies. Future testing in this field may consider modifications of some of the above-mentioned combined strategies. For instance, in the immunization and adoptive transfer studies performed by Holladay et al and by Plautz et al, the systemic adoptive transfer could be altered to intratumoral placements of effector cells. This permutation may be more efficacious because local adoptive immunotherapy approaches involve placement of effector cells where they are needed. Additionally, new avenues of gene therapy are being explored that may offer added beneficial effects for immunization, local or systemic adoptive immunotherapy, or combined chemotherapy and adoptive immunotherapy of tumors. With new genetic tools, such as microarray analyses, SEREX, and creation of cDNA libraries from tumor cells, significant progress in the treatment of neoplasms in the immunologically privileged brain should be forthcoming.

Suppression of human IL-1beta, IL-2, IFN-gamma, and TNF-alpha production by cigarette smoke extracts.

BACKGROUND: Although cigarette smoking is known to have detrimental effects on the immune system, the nature of the immunosuppressive agent or agents is poorly understood. OBJECTIVE: The purpose of the current study was to evaluate the effects of cigarette smoke extracts from high-tar (unfiltered Camel), medium-tar (Marlboro), and low-tar (Carlton) cigarettes on the in vitro production of IL-1beta, IL-2, IFN-gamma, and TNF-alpha. METHODS: The concentrations of hydroquinone and catechol in cigarette smoke extracts were determined by using HPLC. Human PBMCs were treated with cigarette smoke extracts, hydroquinone, or catechol, and stimulated with anti-CD3 and phorbol-12-myristate-13-acetate. Cytokine levels in the supernatants were quantified by ELISA. RESULTS: Pretreatment of PBMCs with cigarette smoke extracts derived from a single high- or low-tar cigarette suppressed the production of IL-1beta, IL-2, IFN-gamma, and TNF-alpha by greater than 90% without significant loss of cell viability. Nicotine, at a concentration comparable with that found in the highest-tar cigarettes (200 microg/mL), suppressed the production of IL-2, IFN-gamma, and TNF-alpha by only 21% to 38%. Catechol (50 micromol/L) inhibited production of IL-2 and IL-1beta by 62% to 73% but had little effect on TNF-alpha or IFN-gamma production. In contrast, hydroquinone inhibited the production of all 4 cytokines with IC(50) values ranging from 3 micromol/L(IL-1beta) to 29 micromol/L (IFN-gamma). However, HPLC determination of the hydroquinone concentrations in cigarette smoke extracts from single Camel (33+/-4 micromol/L), Marlboro (13+/-2 micromol/L), and Carlton (<1 micromol/L) cigarettes clearly demonstrated that the potent inhibitory effects of the low-tar cigarettes could not be accounted for by either hydroquinone or catechol. CONCLUSION: These studies indicate that cigarette smoke contains potent inhibitors of cytokine production, at least one of which is present even in low-tar cigarettes.