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PERFORIN AND LEUCOCYTE CYTOTOXICITY IN MAN
1036
EUROPE AGAINST FOR CANCER
Many people will be shocked to learn that the Commission of the European Communities is actively involved in subsidising tobacco production: Dean’ lately noted that the EC "spends 5 million a year campaigning against smoking but subsidises its tobacco growers to the tune of C740 million". These subsidies dwarf the financial commitment of the EC to cancer prevention and create doubt about its political commitment to this goal. Joossens, in his presentation to the First European Advanced Summer School in Addictions last month, showed that overall tobacco production increased in Europe as did the subsidy level to the industry. Thus 411 017 tons of tobacco were produced in 1989 compared with 353 726 in 1981, and subsidies rose from 671-3 million European currency units (ecu) to 1138-8 million in the period 1983-1989. This represents a subsidy of c2 million a day. When the EC Commission introduced subsidies in 1970 the aims included expansion of tobacco production to disadvantaged farming areas and maintenance of an outlet and income for tobacco producers. To implement this policy the Commission devised a system of norm prices, the price the Community would like first processors to pay the growers; premiums, which are paid to first processors as encouragement and compensation to buy EC tobacco which is higher priced than tobacco grown elsewhere; intervention price, which is the subsidy paid to farmers or processors for excess stock; and finally export restitution, which is a refund for anyone exporting tobacco outside the EC to compensate for the lower prices that the product attains on external markets. (To give a comparison, the EC guarantees a price of 3 ecu/kg to exporters for tobacco that may fetch as little as 0-04/kg.) One outcome of this policy is that the number of tobacco-producing countries has increased. In 1970, virtually the sole producers were France and Italy. There
eight producer states, including Germany, Greece, Spain. Thus one of the goals of the Commission seems to have been satisfied. However, these measures were also designed to produce tobacco for the local market and they have essentially failed in this respect. The Commission classified five types of tobacco: (a) grade I-commercially sought-after varieties; (b) grade IIvarieties experiencing temporary difficulties; (c) grade III-varieties well suited to demand from community manufacturers; (d) grade IV-varieties with unreliable external markets; and (e) grade V-varieties undergoing sharp increases in production, which are unwanted locally. Only grade I varieties are in real demand within the EC. Grades IV and V usually require intervention or export restitution; these varieties were responsible for the main burden of subsidies. In 1989, grade I tobacco made up only 29% of total production. 42% of all tobacco produced was exported, the main recipients being Bulgaria, Egypt, and
The cost of the subsidy policy is even higher in terms of its impact on health. 1257 people die each day in Europe from smoking-related diseases and the costs of chronic ill health to the community amount to hundreds of millions of ecus. So, how can the subsidy policy be reconciled with the anti-smoking policy adopted by the EC? The Community has announced a budget for "Europe Against Cancer" of 9 million ecu per annum-[I5 908 per day. This is a token gesture compared with the potential sum of money that could be made available to combat smoking and compared with the number of smoking-related deaths that could be prevented merely by withdrawing financial support for tobacco growing. The World Health Organisation has long been committed to the introduction of fiscal and economic measures against the tobacco industry as a means of discouraging smoking, reducing tobacco production, and promoting less harmful crops.3 The reluctance of governments and the EC to introduce these measures suggests that political and economic interest in tobacco production is more important than the health costs of tobacco. EC protection of this undesirable industry also compounds the effects of the ruthless export of cigarettes to third-world countries by the multinational conglomerates. Much-needed foreign exchange is being lost to poor nations and these countries are becoming the target market for both low and high grade tobacco. ECs policy therefore contributes to the export and promotion of smoking, disease, and loss of wealth in the poor world. If Europe is to reach its WHO Health for All target of a reduction in cancer deaths by 15% in the under 65s,4 the Commission must adopt measures that will support reductions in tobacco smoking and promote health. Financial support for the growth of tobacco in the European region must be abolished.
are now
and
Romania, while 70% of all tobacco consumed in the EC had to be imported. Italy, the main overproducer, exceeded its quota by 1008% in 1989, and the excess mainly consisted of unwanted varieties. This subsidy policy makes no sense on economic grounds. Farmers are encouraged to grow a poor quality product for which no European market exists. They are paid at rates far in excess of the value of the product, which is then sold to the third world and eastern European countries at "dumping" prices. If the system of subsidies is to exist, it would make more sense for the EC to subsidise the growth of more healthy crops.
King Tobacco under attack. Lancet 1990; 336: 865-66. Joossens L. The European Common Agricultural Policy in the tobacco sector. Paper to the First European Advanced Summer School in Addictions, London, 1990. 3. Roener R. Legislative action to combat the world smoking epidemic. Geneva: World Health Organisation, 1986. 4. WHOEURO. Targets for health for all in the European region. Copenhagen: World Health Organisation, 1985. 1. Dean M.
2.
PERFORIN AND LEUCOCYTE CYTOTOXICITY IN MAN Several mononuclear and granulocytic cells produce potent antimicrobial and cytocidal effector molecules that are crucial for host defence but also able to inflict considerable tissue injury. Many experiments have shown that activated cytotoxic T lymphocytes, for example, can kill virusinfected target cells in vitro by contact-dependent release of granule proteins.1 One of these proteins, perforin, forms characteristic pores in the membrane of a wide variety of target cells when 70 kD monomers aggregate in the membrane in the presence of calcium. The presence of pores alters the osmotic equilibrium across the cell membrane, leading to an influx of water and eventually to cell death. Studiesz3in murine lymphocytic choriomeningitis virus infection show that perforin is produced in vivo by cytotoxic T lymphocytes, which are responsible for elimination of infected cells and cure of the disease. In this issue (p 1019) Young et al show conclusively, with the aid of specific antibodies, that perforin is produced by activated
1037
and natural killer cells in acute human lesions presumed to be viral in origin. Membrane lesions in myocardial cells were displayed in endomyocardial biopsy specimens by ultrastructural methods and consisted of 15-20 nm pores that are typical of perforin action. These pores can be distinguished from the 10 nm lesions induced in cellular targets by the membrane attack complex of complement, a distinct but structurally homologous agent of humoral immune lysis. Many questions remain unanswered about the specific signals responsible for recruitment and activation of different effector cells at sites of inflammation, and about the relative contribution of different granule products to target cell lysis. The cellular mechanisms for target recognition4 and precisely controlled local degranulation are worthy of intense studys as is the polarised process of destruction of the target cell without suicidal injury to effector leucocytes.6 Above all, will it be possible to limit destruction of vital cells, as in the myocardium, without compromising the ability of the immune system to eradicate an intracellular infectious agent? The results of Young et al serve to remind physicians that a mononuclear cell infiltrate brings with it a two-edged sword.
lymphocytes myocarditis
1. Young
J Ding-E. Killing of target cells by lymphocytes: a mechanistic Am Physiol Soc 1989; 69: 250-313. 2. Young LHY, Klavinskis LS, Oldstone MBA, et al. In vivo expression of perforin by CD8+ lymphocytes during an acute viral infection. J Exp Med 1989; 169: 2159-71. 3. Muller C, Kagi D, Aebischer T, et al. Detection of perforin and granzyme A mRNA in infiltrating cells during infection of mice with lymphocytic choriomeningitis virus. Eur J Immunol 1989; 19: 1253-59. 4. Townsend A, Bodmer H. Antigen recognition by class I-restricted T lymphocytes. Annu Rev Immunol 1989; 7: 601-24. 5. Kupfer A, Singer SJ. Cell biology of cytotoxic and helper T-cell view.
functions. Annu Rev Immunol 1989; 7: 309-37. 6. Persechini PM, Young J Ding-E, Almers W. Membrane channel formation by the lymphocyte pore-forming protein: comparison between susceptible and resistant target cells. J Cell Biol 1990; 110: 2109-16.
better tolerated than others. Moreover, availability of so many drugs, mere control of hypertension is not enough. Clinicians must not only strive to minimise drug-specific adverse events but also to assess the possible impact of treatment on a patient’s quality of life. Croog and colleagues4 conducted one of the first large studies to assess quality of life; this work was supported by Squibb. Men with mild to moderate hypertension were
although
some are
with the
recruited into a double-blind randomised trial for 6 months to determine the effects of captopril, methyldopa, or propranolol on their quality of life as assessed by interviews throughout the study. Blood pressure control was similar with all three drugs, although some patients needed additional diuretics. Fewer patients withdrew from therapy with captopril because of adverse events. Patients receiving captopril scored better on measures of general wellbeing and had fewer side-effects and better measures of life satisfaction than those receiving methyldopa. Captopril also scored better than propranolol in measures of wellbeing. The subsequent marketing campaign alerted physicians to examine their prescribing practices but also initiated the controversy about the validity of what was measured. The difficulty is how to make a formal objective assessment of the subjective feelings and needs of an individual and obtain results with scientific credibility. Although captopril appeared best in the study by Croog et al4 the trial did not examine, for example, whether patients were troubled by cough, which is now known to affect 15 % of those who take this drug. The tests were confined to patients’ subjective responses, which may not be enough. Jachuck et al5 asked physicians, patients taking antihypertensive drugs, and patients’ relatives or close companions about quality of life.5 In their overall assessment of each patient’s condition, 100% of physicians thought the patient was improved, 48 % of patients thought that they had improved, but 98% of relatives or companions believed that the patients’ quality of life was worse during
therapy. DOING BETTER, FEELING WORSE
hypertension has undergone a remarkable transformation in the past twenty years; prescribers now have a vast number of drugs from which to choose. However, although much time has been spent on defining groups of patients suited to various classes of drug, none of the resulting classifications is satisfactory. If official guidelines are followed, drug treatment should be offered to anyone with a diastolic pressure consistently greater than 100 mg Hg.l In the UK, for example, use of this criterion would net 10-15% of the adult population, and with the Treatment for
emphasis on detection and prevention, more patients than ever are going to be found. The potential market for antihypertensive agents is enormous and pharmaceutical companies know it. One difficulty about treating high blood pressure is that most patients have no symptoms-therapy may cause side-effects in people who previously felt well. In trials of antihypertensive therapy, adverse reactions to drugs have resulted in withdrawal rates of 16-33%.’ Practitioners are often struck by the lower frequency of side-effects when an agent is used for antianginal rather than antihypertensive therapy, but the patient with angina knows when something is working. No antihypertensive drug is without side-effects,
To refine the objective estimates of quality of life, Bulpitt and Fletcher> have now produced a questionnaire for use in short-term trials (less than 1 year) of antihypertensive treatment.6 The questionnaire covers symptomatic (physical) wellbeing, psychological wellbeing with the symptom rating test/ and perception of the effects of antihypertensive treatment on lifestyle. There are 46 questions, most of which require yes/no responses. This approach must represent the most comprehensive attempt so far to obtain useful information about antihypertensive therapy by means of a standardised repeatable format. However, the feelings of relatives are not assessed. The test has been applied in three comparisons of drug treatments7-9 and the results suggest that propranolol causes a deterioration in symptomatic wellbeing and possibly increases depression, whereas nifedipine may adversely affect self-reported cognitive function. In another study, verapamil was compared with nifedipine with regard to effects on quality of life by use of this questionnaire. 10 There was a significant increase in reporting of side-effects with nifedipine, and measures of psychiatric morbidity tended to improve on verapamil and deteriorate on nifedipine. Only the change in cognitive function was significant between the drugs, being worse on nifedipine. Notwithstanding these results, many patients will be satisfied with P-blockers or nifedipine, and the possibility of a modest improvement in cognitive function
EUROPE AGAINST FOR CANCER
Many people will be shocked to learn that the Commission of the European Communities is actively involved in subsidising tobacco production: Dean’ lately noted that the EC "spends 5 million a year campaigning against smoking but subsidises its tobacco growers to the tune of C740 million". These subsidies dwarf the financial commitment of the EC to cancer prevention and create doubt about its political commitment to this goal. Joossens, in his presentation to the First European Advanced Summer School in Addictions last month, showed that overall tobacco production increased in Europe as did the subsidy level to the industry. Thus 411 017 tons of tobacco were produced in 1989 compared with 353 726 in 1981, and subsidies rose from 671-3 million European currency units (ecu) to 1138-8 million in the period 1983-1989. This represents a subsidy of c2 million a day. When the EC Commission introduced subsidies in 1970 the aims included expansion of tobacco production to disadvantaged farming areas and maintenance of an outlet and income for tobacco producers. To implement this policy the Commission devised a system of norm prices, the price the Community would like first processors to pay the growers; premiums, which are paid to first processors as encouragement and compensation to buy EC tobacco which is higher priced than tobacco grown elsewhere; intervention price, which is the subsidy paid to farmers or processors for excess stock; and finally export restitution, which is a refund for anyone exporting tobacco outside the EC to compensate for the lower prices that the product attains on external markets. (To give a comparison, the EC guarantees a price of 3 ecu/kg to exporters for tobacco that may fetch as little as 0-04/kg.) One outcome of this policy is that the number of tobacco-producing countries has increased. In 1970, virtually the sole producers were France and Italy. There
eight producer states, including Germany, Greece, Spain. Thus one of the goals of the Commission seems to have been satisfied. However, these measures were also designed to produce tobacco for the local market and they have essentially failed in this respect. The Commission classified five types of tobacco: (a) grade I-commercially sought-after varieties; (b) grade IIvarieties experiencing temporary difficulties; (c) grade III-varieties well suited to demand from community manufacturers; (d) grade IV-varieties with unreliable external markets; and (e) grade V-varieties undergoing sharp increases in production, which are unwanted locally. Only grade I varieties are in real demand within the EC. Grades IV and V usually require intervention or export restitution; these varieties were responsible for the main burden of subsidies. In 1989, grade I tobacco made up only 29% of total production. 42% of all tobacco produced was exported, the main recipients being Bulgaria, Egypt, and
The cost of the subsidy policy is even higher in terms of its impact on health. 1257 people die each day in Europe from smoking-related diseases and the costs of chronic ill health to the community amount to hundreds of millions of ecus. So, how can the subsidy policy be reconciled with the anti-smoking policy adopted by the EC? The Community has announced a budget for "Europe Against Cancer" of 9 million ecu per annum-[I5 908 per day. This is a token gesture compared with the potential sum of money that could be made available to combat smoking and compared with the number of smoking-related deaths that could be prevented merely by withdrawing financial support for tobacco growing. The World Health Organisation has long been committed to the introduction of fiscal and economic measures against the tobacco industry as a means of discouraging smoking, reducing tobacco production, and promoting less harmful crops.3 The reluctance of governments and the EC to introduce these measures suggests that political and economic interest in tobacco production is more important than the health costs of tobacco. EC protection of this undesirable industry also compounds the effects of the ruthless export of cigarettes to third-world countries by the multinational conglomerates. Much-needed foreign exchange is being lost to poor nations and these countries are becoming the target market for both low and high grade tobacco. ECs policy therefore contributes to the export and promotion of smoking, disease, and loss of wealth in the poor world. If Europe is to reach its WHO Health for All target of a reduction in cancer deaths by 15% in the under 65s,4 the Commission must adopt measures that will support reductions in tobacco smoking and promote health. Financial support for the growth of tobacco in the European region must be abolished.
are now
and
Romania, while 70% of all tobacco consumed in the EC had to be imported. Italy, the main overproducer, exceeded its quota by 1008% in 1989, and the excess mainly consisted of unwanted varieties. This subsidy policy makes no sense on economic grounds. Farmers are encouraged to grow a poor quality product for which no European market exists. They are paid at rates far in excess of the value of the product, which is then sold to the third world and eastern European countries at "dumping" prices. If the system of subsidies is to exist, it would make more sense for the EC to subsidise the growth of more healthy crops.
King Tobacco under attack. Lancet 1990; 336: 865-66. Joossens L. The European Common Agricultural Policy in the tobacco sector. Paper to the First European Advanced Summer School in Addictions, London, 1990. 3. Roener R. Legislative action to combat the world smoking epidemic. Geneva: World Health Organisation, 1986. 4. WHOEURO. Targets for health for all in the European region. Copenhagen: World Health Organisation, 1985. 1. Dean M.
2.
PERFORIN AND LEUCOCYTE CYTOTOXICITY IN MAN Several mononuclear and granulocytic cells produce potent antimicrobial and cytocidal effector molecules that are crucial for host defence but also able to inflict considerable tissue injury. Many experiments have shown that activated cytotoxic T lymphocytes, for example, can kill virusinfected target cells in vitro by contact-dependent release of granule proteins.1 One of these proteins, perforin, forms characteristic pores in the membrane of a wide variety of target cells when 70 kD monomers aggregate in the membrane in the presence of calcium. The presence of pores alters the osmotic equilibrium across the cell membrane, leading to an influx of water and eventually to cell death. Studiesz3in murine lymphocytic choriomeningitis virus infection show that perforin is produced in vivo by cytotoxic T lymphocytes, which are responsible for elimination of infected cells and cure of the disease. In this issue (p 1019) Young et al show conclusively, with the aid of specific antibodies, that perforin is produced by activated
1037
and natural killer cells in acute human lesions presumed to be viral in origin. Membrane lesions in myocardial cells were displayed in endomyocardial biopsy specimens by ultrastructural methods and consisted of 15-20 nm pores that are typical of perforin action. These pores can be distinguished from the 10 nm lesions induced in cellular targets by the membrane attack complex of complement, a distinct but structurally homologous agent of humoral immune lysis. Many questions remain unanswered about the specific signals responsible for recruitment and activation of different effector cells at sites of inflammation, and about the relative contribution of different granule products to target cell lysis. The cellular mechanisms for target recognition4 and precisely controlled local degranulation are worthy of intense studys as is the polarised process of destruction of the target cell without suicidal injury to effector leucocytes.6 Above all, will it be possible to limit destruction of vital cells, as in the myocardium, without compromising the ability of the immune system to eradicate an intracellular infectious agent? The results of Young et al serve to remind physicians that a mononuclear cell infiltrate brings with it a two-edged sword.
lymphocytes myocarditis
1. Young
J Ding-E. Killing of target cells by lymphocytes: a mechanistic Am Physiol Soc 1989; 69: 250-313. 2. Young LHY, Klavinskis LS, Oldstone MBA, et al. In vivo expression of perforin by CD8+ lymphocytes during an acute viral infection. J Exp Med 1989; 169: 2159-71. 3. Muller C, Kagi D, Aebischer T, et al. Detection of perforin and granzyme A mRNA in infiltrating cells during infection of mice with lymphocytic choriomeningitis virus. Eur J Immunol 1989; 19: 1253-59. 4. Townsend A, Bodmer H. Antigen recognition by class I-restricted T lymphocytes. Annu Rev Immunol 1989; 7: 601-24. 5. Kupfer A, Singer SJ. Cell biology of cytotoxic and helper T-cell view.
functions. Annu Rev Immunol 1989; 7: 309-37. 6. Persechini PM, Young J Ding-E, Almers W. Membrane channel formation by the lymphocyte pore-forming protein: comparison between susceptible and resistant target cells. J Cell Biol 1990; 110: 2109-16.
better tolerated than others. Moreover, availability of so many drugs, mere control of hypertension is not enough. Clinicians must not only strive to minimise drug-specific adverse events but also to assess the possible impact of treatment on a patient’s quality of life. Croog and colleagues4 conducted one of the first large studies to assess quality of life; this work was supported by Squibb. Men with mild to moderate hypertension were
although
some are
with the
recruited into a double-blind randomised trial for 6 months to determine the effects of captopril, methyldopa, or propranolol on their quality of life as assessed by interviews throughout the study. Blood pressure control was similar with all three drugs, although some patients needed additional diuretics. Fewer patients withdrew from therapy with captopril because of adverse events. Patients receiving captopril scored better on measures of general wellbeing and had fewer side-effects and better measures of life satisfaction than those receiving methyldopa. Captopril also scored better than propranolol in measures of wellbeing. The subsequent marketing campaign alerted physicians to examine their prescribing practices but also initiated the controversy about the validity of what was measured. The difficulty is how to make a formal objective assessment of the subjective feelings and needs of an individual and obtain results with scientific credibility. Although captopril appeared best in the study by Croog et al4 the trial did not examine, for example, whether patients were troubled by cough, which is now known to affect 15 % of those who take this drug. The tests were confined to patients’ subjective responses, which may not be enough. Jachuck et al5 asked physicians, patients taking antihypertensive drugs, and patients’ relatives or close companions about quality of life.5 In their overall assessment of each patient’s condition, 100% of physicians thought the patient was improved, 48 % of patients thought that they had improved, but 98% of relatives or companions believed that the patients’ quality of life was worse during
therapy. DOING BETTER, FEELING WORSE
hypertension has undergone a remarkable transformation in the past twenty years; prescribers now have a vast number of drugs from which to choose. However, although much time has been spent on defining groups of patients suited to various classes of drug, none of the resulting classifications is satisfactory. If official guidelines are followed, drug treatment should be offered to anyone with a diastolic pressure consistently greater than 100 mg Hg.l In the UK, for example, use of this criterion would net 10-15% of the adult population, and with the Treatment for
emphasis on detection and prevention, more patients than ever are going to be found. The potential market for antihypertensive agents is enormous and pharmaceutical companies know it. One difficulty about treating high blood pressure is that most patients have no symptoms-therapy may cause side-effects in people who previously felt well. In trials of antihypertensive therapy, adverse reactions to drugs have resulted in withdrawal rates of 16-33%.’ Practitioners are often struck by the lower frequency of side-effects when an agent is used for antianginal rather than antihypertensive therapy, but the patient with angina knows when something is working. No antihypertensive drug is without side-effects,
To refine the objective estimates of quality of life, Bulpitt and Fletcher> have now produced a questionnaire for use in short-term trials (less than 1 year) of antihypertensive treatment.6 The questionnaire covers symptomatic (physical) wellbeing, psychological wellbeing with the symptom rating test/ and perception of the effects of antihypertensive treatment on lifestyle. There are 46 questions, most of which require yes/no responses. This approach must represent the most comprehensive attempt so far to obtain useful information about antihypertensive therapy by means of a standardised repeatable format. However, the feelings of relatives are not assessed. The test has been applied in three comparisons of drug treatments7-9 and the results suggest that propranolol causes a deterioration in symptomatic wellbeing and possibly increases depression, whereas nifedipine may adversely affect self-reported cognitive function. In another study, verapamil was compared with nifedipine with regard to effects on quality of life by use of this questionnaire. 10 There was a significant increase in reporting of side-effects with nifedipine, and measures of psychiatric morbidity tended to improve on verapamil and deteriorate on nifedipine. Only the change in cognitive function was significant between the drugs, being worse on nifedipine. Notwithstanding these results, many patients will be satisfied with P-blockers or nifedipine, and the possibility of a modest improvement in cognitive function