- Email: [email protected]
Role of interferon-γ gene in rheumatoid arthritis?
COMMENTARY
better mass transit, lower emission techniques, and landuse planning to reduce sprawl and encourage cycling and walking.2 New taxes and laws to enable a comprehensive programme of alternatives to driving will not be acceptable unless the public is well informed about the relative benefits and costs. Risk assessments and cost-benefit analyses of air pollution usually end up as lengthy technical reports read by few. Publication of these results in today’s Lancet opens the debate to a wider forum.
Possible allele slippage
Allele
Controls
Cases
130 bp
0
4
128bp
8
10
126bp
8
44
*Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA, and Pan American Health Organization, Mexico DF, Mexico
124bp
44
44
122bp
52
4
1
120bp
0
0
*Stephanie J London, Isabelle Romieu
World Health Organization Regional Office for Europe. Health costs due to road traffic-related air pollution: an impact assessment project of Austria, France and Switzerland. Prepared for the WHO Ministerial Conference on Environment and Health, London 1999. Federal Department of Environment, Transport, Energy and Communications. Bureau for Transport Studies. Bern 1999. http://www.who.dk/london99/transport04.htm 2 Dora C. A different route to health: implications of transport policies. BMJ 1999; 318: 1686–99. 3 Ostro B, Chestnut L. Assessing the health benefits of reducing particulate matter air pollution in the United States. Environ Res 1998; 76: 94–106. 4 Pope CA 3rd, Thun MJ, Namboodiri MM, et al. Particulate air pollution as a predictor of mortality in a prospective study of US adults. Am J Respir Crit Care Med 1995; 151: 669–74. 5 Dockery DW, Pope CA 3rd, Xu X, et al. An association between air pollution and mortality in six US cities. N Engl J Med 1993; 329: 1753–59. 6 Abbey DE, Hwang BL, Burchette RJ, Vancuren T, Mills PK. Estimated long-term ambient concentrations of PM10 and development of respiratory symptoms in a nonsmoking population. Arch Environ Health 1995; 50: 139–52. 7 Burney P. Air pollution and asthma: the dog that doesn’t always bark. Lancet 1999; 353: 859–60. 8 Diaz-Sanchez D, Garcia MP, Wang M, Jyrala M, Saxon A. Nasal challenge with diesel exhaust particles can induce sensitization to a neoallergen in the human mucosa. J Allergy Clin Immunol 1999; 104: 1183–88. 9 Holgate ST, Samet JM, Koren HS, Maynard RL. Air pollution and human health. London: Academic Press, 1999. 10 Guo YL, Lin YC, Sung FC, et al. Climate, traffic-related air pollutants, and asthma prevalence in middle-school children in Taiwan. Environ Health Perspect 1999; 107: 1001–06. 11 Arbour NC, Lorenz E, Schutte BC, et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 2000; 25: 187–91. 12 Ohtsuka Y, Brunson KJ, Jedlicka AE, et al. Genetic linkage analysis of susceptibility to particle exposure in mice. Am J Respir Cell Mol Biol 2000; 22: 574–81.
Role of interferon- gene in rheumatoid arthritis? See page 820 The genetic component of rheumatoid arthritis is estimated to account for some 60% of disease susceptibility, although until recently individual genetic factors have resisted identification and characterisation.1 An early exception was the association of HLA with rheumatoid arthritis described some 25 years ago.2 Current thinking is that HLA is associated more with disease severity or progression rather than initial susceptibility,3 but its mode of action remains unclear.4 The overall contribution of HLA to rheumatoid arthritis has been estimated to account for only a third of the total genetic component.1 Thus the bulk of genetic susceptibility has yet to be identified. It is expected to be the result of accumulated effects of multiple genes for susceptibility to rheumatoid arthritis, each one having a smaller effect than that attributed to HLA. This size of effect seems to be the case for those genes already
THE LANCET • Vol 356 • September 2, 2000
implicated in rheumatoid arthritis.5–7 The study by A Khani-Hanjari and colleagues published in today’s Lancet is therefore surprising because it reports a significant and strong association of an intronic microsatellite marker in the interferon (IFN)- gene with rheumatoid arthritis. The presence of the 126 base-pair allele confers an almost 20-fold increased risk of severe rheumatoid arthritis, which is greater than that already observed with HLA (odds ratios for HLA and severe rheumatoid arthritis usually range from 5 to 10). The genetics of rheumatoid arthritis can be investigated by use of methods based on linkage or association. Linkage analysis can be done only in families in which cosegregation of disease and susceptibiliy gene can be assessed. Linkage analyses, such as those using affectedsibling pairs, are extremely robust but rather insensitive methods for detecting weak genetic effects. They have been used for whole-genome scans, when the genome is systematically examined for linkage without an a priori hypothesis of what and where susceptibility genes will reside. An alternative approach is to use linkage to test candidate genes for rheumatoid arthritis as suggested from the aetiopathogenesis of the disorder. Linkage, however, can be detected over a long genetic distance and, even when it is identified, further studies are required to fine-map and resolve the disease-causing mutation(s). Association studies are more popular than linkage analysis because they are done at the population level and in a case-control setting, to compare the frequency of marker alleles between affected and unaffected individuals. They can be used to test only known candidate genes. Association studies have the advantage of being sensitive (ie, able to detect small genetic effects) but are also prone to generating false-positive associations. The literature is littered with reports of associations that cannot be replicated. It is therefore important for the findings of Khani-Hanji and colleagues to be replicated independently in data sets of sufficient size to provide adequate statistical power. Spurious associations can occur when inappropriate matching of cases and controls causes population stratification. Family-based association methods, such as the transmission disequilibrium test (TDT), can circumvent this problem by using information on parental genotype to create an internal control for comparison. Confirmation of the association reported by Khani-Hanji and colleagues by TDT analysis of simplex families is therefore highly advisable, if not essential. Khani-Hanji and colleagues examined a microsatellite repeat marker in interferon (IFN)- to test for association. Microsatellite alleles are technically more difficult to 783
For personal use only. Not to be reproduced without permission of The Lancet.
COMMENTARY
assign in association studies than in family studies and extreme care must be taken to avoid “allele slippage”. Precautionary steps include random allocation of case and control samples onto electrophoresis gels and inclusion of the same genotype “standards” on all gels. Although the investigators report that great care was taken to assign alleles correctly, examination of their frequencies suggests that their allele calling could have slipped by one position, which would have led to major “differences” between cases and controls (panel). Many groups now favour the use of biallelic singlenucleotide polymorphisms for association studies. There are at least two single-nucleotide polymorphisms in the IFN- gene, and these would be appropriate for examining and confirming the association described. Other studies have previously examined both the chromosomal region containing the IFN- gene by use of linkage, both in a whole-genome scan of European rheumatoid-arthritis families8 and in candidate studies of UK rheumatoid-arthritis families.9 In the former there was no suggestion of linkage around the region of chromosome 12q24. In the latter,9 the investigators used exactly the same microsatellite marker as did Khani-Hanji and colleagues to analyse 200 rheumatoid-arthritis families with affected-sibling pairs. No evidence for linkage with IFN- was observed in the total data set (lod score=0·39, p=NS). Stratification of this data set suggested linkage of marginal significance only in pairs in which both members were not female (ie, male/male and male/female) (lod=0·96, p=0·03). This finding could not be confirmed by TDT analysis, although a subsequent association study testing IFN- single-nucleotide polymorphisms in 165 men with rheumatoid arthritis and 176 controls gave an OR of 1·8 (95% CI 1·0–3·1) (unpublished). In view of what is suspected about the role of T cells in rheumatoid arthritis, IFN- remains an important candidate gene and its involvement as a susceptibility factor cannot as yet be ruled in or out. Although when taken at face value the observations of Khani-Hanji and colleagues seem interesting, they should still be treated with caution until independently confirmed by other analyses. W E R Ollier ARC Epidemiology Unit, Manchester University Medical School, Manchester, M13 9PT, UK 1 2 3 4
5
6
7
8
9
Ollier W, Worthington J. Small fish in a big pond. Br J Rheumatol 1997; 36: 931–34. Stastny P. Association of B cell alloantigen DRw4 with rheumatoid arthritis. N Engl J Med 1978; 298: 869–71. Ollier WER, MacGregor A. Genetic epidemiology of rheumatic disease. Br Med Bull 1995; 51: 267–85. Ollier WER, Hajeer A. Does the HLA-DRB1 shared epitope really contribute that much to the development or severity of rheumatoid arthritis? In: Isenberg DA, Tucker LB, eds. Controversies in rheumatology. London: Martin Dunitz, 1997: 1–9. Cox A, Camp NJ, Cannings C, et al. Combined sib TDT and TDT provide evidence for linkage of the interleukin-1 gene cluster to erosive rheumatoid arthritis. Hum Molec Genet 1999; 8: 1707–13. Fife M, Fisher SA, John S, et al. Multipoint linkage analysis of a candidate gene locus in rheumatoid arthritis: significant evidence of linkage and association with the CRH genomic region. Arthritis Rheum (in press). John S, Myerscough A, Silman AJ, Ollier W, Worthington J. Linkage of a marker in intron D of oestrogen synthase to rheumatoid arthritis. Arthritis Rheum 1999; 42: 1617–20. Cornelius F, Faure S, Martinez M, et al. New susceptibility locus for rheumatoid arthritis suggested by genome-wide linkage study. Proc Natl Acad Sci USA 1998; 95: 10746–50. John S, Myerscough A, Marlow A, et al. Linkage of cytokine genes to rheumatoid arthritis: evidence of genetic heterogenecity. Arthritis Rheum 1998; 57: 361–65.
784
Immunotherapy in hepatocellular carcinoma See page 802 Most cases of hepatocellular carcinoma (HCC) present late, in the context of cirrhosis and with symptoms, and have a very poor prognosis. For now surgery offers the only chance of cure, either by curative tumour resection or orthotopic liver transplantation. Curative resection is not possible for the many patients with poor hepatic reserve, or large or multiple tumours. The recurrence rate remains high after tumour resection. The 5-year survival rate in one centre was 57% for resected lesions of more than 5 cm in diameter and 32% for tumours greater than 10 cm.1 Chemotherapy and tumour embolisation are at best palliative, with no impact on survival or longevity. The challenge is thus to find novel approaches to the treatment of HCC, such as immunotherapy. Adoptive immunotherapy, the reinfusion of activated effector lymphocytes or dendritic cells into the patient, has been used with some success for tumours associated with an inflammatory or immune response, such as melanoma and renal-cell carcinoma.2 HCC resembles these tumours in many respects. Persistent expression of class 1 MHC antigens on tumour cells and an active recruitment of lymphocytes infiltrating the tumour parenchyma indicate the potential for cytotoxic effector-cell activation.3 In today’s Lancet, Tadatoshi Takayama and colleagues offer evidence that adoptive immunotherapy has potential in HCC and provide further evidence that immune mechanisms are important. They activated peripheral blood lymphocytes from patients undergoing resection for HCC with interleukin-2 and OKT3 to generate a pool of effector cells that they hoped would contain cells with antitumour activity. The effects of multiple intravenous infusions of autologous lymphocytes after curative resection were compared with resection alone in a randomised-controlled trial. Adoptive immunotherapy reduced tumour recurrence by 41%. How these IL-2 and OKT3 stimulated lymphocytes produced this effect is not known. Exposure to these conditions favours the growth of non-specific lymphokineactivated killer (LAK) cells,4 so the pool of stimulated cells is likely to contain few antigen-specific cytotoxic T lymphocytes. Nevertheless, the ability of adoptive therapy to reduce tumour recurrence substantially without serious side-effects is extremely encouraging and suggests that more refined approaches based on generation of tumourspecific responses will be even more effective. Recent developments in the understanding of the molecular mechanisms governing the presentation of antigens and the stimulation of cell-mediated immunity have revolutionised approaches to cancer immunotherapy. Thus, the identification of tumour-associated antigens and their HLA-restricted epitopes,5 together with an appreciation of the role of dendritic cells in orchestrating immune responses, continues to spawn a range of novel clinical trials in cancer patients. The main test-bed for these approaches is melanoma,6 for which the discovery of melanoma antigens such as MAGE-1, gp100, and MART-1 has provided the rationale for either peptidebased cancer vaccines7 or the use of antigen-pulsed autologous dendritic cells to promote the generation of antigen-specific cytotosic T lymphocytes in vivo.8 Although there is some way to go before HCC-specific antigens are identified, the demonstration of MAGE-1 on some HCCs and the identification of HLA-restricted epitopes in other HCC-associated antigens (AFP, NY-ESO-1)9 lends credence to the hope that tumour immunology will enable
THE LANCET • Vol 356 • September 2, 2000
For personal use only. Not to be reproduced without permission of The Lancet.
better mass transit, lower emission techniques, and landuse planning to reduce sprawl and encourage cycling and walking.2 New taxes and laws to enable a comprehensive programme of alternatives to driving will not be acceptable unless the public is well informed about the relative benefits and costs. Risk assessments and cost-benefit analyses of air pollution usually end up as lengthy technical reports read by few. Publication of these results in today’s Lancet opens the debate to a wider forum.
Possible allele slippage
Allele
Controls
Cases
130 bp
0
4
128bp
8
10
126bp
8
44
*Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA, and Pan American Health Organization, Mexico DF, Mexico
124bp
44
44
122bp
52
4
1
120bp
0
0
*Stephanie J London, Isabelle Romieu
World Health Organization Regional Office for Europe. Health costs due to road traffic-related air pollution: an impact assessment project of Austria, France and Switzerland. Prepared for the WHO Ministerial Conference on Environment and Health, London 1999. Federal Department of Environment, Transport, Energy and Communications. Bureau for Transport Studies. Bern 1999. http://www.who.dk/london99/transport04.htm 2 Dora C. A different route to health: implications of transport policies. BMJ 1999; 318: 1686–99. 3 Ostro B, Chestnut L. Assessing the health benefits of reducing particulate matter air pollution in the United States. Environ Res 1998; 76: 94–106. 4 Pope CA 3rd, Thun MJ, Namboodiri MM, et al. Particulate air pollution as a predictor of mortality in a prospective study of US adults. Am J Respir Crit Care Med 1995; 151: 669–74. 5 Dockery DW, Pope CA 3rd, Xu X, et al. An association between air pollution and mortality in six US cities. N Engl J Med 1993; 329: 1753–59. 6 Abbey DE, Hwang BL, Burchette RJ, Vancuren T, Mills PK. Estimated long-term ambient concentrations of PM10 and development of respiratory symptoms in a nonsmoking population. Arch Environ Health 1995; 50: 139–52. 7 Burney P. Air pollution and asthma: the dog that doesn’t always bark. Lancet 1999; 353: 859–60. 8 Diaz-Sanchez D, Garcia MP, Wang M, Jyrala M, Saxon A. Nasal challenge with diesel exhaust particles can induce sensitization to a neoallergen in the human mucosa. J Allergy Clin Immunol 1999; 104: 1183–88. 9 Holgate ST, Samet JM, Koren HS, Maynard RL. Air pollution and human health. London: Academic Press, 1999. 10 Guo YL, Lin YC, Sung FC, et al. Climate, traffic-related air pollutants, and asthma prevalence in middle-school children in Taiwan. Environ Health Perspect 1999; 107: 1001–06. 11 Arbour NC, Lorenz E, Schutte BC, et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 2000; 25: 187–91. 12 Ohtsuka Y, Brunson KJ, Jedlicka AE, et al. Genetic linkage analysis of susceptibility to particle exposure in mice. Am J Respir Cell Mol Biol 2000; 22: 574–81.
Role of interferon- gene in rheumatoid arthritis? See page 820 The genetic component of rheumatoid arthritis is estimated to account for some 60% of disease susceptibility, although until recently individual genetic factors have resisted identification and characterisation.1 An early exception was the association of HLA with rheumatoid arthritis described some 25 years ago.2 Current thinking is that HLA is associated more with disease severity or progression rather than initial susceptibility,3 but its mode of action remains unclear.4 The overall contribution of HLA to rheumatoid arthritis has been estimated to account for only a third of the total genetic component.1 Thus the bulk of genetic susceptibility has yet to be identified. It is expected to be the result of accumulated effects of multiple genes for susceptibility to rheumatoid arthritis, each one having a smaller effect than that attributed to HLA. This size of effect seems to be the case for those genes already
THE LANCET • Vol 356 • September 2, 2000
implicated in rheumatoid arthritis.5–7 The study by A Khani-Hanjari and colleagues published in today’s Lancet is therefore surprising because it reports a significant and strong association of an intronic microsatellite marker in the interferon (IFN)- gene with rheumatoid arthritis. The presence of the 126 base-pair allele confers an almost 20-fold increased risk of severe rheumatoid arthritis, which is greater than that already observed with HLA (odds ratios for HLA and severe rheumatoid arthritis usually range from 5 to 10). The genetics of rheumatoid arthritis can be investigated by use of methods based on linkage or association. Linkage analysis can be done only in families in which cosegregation of disease and susceptibiliy gene can be assessed. Linkage analyses, such as those using affectedsibling pairs, are extremely robust but rather insensitive methods for detecting weak genetic effects. They have been used for whole-genome scans, when the genome is systematically examined for linkage without an a priori hypothesis of what and where susceptibility genes will reside. An alternative approach is to use linkage to test candidate genes for rheumatoid arthritis as suggested from the aetiopathogenesis of the disorder. Linkage, however, can be detected over a long genetic distance and, even when it is identified, further studies are required to fine-map and resolve the disease-causing mutation(s). Association studies are more popular than linkage analysis because they are done at the population level and in a case-control setting, to compare the frequency of marker alleles between affected and unaffected individuals. They can be used to test only known candidate genes. Association studies have the advantage of being sensitive (ie, able to detect small genetic effects) but are also prone to generating false-positive associations. The literature is littered with reports of associations that cannot be replicated. It is therefore important for the findings of Khani-Hanji and colleagues to be replicated independently in data sets of sufficient size to provide adequate statistical power. Spurious associations can occur when inappropriate matching of cases and controls causes population stratification. Family-based association methods, such as the transmission disequilibrium test (TDT), can circumvent this problem by using information on parental genotype to create an internal control for comparison. Confirmation of the association reported by Khani-Hanji and colleagues by TDT analysis of simplex families is therefore highly advisable, if not essential. Khani-Hanji and colleagues examined a microsatellite repeat marker in interferon (IFN)- to test for association. Microsatellite alleles are technically more difficult to 783
For personal use only. Not to be reproduced without permission of The Lancet.
COMMENTARY
assign in association studies than in family studies and extreme care must be taken to avoid “allele slippage”. Precautionary steps include random allocation of case and control samples onto electrophoresis gels and inclusion of the same genotype “standards” on all gels. Although the investigators report that great care was taken to assign alleles correctly, examination of their frequencies suggests that their allele calling could have slipped by one position, which would have led to major “differences” between cases and controls (panel). Many groups now favour the use of biallelic singlenucleotide polymorphisms for association studies. There are at least two single-nucleotide polymorphisms in the IFN- gene, and these would be appropriate for examining and confirming the association described. Other studies have previously examined both the chromosomal region containing the IFN- gene by use of linkage, both in a whole-genome scan of European rheumatoid-arthritis families8 and in candidate studies of UK rheumatoid-arthritis families.9 In the former there was no suggestion of linkage around the region of chromosome 12q24. In the latter,9 the investigators used exactly the same microsatellite marker as did Khani-Hanji and colleagues to analyse 200 rheumatoid-arthritis families with affected-sibling pairs. No evidence for linkage with IFN- was observed in the total data set (lod score=0·39, p=NS). Stratification of this data set suggested linkage of marginal significance only in pairs in which both members were not female (ie, male/male and male/female) (lod=0·96, p=0·03). This finding could not be confirmed by TDT analysis, although a subsequent association study testing IFN- single-nucleotide polymorphisms in 165 men with rheumatoid arthritis and 176 controls gave an OR of 1·8 (95% CI 1·0–3·1) (unpublished). In view of what is suspected about the role of T cells in rheumatoid arthritis, IFN- remains an important candidate gene and its involvement as a susceptibility factor cannot as yet be ruled in or out. Although when taken at face value the observations of Khani-Hanji and colleagues seem interesting, they should still be treated with caution until independently confirmed by other analyses. W E R Ollier ARC Epidemiology Unit, Manchester University Medical School, Manchester, M13 9PT, UK 1 2 3 4
5
6
7
8
9
Ollier W, Worthington J. Small fish in a big pond. Br J Rheumatol 1997; 36: 931–34. Stastny P. Association of B cell alloantigen DRw4 with rheumatoid arthritis. N Engl J Med 1978; 298: 869–71. Ollier WER, MacGregor A. Genetic epidemiology of rheumatic disease. Br Med Bull 1995; 51: 267–85. Ollier WER, Hajeer A. Does the HLA-DRB1 shared epitope really contribute that much to the development or severity of rheumatoid arthritis? In: Isenberg DA, Tucker LB, eds. Controversies in rheumatology. London: Martin Dunitz, 1997: 1–9. Cox A, Camp NJ, Cannings C, et al. Combined sib TDT and TDT provide evidence for linkage of the interleukin-1 gene cluster to erosive rheumatoid arthritis. Hum Molec Genet 1999; 8: 1707–13. Fife M, Fisher SA, John S, et al. Multipoint linkage analysis of a candidate gene locus in rheumatoid arthritis: significant evidence of linkage and association with the CRH genomic region. Arthritis Rheum (in press). John S, Myerscough A, Silman AJ, Ollier W, Worthington J. Linkage of a marker in intron D of oestrogen synthase to rheumatoid arthritis. Arthritis Rheum 1999; 42: 1617–20. Cornelius F, Faure S, Martinez M, et al. New susceptibility locus for rheumatoid arthritis suggested by genome-wide linkage study. Proc Natl Acad Sci USA 1998; 95: 10746–50. John S, Myerscough A, Marlow A, et al. Linkage of cytokine genes to rheumatoid arthritis: evidence of genetic heterogenecity. Arthritis Rheum 1998; 57: 361–65.
784
Immunotherapy in hepatocellular carcinoma See page 802 Most cases of hepatocellular carcinoma (HCC) present late, in the context of cirrhosis and with symptoms, and have a very poor prognosis. For now surgery offers the only chance of cure, either by curative tumour resection or orthotopic liver transplantation. Curative resection is not possible for the many patients with poor hepatic reserve, or large or multiple tumours. The recurrence rate remains high after tumour resection. The 5-year survival rate in one centre was 57% for resected lesions of more than 5 cm in diameter and 32% for tumours greater than 10 cm.1 Chemotherapy and tumour embolisation are at best palliative, with no impact on survival or longevity. The challenge is thus to find novel approaches to the treatment of HCC, such as immunotherapy. Adoptive immunotherapy, the reinfusion of activated effector lymphocytes or dendritic cells into the patient, has been used with some success for tumours associated with an inflammatory or immune response, such as melanoma and renal-cell carcinoma.2 HCC resembles these tumours in many respects. Persistent expression of class 1 MHC antigens on tumour cells and an active recruitment of lymphocytes infiltrating the tumour parenchyma indicate the potential for cytotoxic effector-cell activation.3 In today’s Lancet, Tadatoshi Takayama and colleagues offer evidence that adoptive immunotherapy has potential in HCC and provide further evidence that immune mechanisms are important. They activated peripheral blood lymphocytes from patients undergoing resection for HCC with interleukin-2 and OKT3 to generate a pool of effector cells that they hoped would contain cells with antitumour activity. The effects of multiple intravenous infusions of autologous lymphocytes after curative resection were compared with resection alone in a randomised-controlled trial. Adoptive immunotherapy reduced tumour recurrence by 41%. How these IL-2 and OKT3 stimulated lymphocytes produced this effect is not known. Exposure to these conditions favours the growth of non-specific lymphokineactivated killer (LAK) cells,4 so the pool of stimulated cells is likely to contain few antigen-specific cytotoxic T lymphocytes. Nevertheless, the ability of adoptive therapy to reduce tumour recurrence substantially without serious side-effects is extremely encouraging and suggests that more refined approaches based on generation of tumourspecific responses will be even more effective. Recent developments in the understanding of the molecular mechanisms governing the presentation of antigens and the stimulation of cell-mediated immunity have revolutionised approaches to cancer immunotherapy. Thus, the identification of tumour-associated antigens and their HLA-restricted epitopes,5 together with an appreciation of the role of dendritic cells in orchestrating immune responses, continues to spawn a range of novel clinical trials in cancer patients. The main test-bed for these approaches is melanoma,6 for which the discovery of melanoma antigens such as MAGE-1, gp100, and MART-1 has provided the rationale for either peptidebased cancer vaccines7 or the use of antigen-pulsed autologous dendritic cells to promote the generation of antigen-specific cytotosic T lymphocytes in vivo.8 Although there is some way to go before HCC-specific antigens are identified, the demonstration of MAGE-1 on some HCCs and the identification of HLA-restricted epitopes in other HCC-associated antigens (AFP, NY-ESO-1)9 lends credence to the hope that tumour immunology will enable
THE LANCET • Vol 356 • September 2, 2000
For personal use only. Not to be reproduced without permission of The Lancet.