411
that the immune system reacts to its own products too.l For example, mice injected with a homogeneous mouse antibody (of a single antigen-binding specificity) respond by making antibodies to the antigen-binding site.2 Such antibodies are called anti-idiotype antibodies3 and they react with the injected antibody as though they were antigen. Under certain circumstances anti-idiotype antibodies can even substitute for antigen in eliciting an immune response to the homologous antigen,4 suggesting that the shape of the antigen-binding site reproduces that of the antigen. Mice make antiidiotype antibodies to the antibodies they make to injected antigens, and jERNE’s network hypothesis5 proposes that sequential antibody-anti-idiotype responses exert negative feedback on the immune response. There is evidence that anti-idiotype recog-
nition contributes to the control of cell-mediated immune responses, such as graft rejection, as well as antibody responses. Control through idiotype probably acts directly on the clones of lymphocytes which are potentially responsive to a certain antigen, rather than on their products. Immunologists’ interest in anti-idiotype control systems arises , from the possibility that with them it may be possible to achieve selective immunosuppression in man. This is because animals injected with antibody to the idiotype of a clone of their own lymphocytes can become unresponsive to the homolo6 gous antigen. BINZ and WIGZELL’S7 initial exploration of this possibility (which we commented on previously8) involved the immunisation of rats with their own lymphocytes which had been presensitised to the histocompatibility antigens of another strain of rats. The immunised rats subsequently tolerated kidney grafts from the sensitising strain for longer than they tolerated grafts from an unrelated strain. More recently WIGZELL and coworkers have shown that the auto-anti-idiotypic immunity, which is responsible for the specific immunosuppression, can be mediated by antibody or by thymus-derived lymphocytes.9 They also found that pre-existing allograft immunity, which would normally hasten graft rejection, could be diminished by their lymphoblast immunisation procedure. Although the lymphoblasts are at present injected in complete Freund’s adjuvant (which is not suitable for human beingsl°) other adjuvants might be found so that the technique could be
applied clinically.
Auto-anti-idiotype immunity
1. Transplant Rev. 1975, 27, 2. Potter, M., Lieberman, R. J. exp. Med. 1970, 132, 737. 3. Oudin, J. Proc. R. Soc. 1966, 166, 207. 4. Kohler, H. Transplant Rev. 1975, 27, 24. 5. Jerne, N. K. Sci. Am. 1973, 229, 52. 6. Eichmann, K. Eur. J. Immun. 1975, 5, 511. 7. Binz, H., Wigzell, H. Nature, 1976, 262, 294. 8. Lancet, 1976, ii, 505. 9. Aguet, M., Andersson, L. C., Andersson, R., Wight, E., Binz, H. J. exp. Med. 1978, 147, 50. 10. Chapel, H. M., August, P. J. Clin. exp. Immun. 1976, 24, 538.
develop so perhaps the greatest potential in transplantation would be where the donor is known. Kidney grafts for children from HLA-mismatched family donors are a possible example. (Anti-idiotype immunisation is not the only possible advance for transplantation teams: in June two groups reported prolonged acceptance of kidney or heart grafts, in animals treated with cyclosporin A. 11 12) In the sphere of autoimmunity it is the conditakes
some
weeks
to
.
tions in which antibodies to a restricted range of self antigens contribute directly to the pathogenesis which might conceivably respond to auto-anti-idiotype control. An example is the anti-acetylcholine receptor antibody which’ is found in myasthenia gravis. SCHWARTZ and co-workers have lately reported that mice immunised with autologous lymphocytes presensitised to acetylcholine receptors make an antibody which binds directly to antiacetylcholine receptor antibody.13 Evidence that the antibody had anti-idiotype specificity included the observation of competition with the appropriate antigen, acetylcholine receptor, for binding to anti-receptor antibody. The anti-idiotype bound to anti-acetylcholine receptor antibodies raised in several species, including rabbits and monkeys, so this may be a specificity which has been conserved in evolution. Whether auto-anti-idiotype immune animals are resistant to the induction of experimental myasthenia gravis after immunisation with acetylcholine receptors is not yet reported. Antiidiotype immunosuppression would have to be stable to be clinically useful: its possibilities are fascinating, but we have to see whether immunological equilibrium can be altered permanently.
MULTIFACTORIAL CANCER IF a group of polyoma-free young mice are injected with polyoma virus, tumours will usually develop in some of them.The numbers and sites of these will vary with the strain, age, and immunological status of the mice,2but despite these vagaries few people would do other than propose a simple cause-and-effect relationship between the virus and the tumour induction. Various strains of mice (e.g., AKR) have a high spontaneous incidence of leukaemia from about six months of age.3 This disease seems to be associated with possession of the strain of the Gross passage-A virus.4 Although by various manipulations, involving the injection of this virus into AKR mice, the time of onset of the leukxmia
11. Green, C. J., Allison, A. C. Lancet, 1978, i, 1182. 12. Calne, R. Y., et al. ibid. p. 1183. 13. Schwartz, M., Novick, D., Givol, D., Fuchs, S. Nature, 1978, 273, 543. 1. Stewart, S. E., Eddy, B. E., Stanton, M. F. Prog. exp. Tumor Res. 1960, 2.
H., Wigzell,
1, 67. Stewart, S. E., Eddy,
B.
E., Borgese, N. G. J.
natn.
1223.
3. Lynch, C. J. ibid. 1954, 15, 161. 4. Gross, L. Proc. Soc. exp. Biol. Med. 1957, 94, 767.
Cancer Inst.
1958, 20,
412
be advanced,5the exact mechanism of neither the induction nor the acceleration is understood. But again it has been tempting for the experimentalist to suppose a causal relationship between virus and cancer. Those more cautious have, however, observed that in other strains, of mice comparable viruses do not seem to lead to leukaemia.6Thus it can be argued that the presence of the virus itself is not enough and that genetic predisposition and perhaps environmental influences are also involved. In man the same kinds of argument can be adopted but more on epidemiological than experimental evidence. Thus the virtual ubiquity of bone sarcoma among those who painted watch dials with radioactive material’ betokened a clear one-to-one causal relationship between radioactivity and cancer. In such circumstances it would be reasonable to suppose, as Muller did,8 that the radiation induces a mutation in the genetic material of a cell in the appropriate epithelium. In retinoblastoma of childhood the predominant evidence is for the existence of a predisposing genetic change, probably in the long arm of chromosome 13.9 10 Again the genetic deletion is easily regarded as the cause of the cancer, but the change is probably present in every cell in the body whereas the cancers are initiated in pnly very few cells. Furthermore, a deletion per se can hardly be directly causal, although it may cause a genetic imbalance which can
predisposes to malignant change. The argument vis-a-vis smoking illustrates the point better, in that the epidemiological evidence for smoking as a cause of cancer seems overwhelming" but has also been held possibly to indicate an association between genetic predisposition to cancer12 and the smoking habit. The general difficulty that has been experienced in pointing to a single predominant chemical carcinogen in cigarette smoke13 has also detracted from the apparent certainty of the epidemiological data. Whatever the truth of the matter, it is fortunately clear that not all people who smoke get lung cancer, despite the damage to their lungs caused by smoking; nor are all lung cancers caused by smoking. Thus, in mice and men, it is occasionally convenient to think in terms of single causes for the single event - onset of clonal cancer-but clearly this is quite unsatisfactory in mechanistic terms. Latterly Jarrett and his colleagues14 have examined the development of certain carcinomas in what veterinary surgeons call the bovine. Their th9rough analysis serves to re-emphasise that many if not all cancers must be supposed to have a multifactorial aetiology. In the upland areas of Scotland and northern England, and in certain other parts of the world, the cattle have a remarkably high incidence of squamous carcinoma of the upper alimentary tract. Jarrett and his colleagues found that most of the affected animals had papillomatosis at the exact sites of occurrence
of the
tumours
and many had in addition
neo-
5. Rudali, G., Duplan, J. F., Latarjet, R. C. r. Acad. Sci. Paris, 1956, 247, 837. 6. Miller, J. F. A. P. Adv. Cancer Res. 1961, 6, 291. 7. Martland, H. S. Am. J. Cancer, 1931, 15, 2435. 8. Muller, H. J. Science, 1927, 66, 84. 9. Wilson, M. G., Towner, J. W., Fujimoto, A. Am. J. hum. Genet. 1973, 25, 57. 10. McKusick, V. A. Mendelian Inheritance in Man. Baltimore, 1975. 11. Royal College of Physicians of London. Smoking or Health. London, 1977. 12. Burch, P. R. J. The Biology of Smoking, a new approach; p. 303. Lancaster, 1976. 13. Cook, J. W. Lancet, 1957, i, 333. 14. Jarrett, W. F. H., McNeil, P. E., Grimshaw, W. T. R., Selman, I. E. McIntyre, W. I. M. Nature, 1978, 274, 215.
plastic changes in the intestine and bladder. From papillomas a virus was isolated which was morphologically similar to the bovine cutaneous-papilloma virus. The virus isolated from the oesophageal papillomas caused fibromas and papillomas when injected into normal cattle but not (so far) malignant growth. In some instances it was impossible to escape the conclusion that papillomas were giving rise to squamous carcinomas. Thus the aetiological chain seemed almost complete. And yet, as Jarrett emphasises, the most likely causal agent of squamous carcinoma of the oesophagus in the western highlands of Scotland is the bracken fern, Pteridium aquilinum. In the adjacent lowland areas, with genetically comparable cattle herds, few squamous carcinomas are found. We are not told the extent to which papillomatosis and the papilloma virus occur, nor the frequency of bracken fern. All that is explicit is that on the hill farms bracken is ubiquitous whereas on the lowland farms (by inference) it is less common. In some parts of the world in which tumours of the alimentary tract occur in cattle, bracken is present but not obviously the virus. Also the associated neoplasms in intestine and bladder are seemingly not present to the same extent as in Scotland. Does the bracken cause papillomatosis only in virus-infected cattle? Does the bracken, with its radiomimetic constituents, cause mutational changes in already virus-infected cells? These questions will not be easily answered, but what is clear is that in multifactorial aetiologies, in which several independent agencies are required to engender the "catastrophic" tumour, elimination of any single agency will reduce but not necessarily eliminate the undesired end-result. In relation to cattle herds it has been claimed that elimination of bracken can reduce the incidence of tumours. 15 In man, by analogy, reduction in smoking habits would in the long run lead to a reduction in bronchial carcinoma. "
APHTHOUS IMMUNOLOGY MINOR recurrent aphthous ulcers are shallow painful lesions which heal within ten days without scarring. Major oral aphthae are large deep craters, often painful enough to interfere with speaking, eating, and swallowing ; the oral ulcers in Behçet’s syndrome are very similar. The immunological aspects of these lesions have attracted much attention since Lehner reported antibody to,2 and enhanced lymphocyte stimulation by,3 fetal oral mucosal antigen in aphthous patients; these abnormalities were even more striking in Behcet’s syndrome. One suggestion is that the disease is mediated by peripheral-blood lymphocytes, which in aphthous patients are cytotoxic for oral epithelial cells.4 5 Another is that streptococcal6 or viral’ antigens are the culprits, acting alone or as haptens in the mucosa. The lymphocyte and histiocyte infiltration of early lesions68 is con15.
Dobereiner, J., Tokarnia, C. H., Canella, C. F. C. Pesq. Agropec. Bras. 1967, 2, 489. 1. Truelove, S. C., Morris-Owen, R. M. Br. med. J. 1958, i, 603. 2. Lehner, T. Lancet, 1964, ii, 1154. 3. Lehner, T. Immunology, 1967, 13, 159. 4. Dolby, A. E. ibid. 1969, 17, 709. 5. Rogers, R. S., Sams, W. M., Shorter, R. G. Archs Derm. 1974, 109, 361. 6. Graykowski, E. A., Barile, M. F., Lee, W. B., Stanley, H. R. J. Am. med. Ass. 1966, 196, 637. 7. Sallay, K., Dan, P., Kulcsar, G., Nasz, L. Rev. Immun. 1971, 35, 17. 8. Lehner, T. J. Path. 1969, 97, 481.
that the immune system reacts to its own products too.l For example, mice injected with a homogeneous mouse antibody (of a single antigen-binding specificity) respond by making antibodies to the antigen-binding site.2 Such antibodies are called anti-idiotype antibodies3 and they react with the injected antibody as though they were antigen. Under certain circumstances anti-idiotype antibodies can even substitute for antigen in eliciting an immune response to the homologous antigen,4 suggesting that the shape of the antigen-binding site reproduces that of the antigen. Mice make antiidiotype antibodies to the antibodies they make to injected antigens, and jERNE’s network hypothesis5 proposes that sequential antibody-anti-idiotype responses exert negative feedback on the immune response. There is evidence that anti-idiotype recog-
nition contributes to the control of cell-mediated immune responses, such as graft rejection, as well as antibody responses. Control through idiotype probably acts directly on the clones of lymphocytes which are potentially responsive to a certain antigen, rather than on their products. Immunologists’ interest in anti-idiotype control systems arises , from the possibility that with them it may be possible to achieve selective immunosuppression in man. This is because animals injected with antibody to the idiotype of a clone of their own lymphocytes can become unresponsive to the homolo6 gous antigen. BINZ and WIGZELL’S7 initial exploration of this possibility (which we commented on previously8) involved the immunisation of rats with their own lymphocytes which had been presensitised to the histocompatibility antigens of another strain of rats. The immunised rats subsequently tolerated kidney grafts from the sensitising strain for longer than they tolerated grafts from an unrelated strain. More recently WIGZELL and coworkers have shown that the auto-anti-idiotypic immunity, which is responsible for the specific immunosuppression, can be mediated by antibody or by thymus-derived lymphocytes.9 They also found that pre-existing allograft immunity, which would normally hasten graft rejection, could be diminished by their lymphoblast immunisation procedure. Although the lymphoblasts are at present injected in complete Freund’s adjuvant (which is not suitable for human beingsl°) other adjuvants might be found so that the technique could be
applied clinically.
Auto-anti-idiotype immunity
1. Transplant Rev. 1975, 27, 2. Potter, M., Lieberman, R. J. exp. Med. 1970, 132, 737. 3. Oudin, J. Proc. R. Soc. 1966, 166, 207. 4. Kohler, H. Transplant Rev. 1975, 27, 24. 5. Jerne, N. K. Sci. Am. 1973, 229, 52. 6. Eichmann, K. Eur. J. Immun. 1975, 5, 511. 7. Binz, H., Wigzell, H. Nature, 1976, 262, 294. 8. Lancet, 1976, ii, 505. 9. Aguet, M., Andersson, L. C., Andersson, R., Wight, E., Binz, H. J. exp. Med. 1978, 147, 50. 10. Chapel, H. M., August, P. J. Clin. exp. Immun. 1976, 24, 538.
develop so perhaps the greatest potential in transplantation would be where the donor is known. Kidney grafts for children from HLA-mismatched family donors are a possible example. (Anti-idiotype immunisation is not the only possible advance for transplantation teams: in June two groups reported prolonged acceptance of kidney or heart grafts, in animals treated with cyclosporin A. 11 12) In the sphere of autoimmunity it is the conditakes
some
weeks
to
.
tions in which antibodies to a restricted range of self antigens contribute directly to the pathogenesis which might conceivably respond to auto-anti-idiotype control. An example is the anti-acetylcholine receptor antibody which’ is found in myasthenia gravis. SCHWARTZ and co-workers have lately reported that mice immunised with autologous lymphocytes presensitised to acetylcholine receptors make an antibody which binds directly to antiacetylcholine receptor antibody.13 Evidence that the antibody had anti-idiotype specificity included the observation of competition with the appropriate antigen, acetylcholine receptor, for binding to anti-receptor antibody. The anti-idiotype bound to anti-acetylcholine receptor antibodies raised in several species, including rabbits and monkeys, so this may be a specificity which has been conserved in evolution. Whether auto-anti-idiotype immune animals are resistant to the induction of experimental myasthenia gravis after immunisation with acetylcholine receptors is not yet reported. Antiidiotype immunosuppression would have to be stable to be clinically useful: its possibilities are fascinating, but we have to see whether immunological equilibrium can be altered permanently.
MULTIFACTORIAL CANCER IF a group of polyoma-free young mice are injected with polyoma virus, tumours will usually develop in some of them.The numbers and sites of these will vary with the strain, age, and immunological status of the mice,2but despite these vagaries few people would do other than propose a simple cause-and-effect relationship between the virus and the tumour induction. Various strains of mice (e.g., AKR) have a high spontaneous incidence of leukaemia from about six months of age.3 This disease seems to be associated with possession of the strain of the Gross passage-A virus.4 Although by various manipulations, involving the injection of this virus into AKR mice, the time of onset of the leukxmia
11. Green, C. J., Allison, A. C. Lancet, 1978, i, 1182. 12. Calne, R. Y., et al. ibid. p. 1183. 13. Schwartz, M., Novick, D., Givol, D., Fuchs, S. Nature, 1978, 273, 543. 1. Stewart, S. E., Eddy, B. E., Stanton, M. F. Prog. exp. Tumor Res. 1960, 2.
H., Wigzell,
1, 67. Stewart, S. E., Eddy,
B.
E., Borgese, N. G. J.
natn.
1223.
3. Lynch, C. J. ibid. 1954, 15, 161. 4. Gross, L. Proc. Soc. exp. Biol. Med. 1957, 94, 767.
Cancer Inst.
1958, 20,
412
be advanced,5the exact mechanism of neither the induction nor the acceleration is understood. But again it has been tempting for the experimentalist to suppose a causal relationship between virus and cancer. Those more cautious have, however, observed that in other strains, of mice comparable viruses do not seem to lead to leukaemia.6Thus it can be argued that the presence of the virus itself is not enough and that genetic predisposition and perhaps environmental influences are also involved. In man the same kinds of argument can be adopted but more on epidemiological than experimental evidence. Thus the virtual ubiquity of bone sarcoma among those who painted watch dials with radioactive material’ betokened a clear one-to-one causal relationship between radioactivity and cancer. In such circumstances it would be reasonable to suppose, as Muller did,8 that the radiation induces a mutation in the genetic material of a cell in the appropriate epithelium. In retinoblastoma of childhood the predominant evidence is for the existence of a predisposing genetic change, probably in the long arm of chromosome 13.9 10 Again the genetic deletion is easily regarded as the cause of the cancer, but the change is probably present in every cell in the body whereas the cancers are initiated in pnly very few cells. Furthermore, a deletion per se can hardly be directly causal, although it may cause a genetic imbalance which can
predisposes to malignant change. The argument vis-a-vis smoking illustrates the point better, in that the epidemiological evidence for smoking as a cause of cancer seems overwhelming" but has also been held possibly to indicate an association between genetic predisposition to cancer12 and the smoking habit. The general difficulty that has been experienced in pointing to a single predominant chemical carcinogen in cigarette smoke13 has also detracted from the apparent certainty of the epidemiological data. Whatever the truth of the matter, it is fortunately clear that not all people who smoke get lung cancer, despite the damage to their lungs caused by smoking; nor are all lung cancers caused by smoking. Thus, in mice and men, it is occasionally convenient to think in terms of single causes for the single event - onset of clonal cancer-but clearly this is quite unsatisfactory in mechanistic terms. Latterly Jarrett and his colleagues14 have examined the development of certain carcinomas in what veterinary surgeons call the bovine. Their th9rough analysis serves to re-emphasise that many if not all cancers must be supposed to have a multifactorial aetiology. In the upland areas of Scotland and northern England, and in certain other parts of the world, the cattle have a remarkably high incidence of squamous carcinoma of the upper alimentary tract. Jarrett and his colleagues found that most of the affected animals had papillomatosis at the exact sites of occurrence
of the
tumours
and many had in addition
neo-
5. Rudali, G., Duplan, J. F., Latarjet, R. C. r. Acad. Sci. Paris, 1956, 247, 837. 6. Miller, J. F. A. P. Adv. Cancer Res. 1961, 6, 291. 7. Martland, H. S. Am. J. Cancer, 1931, 15, 2435. 8. Muller, H. J. Science, 1927, 66, 84. 9. Wilson, M. G., Towner, J. W., Fujimoto, A. Am. J. hum. Genet. 1973, 25, 57. 10. McKusick, V. A. Mendelian Inheritance in Man. Baltimore, 1975. 11. Royal College of Physicians of London. Smoking or Health. London, 1977. 12. Burch, P. R. J. The Biology of Smoking, a new approach; p. 303. Lancaster, 1976. 13. Cook, J. W. Lancet, 1957, i, 333. 14. Jarrett, W. F. H., McNeil, P. E., Grimshaw, W. T. R., Selman, I. E. McIntyre, W. I. M. Nature, 1978, 274, 215.
plastic changes in the intestine and bladder. From papillomas a virus was isolated which was morphologically similar to the bovine cutaneous-papilloma virus. The virus isolated from the oesophageal papillomas caused fibromas and papillomas when injected into normal cattle but not (so far) malignant growth. In some instances it was impossible to escape the conclusion that papillomas were giving rise to squamous carcinomas. Thus the aetiological chain seemed almost complete. And yet, as Jarrett emphasises, the most likely causal agent of squamous carcinoma of the oesophagus in the western highlands of Scotland is the bracken fern, Pteridium aquilinum. In the adjacent lowland areas, with genetically comparable cattle herds, few squamous carcinomas are found. We are not told the extent to which papillomatosis and the papilloma virus occur, nor the frequency of bracken fern. All that is explicit is that on the hill farms bracken is ubiquitous whereas on the lowland farms (by inference) it is less common. In some parts of the world in which tumours of the alimentary tract occur in cattle, bracken is present but not obviously the virus. Also the associated neoplasms in intestine and bladder are seemingly not present to the same extent as in Scotland. Does the bracken cause papillomatosis only in virus-infected cattle? Does the bracken, with its radiomimetic constituents, cause mutational changes in already virus-infected cells? These questions will not be easily answered, but what is clear is that in multifactorial aetiologies, in which several independent agencies are required to engender the "catastrophic" tumour, elimination of any single agency will reduce but not necessarily eliminate the undesired end-result. In relation to cattle herds it has been claimed that elimination of bracken can reduce the incidence of tumours. 15 In man, by analogy, reduction in smoking habits would in the long run lead to a reduction in bronchial carcinoma. "
APHTHOUS IMMUNOLOGY MINOR recurrent aphthous ulcers are shallow painful lesions which heal within ten days without scarring. Major oral aphthae are large deep craters, often painful enough to interfere with speaking, eating, and swallowing ; the oral ulcers in Behçet’s syndrome are very similar. The immunological aspects of these lesions have attracted much attention since Lehner reported antibody to,2 and enhanced lymphocyte stimulation by,3 fetal oral mucosal antigen in aphthous patients; these abnormalities were even more striking in Behcet’s syndrome. One suggestion is that the disease is mediated by peripheral-blood lymphocytes, which in aphthous patients are cytotoxic for oral epithelial cells.4 5 Another is that streptococcal6 or viral’ antigens are the culprits, acting alone or as haptens in the mucosa. The lymphocyte and histiocyte infiltration of early lesions68 is con15.
Dobereiner, J., Tokarnia, C. H., Canella, C. F. C. Pesq. Agropec. Bras. 1967, 2, 489. 1. Truelove, S. C., Morris-Owen, R. M. Br. med. J. 1958, i, 603. 2. Lehner, T. Lancet, 1964, ii, 1154. 3. Lehner, T. Immunology, 1967, 13, 159. 4. Dolby, A. E. ibid. 1969, 17, 709. 5. Rogers, R. S., Sams, W. M., Shorter, R. G. Archs Derm. 1974, 109, 361. 6. Graykowski, E. A., Barile, M. F., Lee, W. B., Stanley, H. R. J. Am. med. Ass. 1966, 196, 637. 7. Sallay, K., Dan, P., Kulcsar, G., Nasz, L. Rev. Immun. 1971, 35, 17. 8. Lehner, T. J. Path. 1969, 97, 481.
