- Email: [email protected]
VERTICAL TRANSMISSION
592
clinically important differences in the ease with which immunosuppression has been achieved and in the toxicity of the immunosuppressive regimens. For the present, however, it is only in the form of actuarial survival curves that the data are in any serise manageable, and despite their limitations they tend to support the view that donor/recipient matching at HLA A and B loci improves the prospect of prolonged graft function. 1,8,9 Conversely, where there is a major degree of mismatching, not only is the graft liable to fail but also the rejection process often entails production of cytotoxic antibodies and cytotoxic primed lymphocytes which persist in the host after removal of the donor kidney and seriously prejudice the prospects of success in any subsequent transplant attempt. 1, 10, 11 To this extent, then, predictions from experimental tissue transplants are borne out in the clinical setting and there is every reason to believe that improved histocompatibility matching will lead to even better results. This should not imply commitment to the unattainable goal of a perfect match for all antigen systems. It points rather to the need for increased understanding of the "rejectioninducing potential" of particular combinations of donor and recipient antigens, given that certain mismatches are likely to have more serious consequences than others.1,12 Particular attention is currently focused on the HLA D locus, coding for antigens that determine mixed-leucocyte reactions.9,13 The corresponding antigens in animals are the ones most directly involved in rejection of foreign tissue.1 Until lately it has been very difficult, for technical reasons, to include D-locus typing in the pretransplant matching process. Now the availability of DR (formerly known as Ia) typing sera allows the rapid identification of alleles on B lymphocytes which, if not identical to D locus antigens, are at least very closely linked to them. 14 In a preliminary report on p. 575, Dr TING and Professor MORRIS show an association between early graft rejection and donor/recipient mismatching for DR antigens. Their cases have not been subdivided according to the degree of HLA A and B locus compatibility and the observations cover only a short follow-up period. Nevertheless the results are encouraging. Closely linked to the refinement of tissue matching is the question of developing more "physiological" methods of enhancing graft tolerance. It is believed that pretransplant blood-transfusion exerts its tolerogenic effect partly 8. Van Rood, J. J., Van Leeuwen, A., Bruning, J. W., Porter, K. A. in Advances in Transplantation (edited by J. Dausset, J. Hamburger, and G. Mathé); p. 213. Copenhagen, 1967. 9. Festenstein, H., Sachs, J., Paris, A. M. I., et al. Lancet, 1976, i, 157. 10. Patel, R., Terasaki, P. I. New Engl. J. Med. 1969, 280, 735. 11. Williams, G. M., Hume, D. M., Hudson, R. P., et al. ibid. 1968, 279, 611. 12. Kristenson, T., Grunnet, N., Kissmeyer-Nielsen, F. Tissue Antigens, 1975,
6, 221.
K. C., Perkins, H. A., Payne, R. O., et al. Transplant. Proc. 1973, 5, 391. 14. Lancet, 1976, ii, 240. 13. Cochrum,
the production of blocking antibodies. 1,6 Similar antibodies can sometimes be demonstrated as a consequence of transplantation itself.ls,z6 There are intriguing prospects in the use of factors, extracted from the serum of women in late pregnancy, which are thought to inhibit of the fetus and which may have a similar protective effect on kidney grafts.17 All these mechanisms are likely to be most effective when the degree of histo-incompatibility between donor and recipient is slight. 18 Tissue typers therefore expect to retain a central role in human organ transplantation, looking towards the day when they will not only match kidney to patient with confidence but will also provide guidance on the most appropriate immunosuppressive regimen for that particular
by stimulating
"rejection"
donor/recipient combination.
VERTICAL TRANSMISSION VERTICAL transmission is a the overlapping concepts of
general term embracing cytoplasmic inheritance (extra-chromosomal inheritance), infection from parent to child ("infectious heredity’’), and related mechanisms. Congenital infections with the rubella virus, cylomegalovirus, Treponema pallidum, and Toxoplasma gondii, are some wel-known examples of one type of vertical transmission (of a nucleic-acid-containing agent). In some of these examples, the organism can produce malformations of the embryo by disturbing its development. But it is probable that, whatever the organism, a disseminated infection in themother will, on occasion at least, lead to infection of the fetus, and malformation may be a possible sequel. If the organism is one of the many that produce long term immunity, the risk of "recurrence" in subsequent sibs is lower than it is in the general population-a, unique phenomenon, a sort of familial protection., familial exclusion, or negative familial
This is obviously so for rubella and other viruses that produce long-term immunity in the mother, bus- it may also apply in less obvious situations. For example, among the sibs born after a case of congenital Chagas’ disease, there seems to be only a low incidence of Trypanosoma cruzii infection,despite continuing infection in the mother (symptomatic or other-
aggregation.
some
wise) ’ As in that example, the viræmia, bacteræmia, or parasitæmia in the mother can be of a low order and quite symptomless, yet lead M infection of the fetus. If, in addition, infection were sometimes to lead to a disease process in the offspring, but only after a long delay, the underlying mechanism of transmission could seem mysterious. When looked for, some aggregation or its opposite within sibships might be noted, together with aggregation among mauc relatives. (Individuals are matroclinally related if there is at least one path, 15. 16. 17
Hattler, B. G., Karesh, C. Miler, J. Transplantation. 1971, 11, 268. Sengar, D. P. S., Opelz, G. Terasaki P. I.Transplant. Proc. 1973, 5, 641. Riggio, R. R., Kim, S, J. Saal.,S. D., Stubenbord W. T., Cheigh, J. S., Stenzel, K H., Rubin. A. L. Lancet, 1978, i, 238.
18.
Carpenter. C. B., d’Apice,J. F., Abbas, A. K. Adv.Immun. 1976, 22, 1. 1. Howard, J., Rubio V., Trop Dis. Bull. 1970, 67, 142.
593
that has no male step.) The comes, of course, from the unique for mothers to transmit replicatable entities opportunity to their offspring by one or more of several routes-particularly those via the ovum, via the placenta, or via the breast milk. By contrast, the spermatozoon is too small to compete, except on a limited scale. Fine2 has lately tried to put this matroclinal bias on a quantitative basis, the ultimate aim being to test the plausibility of vertical-transmission hypotheses by estimating the magnitude of the matroclinal bias in suitable family data. Potentially, extensions of the analysis, to allow for ascertainment bias and for the tendency for matroclinal relatives to be particularly aware of each other, could be undertaken and perhaps they should be. But, even when these troublesome factors have been dealt with, there will remain the low capacity of pedigree studies to distinguish between alternative mechanisms, a situation well-known in comparisons of orthodox genetical mechanisms. In the genetical case, only the simple sets of genotype-phenotype relationships can be distinguished: the introduction of uncertainty (penetrance factors) or complexity (two or more gene loci) into these relationships usually makes resolution imprac-
through
the
pedigree,
matroclinal bias
ticable.3
What, then, is being gained by elaboration of methods that are unlikely by themselves to give definitive indications ? The answer is that there may be indirect benefits. First, attention is focused on this area. Second, even the hypothetical finding of a weak indication, from family studies well analysed, that a particular disease (e.g., earlyonset diabetes) might be partly or wholly transmitted in this manner, could be a sufficient stimulus for more definitive work to be done in identifying the agents (rubella virus?4-6 Coxsackie B virus?) and in developing animal models for their study. In general, research into the role of vertical transmission would be more fruitful than that aimed at the vague and probably dead-end concepts of multifactorial determination. "To say ’X disease is multifactorial ...’ is a statement of the same order of informativeness as ’Moon dust is made of chemicals’ ", as Edwards remarks with insight. Others, with less insight, have provisionally classified multifactorial malformations among malformations of known rather than of unknown ætiology.8 The reason for past neglect of vertical transmission need not detain i.s long. As a mechanism, it is difficult to study in man, it does not lead to simple, elegant mathematical models, and, by contrast with "horizontal transmission", it seems rarely to lead to alarming outbreaks. However, there is a case for studying it in two main groups-in certain rare diseases, such as Leber’s optic atrophy,9,10 where the probability of its involvement is moderately high; and in some important common diseases, such as early-onset diabetes or carcinoma 2.Fine, P. E. M. J. med.Genet. 1977, 14, 399. 3.Edwards, J. H. Acta genet. 1960, 10, 63. 4.Menser, M. A., Forest, J. M., Bransby, R. D. Lancet, 1978,i, 57. 5.Smithells, R. W., Sheppard, S., Marshall, W. C., Peckham, C. ibid. p. 439. 6. de Prinz, F., van Assche, F. A., Desmyter, J., de Groote, G., Gepts, W. ibid.
p. 434. 7.Edwards, J. H. Nature, 1973,243, 475. 8. Smith, D., Christian, R. L., Feingold, M., Gorlin, Lancet,1974,i, 798.
B.
G., Poswillo, D. E.
9. van Senus, A. H. C. Leber’s Disease m the Netherlands; p. 163. Hague, 1963. 10. Erickson, R. P. Am. J. hum. Genet. 1972, 24, 348.
of the breast. Vertical transmission might well be uncommon in man and it might make only a small contribution even where it exists. But it is worth seeking. Harper11 points out how closely the apparently vertical transmission of the agents of Creutzfeldt-Jakob disease and of some forms of Alzheimer’s disease can mimic, in pedigree pattern, even simple forms of mendelian transmission. The evolutionary significance of extrachromosomal elements in general has been exhaustively reviewed by Reanney. 12
SULPHINPYRAZONE AFTER MYOCARDIAL INFARCTION AT mary
time when
no great progress was evident in priof prevention coronary heart-disease,1 hopes for secondary prevention received a boost from the multicentre practolol trial. Though the trial had to be abandoned because of adverse effects, practolol did substantially reduce the death-rate, and there was reason to
a
believe that other -blockers might likewise be beneficial. Now an equally striking benefit is reported with a completely different agent, the uricosuric drug sulphinpyrazone. Sulphinpyrazone has been used in the treatment of gout since 1959. In the mid-1960s it was reported to lengthen platelet survival and decrease platelet turnover in gouty patients with thromboembolic disorders ;3 and these antithrombotic properties were later exploited in patients with carotid-artery stenosis, with prosthetic heart-valves, and with recurrent venous thrombosis. The mechanisms of action are still uncertain but, in vitro and in vivo, platelet adhesion and aggregation are inhibited. The bleeding-time is not lengthened. Workers in the United States and Canada now report the effects of sulphinpyrazone versus placebo after myocardial infarction.4 So far, 1475 patients are eligible for analysis. They were aged 45-70, both male and female, and all had had a myocardial infarction, 25-35 days before enrolment. Patients were excluded if they were on drugs influencing platelets or clotting, had untreated hypertension, or had previously undergone coronary bypass surgery. More arbitrarily, those with large hearts were also excluded. Of 69 deaths in the study period, 68 were cardiac and 1 was cerebrovascular. The annual total death-rate corrected for exposure time was 95% in the placebo group and 5.1%n in the treated group-thus, the reduction in overall death-rate was 46%. 61% of all deaths were sudden and cardiac, and the sudden-death reduction attributable to sulphinpyrazone was 57%. Sulphinpyrazone was well tolerated. More than 80% of patients took the drug conscientiously as judged by reduced serum-uric-acid levels, and there were no hæmatological side-effects. The trial is not yet complete, but these results suggest that a substantial drop in reinfarction deaths may now be possible. 11. Harper, P. S. J. med. genet. 1977, 14, 389. 12. Reanney, D. Bact. Revs, 1976, 40, 552. 1. Lancet, 1974, i, 605. 2. Multicentre International Study. Br. med. J. 1975, iii, 735. 3. Smythe, H. A., Ogryzlo, M. A., Murphy, E. A., et al. Can. med.
Ass. J. 1965,
92, 818. 4. Anturane Reinfarction Trial Research 289.
Group. New Engl. J.
Med. 1978,
298,
clinically important differences in the ease with which immunosuppression has been achieved and in the toxicity of the immunosuppressive regimens. For the present, however, it is only in the form of actuarial survival curves that the data are in any serise manageable, and despite their limitations they tend to support the view that donor/recipient matching at HLA A and B loci improves the prospect of prolonged graft function. 1,8,9 Conversely, where there is a major degree of mismatching, not only is the graft liable to fail but also the rejection process often entails production of cytotoxic antibodies and cytotoxic primed lymphocytes which persist in the host after removal of the donor kidney and seriously prejudice the prospects of success in any subsequent transplant attempt. 1, 10, 11 To this extent, then, predictions from experimental tissue transplants are borne out in the clinical setting and there is every reason to believe that improved histocompatibility matching will lead to even better results. This should not imply commitment to the unattainable goal of a perfect match for all antigen systems. It points rather to the need for increased understanding of the "rejectioninducing potential" of particular combinations of donor and recipient antigens, given that certain mismatches are likely to have more serious consequences than others.1,12 Particular attention is currently focused on the HLA D locus, coding for antigens that determine mixed-leucocyte reactions.9,13 The corresponding antigens in animals are the ones most directly involved in rejection of foreign tissue.1 Until lately it has been very difficult, for technical reasons, to include D-locus typing in the pretransplant matching process. Now the availability of DR (formerly known as Ia) typing sera allows the rapid identification of alleles on B lymphocytes which, if not identical to D locus antigens, are at least very closely linked to them. 14 In a preliminary report on p. 575, Dr TING and Professor MORRIS show an association between early graft rejection and donor/recipient mismatching for DR antigens. Their cases have not been subdivided according to the degree of HLA A and B locus compatibility and the observations cover only a short follow-up period. Nevertheless the results are encouraging. Closely linked to the refinement of tissue matching is the question of developing more "physiological" methods of enhancing graft tolerance. It is believed that pretransplant blood-transfusion exerts its tolerogenic effect partly 8. Van Rood, J. J., Van Leeuwen, A., Bruning, J. W., Porter, K. A. in Advances in Transplantation (edited by J. Dausset, J. Hamburger, and G. Mathé); p. 213. Copenhagen, 1967. 9. Festenstein, H., Sachs, J., Paris, A. M. I., et al. Lancet, 1976, i, 157. 10. Patel, R., Terasaki, P. I. New Engl. J. Med. 1969, 280, 735. 11. Williams, G. M., Hume, D. M., Hudson, R. P., et al. ibid. 1968, 279, 611. 12. Kristenson, T., Grunnet, N., Kissmeyer-Nielsen, F. Tissue Antigens, 1975,
6, 221.
K. C., Perkins, H. A., Payne, R. O., et al. Transplant. Proc. 1973, 5, 391. 14. Lancet, 1976, ii, 240. 13. Cochrum,
the production of blocking antibodies. 1,6 Similar antibodies can sometimes be demonstrated as a consequence of transplantation itself.ls,z6 There are intriguing prospects in the use of factors, extracted from the serum of women in late pregnancy, which are thought to inhibit of the fetus and which may have a similar protective effect on kidney grafts.17 All these mechanisms are likely to be most effective when the degree of histo-incompatibility between donor and recipient is slight. 18 Tissue typers therefore expect to retain a central role in human organ transplantation, looking towards the day when they will not only match kidney to patient with confidence but will also provide guidance on the most appropriate immunosuppressive regimen for that particular
by stimulating
"rejection"
donor/recipient combination.
VERTICAL TRANSMISSION VERTICAL transmission is a the overlapping concepts of
general term embracing cytoplasmic inheritance (extra-chromosomal inheritance), infection from parent to child ("infectious heredity’’), and related mechanisms. Congenital infections with the rubella virus, cylomegalovirus, Treponema pallidum, and Toxoplasma gondii, are some wel-known examples of one type of vertical transmission (of a nucleic-acid-containing agent). In some of these examples, the organism can produce malformations of the embryo by disturbing its development. But it is probable that, whatever the organism, a disseminated infection in themother will, on occasion at least, lead to infection of the fetus, and malformation may be a possible sequel. If the organism is one of the many that produce long term immunity, the risk of "recurrence" in subsequent sibs is lower than it is in the general population-a, unique phenomenon, a sort of familial protection., familial exclusion, or negative familial
This is obviously so for rubella and other viruses that produce long-term immunity in the mother, bus- it may also apply in less obvious situations. For example, among the sibs born after a case of congenital Chagas’ disease, there seems to be only a low incidence of Trypanosoma cruzii infection,despite continuing infection in the mother (symptomatic or other-
aggregation.
some
wise) ’ As in that example, the viræmia, bacteræmia, or parasitæmia in the mother can be of a low order and quite symptomless, yet lead M infection of the fetus. If, in addition, infection were sometimes to lead to a disease process in the offspring, but only after a long delay, the underlying mechanism of transmission could seem mysterious. When looked for, some aggregation or its opposite within sibships might be noted, together with aggregation among mauc relatives. (Individuals are matroclinally related if there is at least one path, 15. 16. 17
Hattler, B. G., Karesh, C. Miler, J. Transplantation. 1971, 11, 268. Sengar, D. P. S., Opelz, G. Terasaki P. I.Transplant. Proc. 1973, 5, 641. Riggio, R. R., Kim, S, J. Saal.,S. D., Stubenbord W. T., Cheigh, J. S., Stenzel, K H., Rubin. A. L. Lancet, 1978, i, 238.
18.
Carpenter. C. B., d’Apice,J. F., Abbas, A. K. Adv.Immun. 1976, 22, 1. 1. Howard, J., Rubio V., Trop Dis. Bull. 1970, 67, 142.
593
that has no male step.) The comes, of course, from the unique for mothers to transmit replicatable entities opportunity to their offspring by one or more of several routes-particularly those via the ovum, via the placenta, or via the breast milk. By contrast, the spermatozoon is too small to compete, except on a limited scale. Fine2 has lately tried to put this matroclinal bias on a quantitative basis, the ultimate aim being to test the plausibility of vertical-transmission hypotheses by estimating the magnitude of the matroclinal bias in suitable family data. Potentially, extensions of the analysis, to allow for ascertainment bias and for the tendency for matroclinal relatives to be particularly aware of each other, could be undertaken and perhaps they should be. But, even when these troublesome factors have been dealt with, there will remain the low capacity of pedigree studies to distinguish between alternative mechanisms, a situation well-known in comparisons of orthodox genetical mechanisms. In the genetical case, only the simple sets of genotype-phenotype relationships can be distinguished: the introduction of uncertainty (penetrance factors) or complexity (two or more gene loci) into these relationships usually makes resolution imprac-
through
the
pedigree,
matroclinal bias
ticable.3
What, then, is being gained by elaboration of methods that are unlikely by themselves to give definitive indications ? The answer is that there may be indirect benefits. First, attention is focused on this area. Second, even the hypothetical finding of a weak indication, from family studies well analysed, that a particular disease (e.g., earlyonset diabetes) might be partly or wholly transmitted in this manner, could be a sufficient stimulus for more definitive work to be done in identifying the agents (rubella virus?4-6 Coxsackie B virus?) and in developing animal models for their study. In general, research into the role of vertical transmission would be more fruitful than that aimed at the vague and probably dead-end concepts of multifactorial determination. "To say ’X disease is multifactorial ...’ is a statement of the same order of informativeness as ’Moon dust is made of chemicals’ ", as Edwards remarks with insight. Others, with less insight, have provisionally classified multifactorial malformations among malformations of known rather than of unknown ætiology.8 The reason for past neglect of vertical transmission need not detain i.s long. As a mechanism, it is difficult to study in man, it does not lead to simple, elegant mathematical models, and, by contrast with "horizontal transmission", it seems rarely to lead to alarming outbreaks. However, there is a case for studying it in two main groups-in certain rare diseases, such as Leber’s optic atrophy,9,10 where the probability of its involvement is moderately high; and in some important common diseases, such as early-onset diabetes or carcinoma 2.Fine, P. E. M. J. med.Genet. 1977, 14, 399. 3.Edwards, J. H. Acta genet. 1960, 10, 63. 4.Menser, M. A., Forest, J. M., Bransby, R. D. Lancet, 1978,i, 57. 5.Smithells, R. W., Sheppard, S., Marshall, W. C., Peckham, C. ibid. p. 439. 6. de Prinz, F., van Assche, F. A., Desmyter, J., de Groote, G., Gepts, W. ibid.
p. 434. 7.Edwards, J. H. Nature, 1973,243, 475. 8. Smith, D., Christian, R. L., Feingold, M., Gorlin, Lancet,1974,i, 798.
B.
G., Poswillo, D. E.
9. van Senus, A. H. C. Leber’s Disease m the Netherlands; p. 163. Hague, 1963. 10. Erickson, R. P. Am. J. hum. Genet. 1972, 24, 348.
of the breast. Vertical transmission might well be uncommon in man and it might make only a small contribution even where it exists. But it is worth seeking. Harper11 points out how closely the apparently vertical transmission of the agents of Creutzfeldt-Jakob disease and of some forms of Alzheimer’s disease can mimic, in pedigree pattern, even simple forms of mendelian transmission. The evolutionary significance of extrachromosomal elements in general has been exhaustively reviewed by Reanney. 12
SULPHINPYRAZONE AFTER MYOCARDIAL INFARCTION AT mary
time when
no great progress was evident in priof prevention coronary heart-disease,1 hopes for secondary prevention received a boost from the multicentre practolol trial. Though the trial had to be abandoned because of adverse effects, practolol did substantially reduce the death-rate, and there was reason to
a
believe that other -blockers might likewise be beneficial. Now an equally striking benefit is reported with a completely different agent, the uricosuric drug sulphinpyrazone. Sulphinpyrazone has been used in the treatment of gout since 1959. In the mid-1960s it was reported to lengthen platelet survival and decrease platelet turnover in gouty patients with thromboembolic disorders ;3 and these antithrombotic properties were later exploited in patients with carotid-artery stenosis, with prosthetic heart-valves, and with recurrent venous thrombosis. The mechanisms of action are still uncertain but, in vitro and in vivo, platelet adhesion and aggregation are inhibited. The bleeding-time is not lengthened. Workers in the United States and Canada now report the effects of sulphinpyrazone versus placebo after myocardial infarction.4 So far, 1475 patients are eligible for analysis. They were aged 45-70, both male and female, and all had had a myocardial infarction, 25-35 days before enrolment. Patients were excluded if they were on drugs influencing platelets or clotting, had untreated hypertension, or had previously undergone coronary bypass surgery. More arbitrarily, those with large hearts were also excluded. Of 69 deaths in the study period, 68 were cardiac and 1 was cerebrovascular. The annual total death-rate corrected for exposure time was 95% in the placebo group and 5.1%n in the treated group-thus, the reduction in overall death-rate was 46%. 61% of all deaths were sudden and cardiac, and the sudden-death reduction attributable to sulphinpyrazone was 57%. Sulphinpyrazone was well tolerated. More than 80% of patients took the drug conscientiously as judged by reduced serum-uric-acid levels, and there were no hæmatological side-effects. The trial is not yet complete, but these results suggest that a substantial drop in reinfarction deaths may now be possible. 11. Harper, P. S. J. med. genet. 1977, 14, 389. 12. Reanney, D. Bact. Revs, 1976, 40, 552. 1. Lancet, 1974, i, 605. 2. Multicentre International Study. Br. med. J. 1975, iii, 735. 3. Smythe, H. A., Ogryzlo, M. A., Murphy, E. A., et al. Can. med.
Ass. J. 1965,
92, 818. 4. Anturane Reinfarction Trial Research 289.
Group. New Engl. J.
Med. 1978,
298,