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Bone marrow transplantation: unexpected results
26
THE LANCET,JANUARY2, 1971
endometrium, ~9 but the development of suspicious breast changes in bitches given chlormadinone acetate has led to the withdrawal of this compound in Great Britain and other countries. The thromboembolic risk associated with a combined oestrogen/progestagen pill seems to be related to the (estrogen component, but there are suggestions that certain progestagens may also contribute to the risk. z° Alternative routes of progestagen administration are now under investigation. A small silicone polymer capsule containing progestagen has been designed for implantation under the skin. Such capsules will release low-dose progestagen for several years and can be removed to restore fertility. Vaginal rings and intrauterine devices impregnated with progestagen are also being evaluated, and they have the added advantage that the effects of the steroid are more likely to be confined to the uterus. Undoubtedly, if synthetic steroids of any type are to be used in healthy women for contraceptive purposes, their effects on the health of the users must be monitored on a large scale over several decades.
Bone-marrow Transplantation : Unexpected Results FROM time to time attempts have been made to transplant human bone-marrowfl1 but they usually failed. Among the many reasons for failure was the lack of information about human transplantation antigens. During the past few years, however, the main transplantation antigen system of manmthe HL-A system--has been identified and analysed in detail, "2,2'~ and this progress has encouraged the hope that clinical bone-marrow transplantation would be worth reinvestigating. At this stage, it is obviously wise to attempt bone-marrow transplantation from a donor who is HL-A identical with the recipient. Theoretically, this should minimise both the danger of inducing graft-versus-host (G.V.H.) disease 24 and the threat of graft rejection. It might also be expected tO reduce the poor marrow growth effect, a potential hazard which has been observed in experiments with incompatible marrow grafts in mice.95 GP,AW et al. z8 described the results of transplanting into 8 patients with acute lymphocytic leuk~emia bone-marrow from HL-A identical siblings. Some unexpected features were noted. The most important one was that, of 7 patients in whom successful engraftment was obtained, 3 had G.v.H. reactions, 19. Briggs, M. H., Caldwell, A. D. S., Pitchford, A. G. Hosp. Meal. 1967, 2, 63. 20. Inman, W. H. W., Vessey, M. P., Westerholm, B., Engelund, A. Br. med. J. 1970, ii, 203. 21. Bortin, M. M. Transplantation, 1970, 9, 571. 22. Walford, R. L. Ser. tt
and 2 patients died from this complication. Several explanations could be proposed to account for this high rate of G.v.H. reactions. Firstly, the marrow donors might not be HL-A identical with the respective recipients, but this seems unlikely, not only because the lymphocyte typing data indicated HL-A identity but also because donor and recipient cells were mutually non-responsive in culture, a characteristic of HL-A identity. 2r A second explana, tion is that other antigenic systems apart from HL-A might have been responsible for inducing the G.v.rI. reactions. Although non-HL-A transplantation antigen systems are presumed to exist, no other human transplantation antigen system has been specifically identified except for ABO. In GRaW et al.'s series, ABO compatibility was respected except for case 3, in which the graft failed to take. If transplantation antigens which do not belong to the HL-A or ABO systems account for the G.v.H. reactions, either the marrow donors must have been prc-immunised against the recipients (an unlikely possibility) or it is necessary to postulate the existence of other " s t r o n g " human transplantation antigens. 2s So far there is no other evidence indicating their existence. Another, more speculative, notion is that leuk~emic cells may bear tumour-specific antigens which function as transplantation antigens and thus provoke a G.V.m reaction. VIZA et al. 29 showed that leuka:mic cells can stimulate autologous lymphocytes, taken during a remission, to undergo blast-cell transformation. Although other interpretations are possible, this observation could be explained by the existence of leuka:mia-specific antigens. But the syndrome described by GRAW et al. may not necessarily have arisen as a consequence of G.v.H. activity. It may have been due to depletion of the patient's own lymphocytes caused by another factor. Severe lymphocyte depletion, however induced, is known to be capable of causing the same syndrome 30~:~ and it is possible that the immuno -, suppressive regimen used in these patients produced this effect. Finding a clinically satisfactory protocol of immunosuppression which is both effective and non-toxic is likely to prove harder in bone-marrow grafting than in other forms of transplantatiofi. In 1 of the patients in this series a toxic epidermal necrolysis developed and the serum was found to contain a cytotoxic antibody which reacted with the patient's epithelial cells but not lymphoid cells. It may be that, in this patient, donor ceils had replaced a large proportion of the recipient's own lymphoid tissues. 27. Amos, D. B., Bach, F. H . J . exp. &led. 1968, 128, 623. 28. Simonsen, M. Transplant. Rev. 1970~ 3, 22. 29. Viza, D. C., Bernard-Degani, O , Bernard, C., Harris, R. Lanceb 1969, ii, 493. 30. Miller, j. F. A. P. in Transplantation (edited by G. E. W. WolsteO" holme and M. P. Cameron); p. 384. London, 1962. 31. Barnes, D. W. H., Loutit, J. F., Micklem, H. S. Ann. N. Y. Acad. Sd. 1962, 99, 374. 32. Sehlesinger, M., Marks, R. Science, 1964, 143, 965. 33. Batchelor, ]'. R. in Regulation of the Antibody Response (edited by B. Cinader); p. 276. Springfield, Illinois, 1968..
THE LANCET, JANUARY 2 ,
1971
If the circulating antibody was the product of donor
cells, this differential cytotoxicity would be expected. There is also the possibility, however, that the recipient's lymphoid tissue h a d not been replaced by donor cells b u t that the patient's skin cells carried an alloantigen not present oh his ' lymphoid cells. BoYsE et al. x~ demonstrated ~n mice the existence of alloantigens with this tissue-'limited distribution. If such antigens do also exist in man, they could present another class of antigen potentially capable of inducing a tissue-limited f o r m of G.v.~L reaction. At present the scope for ~linical bone-marrow transplantation is obviously small. But i C e i t h e r specific tolerance or immunolpgical enhancement become clinical possibilities, the prospects "could change radically.
TESTING NEW DRUGS EARLY testing of new drugs in man is of the utmost ,concern both to doctors and to the pharmaceutical industry. F o r the doctor, it may m e a n the prompt detection of a treatment superior either in efficacy or lack of toxicity to any hitherto available. For the industry, the early selection of a promising d r u g , or the recognition of unwanted and unacceptable sideeffects, would be a great ecor/omic asset, promoting the more efficient use of research and development resources. Furthermore, with the advent of the Medicines Commission, the requirements for t e s t i n g of drugs, once voluntary, become mandatory. I t is vital, therefore, that means should be readily accessible for the study of new drugs in normal subjects and in patients. Implicit in a report 15 by a working-party o f the Medico-Pharmaceutical Forum, 1° which has been studying the organisation of early clinical studies of new medicines in the United Kingdoms is the belief that the place for such studies, or the centre of their organisation, should be units of clinical pharmacology. Such a umt should b e part of each medical school and also a feature of certain other suitable centres, making a total of 25-30 units in Great Britain. Most units Would cover a range of drugs and diseases, although individual members of a unit would tend to speciakise in some particular area. T h e minimum cost of setting u p a workable unit with 2 established staff, a research fellow, technical and secretarial assistance, running costs, and capital equipment would be about £40,000 in the first year, and £20,000 in subsequent years. This money should come from Government sources-namely, the Department of Health and Social Security and the Department of Education and Science." Additional support by funds from industrial firms for .
- "Jf'o
i4. Boyse, E. A., Lance, E. M., Carsweli, E. A., Cooper, S., Old, L. ]'. Natu~'e~ 1970~ 227, 901. 15. Medico-Pharmaceutical Forum: a report by the Forum's committee on clinical pharmacology on facilities for the early clinical studies of new medicines. 1 Wimpole Street, London W1M 8AE. October, 1970. 16. The Forum was established in 1968, under the chairmanship of Prof. D. R. Lat~rence, to provide an opportunity for representatives of established medical institutions, on the one hand, and of the pharmaceutical industry, on the other, to discuss problems of mutual interest.
work oriented to'yards their projects o r products would enable the units to expand and increase their work output. When work is done for industry, agreements with the company concerned should be negotiated after the project has been costed on a realistic basis, taking into account the time spent by scientific staff and technicians, use of materials, and depreciation of instruments. There are two aspects of the subject on which the report does not dwell and to which the Forum might profitably give attention. T h e first is the training of clinical pharmacologists. T h e report suggests that at least 5 new units should be set up in the next academic quinquenulum, plus the development of existing nucIei in medical schools with a lecturer in clinical pharmacology but little or no supporting facilities. If, however, the report is right in estimating that there are less than 10 units at present in existence in the United Kingdom, and that most of them are small, then it is imperative that urgent consideration be given to the training of clinical pharmacologists to supervise the service, teaching, and research activities of the proposed new departments. This matter has recently been discussed in a W.H.O. technical reportW T h e second aspect is the role of the whole-time medical adviser in the pharmaceutical industry. T h e Association of Medical Advisers in the Pharmaceutical I n dustry has already concerned itself, through symposia -and publications, with p'roblems Of clinical assessment of new drugs, and close association between medical advisers and clinical pharmacology units is essential. Such links can be nothing but beneficial to both parties. T h e inauguration of a section of clinical pharmacology of the British Pharmacological Society 18 has provided an opportunity for all those concerned in the study of drugs in man to meet and discuss their work. I t is to be hoped that this exchange of ideas between medical scientists working in different areas of pharmacology, together with the establishment of clinical pharmacology units staffed by scientists and supervised by trained clinical" pharmacologists, will result in the more rapid recognition, testing, and use of promising drugs.
MERCURY IN FISH MERCURY levels ranging from 0.1 to 0.8 mg. per leg. have been found in samples of canned tuna fish bought in central London on Dec. 16. Following the discovery of high mercury content in canned tuna in the United States, the Government Chemist has now examined over 50 samples from London and elsewhere. No-one is certain just how the mercury got there, though fungicides and industrial wastes are usually named as the original culprits. T h e details of the food chain which carries the mercury ~o the tuna are not d e a r ; but the contamination must be widespread, since mercury has been found in fish from many different seas. I n Britain the Government has told housewives that there is no reason why they should not buy tuna fish, t h o u g h in Sweden the advice to the public has been to eat fish no more than once a week. I n London the Minister of 17. Tech. Rep. Set. Wld Hlth Org. 1970, no. 446. 18." Lancet, 1970~ i, 129.
THE LANCET,JANUARY2, 1971
endometrium, ~9 but the development of suspicious breast changes in bitches given chlormadinone acetate has led to the withdrawal of this compound in Great Britain and other countries. The thromboembolic risk associated with a combined oestrogen/progestagen pill seems to be related to the (estrogen component, but there are suggestions that certain progestagens may also contribute to the risk. z° Alternative routes of progestagen administration are now under investigation. A small silicone polymer capsule containing progestagen has been designed for implantation under the skin. Such capsules will release low-dose progestagen for several years and can be removed to restore fertility. Vaginal rings and intrauterine devices impregnated with progestagen are also being evaluated, and they have the added advantage that the effects of the steroid are more likely to be confined to the uterus. Undoubtedly, if synthetic steroids of any type are to be used in healthy women for contraceptive purposes, their effects on the health of the users must be monitored on a large scale over several decades.
Bone-marrow Transplantation : Unexpected Results FROM time to time attempts have been made to transplant human bone-marrowfl1 but they usually failed. Among the many reasons for failure was the lack of information about human transplantation antigens. During the past few years, however, the main transplantation antigen system of manmthe HL-A system--has been identified and analysed in detail, "2,2'~ and this progress has encouraged the hope that clinical bone-marrow transplantation would be worth reinvestigating. At this stage, it is obviously wise to attempt bone-marrow transplantation from a donor who is HL-A identical with the recipient. Theoretically, this should minimise both the danger of inducing graft-versus-host (G.V.H.) disease 24 and the threat of graft rejection. It might also be expected tO reduce the poor marrow growth effect, a potential hazard which has been observed in experiments with incompatible marrow grafts in mice.95 GP,AW et al. z8 described the results of transplanting into 8 patients with acute lymphocytic leuk~emia bone-marrow from HL-A identical siblings. Some unexpected features were noted. The most important one was that, of 7 patients in whom successful engraftment was obtained, 3 had G.v.H. reactions, 19. Briggs, M. H., Caldwell, A. D. S., Pitchford, A. G. Hosp. Meal. 1967, 2, 63. 20. Inman, W. H. W., Vessey, M. P., Westerholm, B., Engelund, A. Br. med. J. 1970, ii, 203. 21. Bortin, M. M. Transplantation, 1970, 9, 571. 22. Walford, R. L. Ser. tt
and 2 patients died from this complication. Several explanations could be proposed to account for this high rate of G.v.H. reactions. Firstly, the marrow donors might not be HL-A identical with the respective recipients, but this seems unlikely, not only because the lymphocyte typing data indicated HL-A identity but also because donor and recipient cells were mutually non-responsive in culture, a characteristic of HL-A identity. 2r A second explana, tion is that other antigenic systems apart from HL-A might have been responsible for inducing the G.v.rI. reactions. Although non-HL-A transplantation antigen systems are presumed to exist, no other human transplantation antigen system has been specifically identified except for ABO. In GRaW et al.'s series, ABO compatibility was respected except for case 3, in which the graft failed to take. If transplantation antigens which do not belong to the HL-A or ABO systems account for the G.v.H. reactions, either the marrow donors must have been prc-immunised against the recipients (an unlikely possibility) or it is necessary to postulate the existence of other " s t r o n g " human transplantation antigens. 2s So far there is no other evidence indicating their existence. Another, more speculative, notion is that leuk~emic cells may bear tumour-specific antigens which function as transplantation antigens and thus provoke a G.V.m reaction. VIZA et al. 29 showed that leuka:mic cells can stimulate autologous lymphocytes, taken during a remission, to undergo blast-cell transformation. Although other interpretations are possible, this observation could be explained by the existence of leuka:mia-specific antigens. But the syndrome described by GRAW et al. may not necessarily have arisen as a consequence of G.v.H. activity. It may have been due to depletion of the patient's own lymphocytes caused by another factor. Severe lymphocyte depletion, however induced, is known to be capable of causing the same syndrome 30~:~ and it is possible that the immuno -, suppressive regimen used in these patients produced this effect. Finding a clinically satisfactory protocol of immunosuppression which is both effective and non-toxic is likely to prove harder in bone-marrow grafting than in other forms of transplantatiofi. In 1 of the patients in this series a toxic epidermal necrolysis developed and the serum was found to contain a cytotoxic antibody which reacted with the patient's epithelial cells but not lymphoid cells. It may be that, in this patient, donor ceils had replaced a large proportion of the recipient's own lymphoid tissues. 27. Amos, D. B., Bach, F. H . J . exp. &led. 1968, 128, 623. 28. Simonsen, M. Transplant. Rev. 1970~ 3, 22. 29. Viza, D. C., Bernard-Degani, O , Bernard, C., Harris, R. Lanceb 1969, ii, 493. 30. Miller, j. F. A. P. in Transplantation (edited by G. E. W. WolsteO" holme and M. P. Cameron); p. 384. London, 1962. 31. Barnes, D. W. H., Loutit, J. F., Micklem, H. S. Ann. N. Y. Acad. Sd. 1962, 99, 374. 32. Sehlesinger, M., Marks, R. Science, 1964, 143, 965. 33. Batchelor, ]'. R. in Regulation of the Antibody Response (edited by B. Cinader); p. 276. Springfield, Illinois, 1968..
THE LANCET, JANUARY 2 ,
1971
If the circulating antibody was the product of donor
cells, this differential cytotoxicity would be expected. There is also the possibility, however, that the recipient's lymphoid tissue h a d not been replaced by donor cells b u t that the patient's skin cells carried an alloantigen not present oh his ' lymphoid cells. BoYsE et al. x~ demonstrated ~n mice the existence of alloantigens with this tissue-'limited distribution. If such antigens do also exist in man, they could present another class of antigen potentially capable of inducing a tissue-limited f o r m of G.v.~L reaction. At present the scope for ~linical bone-marrow transplantation is obviously small. But i C e i t h e r specific tolerance or immunolpgical enhancement become clinical possibilities, the prospects "could change radically.
TESTING NEW DRUGS EARLY testing of new drugs in man is of the utmost ,concern both to doctors and to the pharmaceutical industry. F o r the doctor, it may m e a n the prompt detection of a treatment superior either in efficacy or lack of toxicity to any hitherto available. For the industry, the early selection of a promising d r u g , or the recognition of unwanted and unacceptable sideeffects, would be a great ecor/omic asset, promoting the more efficient use of research and development resources. Furthermore, with the advent of the Medicines Commission, the requirements for t e s t i n g of drugs, once voluntary, become mandatory. I t is vital, therefore, that means should be readily accessible for the study of new drugs in normal subjects and in patients. Implicit in a report 15 by a working-party o f the Medico-Pharmaceutical Forum, 1° which has been studying the organisation of early clinical studies of new medicines in the United Kingdoms is the belief that the place for such studies, or the centre of their organisation, should be units of clinical pharmacology. Such a umt should b e part of each medical school and also a feature of certain other suitable centres, making a total of 25-30 units in Great Britain. Most units Would cover a range of drugs and diseases, although individual members of a unit would tend to speciakise in some particular area. T h e minimum cost of setting u p a workable unit with 2 established staff, a research fellow, technical and secretarial assistance, running costs, and capital equipment would be about £40,000 in the first year, and £20,000 in subsequent years. This money should come from Government sources-namely, the Department of Health and Social Security and the Department of Education and Science." Additional support by funds from industrial firms for .
- "Jf'o
i4. Boyse, E. A., Lance, E. M., Carsweli, E. A., Cooper, S., Old, L. ]'. Natu~'e~ 1970~ 227, 901. 15. Medico-Pharmaceutical Forum: a report by the Forum's committee on clinical pharmacology on facilities for the early clinical studies of new medicines. 1 Wimpole Street, London W1M 8AE. October, 1970. 16. The Forum was established in 1968, under the chairmanship of Prof. D. R. Lat~rence, to provide an opportunity for representatives of established medical institutions, on the one hand, and of the pharmaceutical industry, on the other, to discuss problems of mutual interest.
work oriented to'yards their projects o r products would enable the units to expand and increase their work output. When work is done for industry, agreements with the company concerned should be negotiated after the project has been costed on a realistic basis, taking into account the time spent by scientific staff and technicians, use of materials, and depreciation of instruments. There are two aspects of the subject on which the report does not dwell and to which the Forum might profitably give attention. T h e first is the training of clinical pharmacologists. T h e report suggests that at least 5 new units should be set up in the next academic quinquenulum, plus the development of existing nucIei in medical schools with a lecturer in clinical pharmacology but little or no supporting facilities. If, however, the report is right in estimating that there are less than 10 units at present in existence in the United Kingdom, and that most of them are small, then it is imperative that urgent consideration be given to the training of clinical pharmacologists to supervise the service, teaching, and research activities of the proposed new departments. This matter has recently been discussed in a W.H.O. technical reportW T h e second aspect is the role of the whole-time medical adviser in the pharmaceutical industry. T h e Association of Medical Advisers in the Pharmaceutical I n dustry has already concerned itself, through symposia -and publications, with p'roblems Of clinical assessment of new drugs, and close association between medical advisers and clinical pharmacology units is essential. Such links can be nothing but beneficial to both parties. T h e inauguration of a section of clinical pharmacology of the British Pharmacological Society 18 has provided an opportunity for all those concerned in the study of drugs in man to meet and discuss their work. I t is to be hoped that this exchange of ideas between medical scientists working in different areas of pharmacology, together with the establishment of clinical pharmacology units staffed by scientists and supervised by trained clinical" pharmacologists, will result in the more rapid recognition, testing, and use of promising drugs.
MERCURY IN FISH MERCURY levels ranging from 0.1 to 0.8 mg. per leg. have been found in samples of canned tuna fish bought in central London on Dec. 16. Following the discovery of high mercury content in canned tuna in the United States, the Government Chemist has now examined over 50 samples from London and elsewhere. No-one is certain just how the mercury got there, though fungicides and industrial wastes are usually named as the original culprits. T h e details of the food chain which carries the mercury ~o the tuna are not d e a r ; but the contamination must be widespread, since mercury has been found in fish from many different seas. I n Britain the Government has told housewives that there is no reason why they should not buy tuna fish, t h o u g h in Sweden the advice to the public has been to eat fish no more than once a week. I n London the Minister of 17. Tech. Rep. Set. Wld Hlth Org. 1970, no. 446. 18." Lancet, 1970~ i, 129.