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STRONG TRANSPLANTATION ANTIGENS IN MAN
1117
arguments of Dr. Doll. Eight years ago smoke was carcinogenic, now it is only a vague " promoter ". Lung cancer had an induction period of twenty years, and then giving up smoking had little effect; now the period approaches the lifespan of man and giving up smoking has
TABLE II-MOORHEAD AND
RESULTS REVISED
"
surprising " effect. It is ironical that the Government should now irretrievably commit itself in support of Doll’s claim to have found the cause of cancer by statistics, when this unfortunate controversy is ending in fiasco.
a
PATEL’S
Law Hospital, Carluke, Lanarkshire.
T. W. LEES.
STRONG TRANSPLANTATION ANTIGENS IN MAN SIR,-Dr. Simonsen’s hypothesis (Feb. 20) interested me greatly, as I too have been striving for a genetical interpretation in terms histo-compatibility genes, of the results of Moorhead and Patel with the normal lymphocyte transfer (N.L.T.) test.! Unfortunately these results are not suitable for Dr. Simonsen’s estimate of the number of histo-compatibility alleles in man. The working hypothesis of Moorhead and Patel, following Brent and Medawar,2 and also accepted by Simonsen, is that the primary reaction (appearing at its maximum 48 hours after injection of the lymphocytes) is graft-versus-host, and the secondary reaction (measured at 11 days) is host-versusgraft. If this were true the reciprocal tests advocated by Simonsen would be redundant since they would merely duplicate the information from the primary and secondary reactions in a unilateral N.L.T. test. The evidence of Moorhead and Patel is, however, incompatible with such an interpretation. They found 15 double negatives (first and second reactions both negative) in 80 tests (table I). According to Simonsen this can be accounted TABLE I-MOORHEAD AND
PATEL’S
RESULTS IN CONDENSED FORM
+ =primary and/or secondary weals. 0 =no weals. M=male. F =female.
recording the reaction
to distinguish between erythema and The weal-which has since been more accurately described3 as a " shotty induration," more palpable than visible-is probably more relevant than the erythema to histo-
weal.
compatibility. If Moorhead and Patel’s results are re-analysed in terms of weals only, there is a great increase in negative reactions and in double negatives (table 11), making interpretation along the lines of Brent and Medawar even more inappropriate. Reciprocal N.L.T. provides a further test of the hypothesis, under which each primary reaction is equivalent to the reciprocal secondary. Harris et al. have made such tests using the four donors of Moorhead and Patel and the recipient who gave doubly negative reactions with all four donors (female no. 4, table I). These tests showed that primary and reciprocal secondary reactions are unlike-the absence of correlation between them applies both to the sign (positive or negative) and to the magnitude of the reaction. It is obviously premature to propose a genetic model for the results of N.L.T. From the independent variation of weals and erythema, and primary and secondary reactions, it may turn out that primary weal, secondary weal, primary erythema, and secondary erythema represent four different incompatibility systems, of which some or all are concerned with homograft compatibility for skin and organs. The lack of a theoretical interpretation of N.L.T. does not necessarily detract from its prognostic value as an empirical test for skin and organ grafting. Indeed, comparisons of skin grafts and N.L.T. tests on the same individuals may provide the solution to the theoretical
problem. A and B refer to blood-groups. + =primary and/or secondary reaction. 0 =doubly negative reaction.
M =male.
Moorhead, J. F., Patel, A. R. Br. med. J. 1964, ii, 1111. Brent, L., Medawar, P. B. ibid. 1963, ii, 269. Harris, R., et. al. Unpublished.
A. J. BATEMAN.
" CHEAP" DRUGS
F =female.
for by 4 compatibility alleles of equal frequency-but on his hypothesis double negatives indicate genetic identity of donor and recipient. Donors giving double negatives with the same recipient should be identical, as should recipients giving double negatives with the same donor-from table I, this is obviously untrue. Two recipients, both doubly negative with one donor behave differently with other donors, and vice versa. The non-identity of two persons giving double negative reactions with a third person is all the more striking when one takes into account the sign and size of primary and secondary reactions, as given in the original published data. The hypothesis is therefore untenable. Further, in the original records of these N.L.T. tests (to which I have had access by kind permission of Prof. P. M. Sheppard and Dr. C. A. Clarke of Liverpool University), the area of the weal and the total area of the reaction (weal and/or erythema) are shown separately, while in their paper 1 Moorhead and Patel give only the total areas. In about half the tests the erythema had an area greater than the weal, and in many of these cases no weal was recorded. In subsequent tests3 special efforts have been made to reduce the amount of red cells with the injected lymphocytes, and erythema is greatly reduced. It is obviously important in 1. 2. 3.
Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester, 20.
SIR,-We pleased to read your annotation (May 1) and of the doubts which are now being raised about the " efficacy of cheap " drugs. We have noticed a striking increase in the number of toxic were
reactions in patients treated with Italian chloramphenicol and tetracycline. Whereas, in the past, reactions to chloramphenicol and, particularly, tetracycline had been unusual in our experience, within three months of the changeover to foreignmanufactured antibiotics 10 cases were observed-mainly with skin rashes, at times amounting to exfoliative dermatitis.
We decided that the interests of economy in prescribing did not justify the exposure of seriously ill patients to an increased risk of reactions, and therefore insisted on supplies of British-made antibiotics. At the same time, we expressed our concern to the firm distributing the cheap antibiotics in this country, and asked for proof of their purity and safety, which they were unable to provide. We then received a warning from the Ministry that, although they could not prevent us using British antibiotics, we might be called upon to justify our action. Despite this threat we have continued to use proven products. S. Z. KALINOWSKI E. N. MOYES. Worcester Royal Infirmary.
arguments of Dr. Doll. Eight years ago smoke was carcinogenic, now it is only a vague " promoter ". Lung cancer had an induction period of twenty years, and then giving up smoking had little effect; now the period approaches the lifespan of man and giving up smoking has
TABLE II-MOORHEAD AND
RESULTS REVISED
"
surprising " effect. It is ironical that the Government should now irretrievably commit itself in support of Doll’s claim to have found the cause of cancer by statistics, when this unfortunate controversy is ending in fiasco.
a
PATEL’S
Law Hospital, Carluke, Lanarkshire.
T. W. LEES.
STRONG TRANSPLANTATION ANTIGENS IN MAN SIR,-Dr. Simonsen’s hypothesis (Feb. 20) interested me greatly, as I too have been striving for a genetical interpretation in terms histo-compatibility genes, of the results of Moorhead and Patel with the normal lymphocyte transfer (N.L.T.) test.! Unfortunately these results are not suitable for Dr. Simonsen’s estimate of the number of histo-compatibility alleles in man. The working hypothesis of Moorhead and Patel, following Brent and Medawar,2 and also accepted by Simonsen, is that the primary reaction (appearing at its maximum 48 hours after injection of the lymphocytes) is graft-versus-host, and the secondary reaction (measured at 11 days) is host-versusgraft. If this were true the reciprocal tests advocated by Simonsen would be redundant since they would merely duplicate the information from the primary and secondary reactions in a unilateral N.L.T. test. The evidence of Moorhead and Patel is, however, incompatible with such an interpretation. They found 15 double negatives (first and second reactions both negative) in 80 tests (table I). According to Simonsen this can be accounted TABLE I-MOORHEAD AND
PATEL’S
RESULTS IN CONDENSED FORM
+ =primary and/or secondary weals. 0 =no weals. M=male. F =female.
recording the reaction
to distinguish between erythema and The weal-which has since been more accurately described3 as a " shotty induration," more palpable than visible-is probably more relevant than the erythema to histo-
weal.
compatibility. If Moorhead and Patel’s results are re-analysed in terms of weals only, there is a great increase in negative reactions and in double negatives (table 11), making interpretation along the lines of Brent and Medawar even more inappropriate. Reciprocal N.L.T. provides a further test of the hypothesis, under which each primary reaction is equivalent to the reciprocal secondary. Harris et al. have made such tests using the four donors of Moorhead and Patel and the recipient who gave doubly negative reactions with all four donors (female no. 4, table I). These tests showed that primary and reciprocal secondary reactions are unlike-the absence of correlation between them applies both to the sign (positive or negative) and to the magnitude of the reaction. It is obviously premature to propose a genetic model for the results of N.L.T. From the independent variation of weals and erythema, and primary and secondary reactions, it may turn out that primary weal, secondary weal, primary erythema, and secondary erythema represent four different incompatibility systems, of which some or all are concerned with homograft compatibility for skin and organs. The lack of a theoretical interpretation of N.L.T. does not necessarily detract from its prognostic value as an empirical test for skin and organ grafting. Indeed, comparisons of skin grafts and N.L.T. tests on the same individuals may provide the solution to the theoretical
problem. A and B refer to blood-groups. + =primary and/or secondary reaction. 0 =doubly negative reaction.
M =male.
Moorhead, J. F., Patel, A. R. Br. med. J. 1964, ii, 1111. Brent, L., Medawar, P. B. ibid. 1963, ii, 269. Harris, R., et. al. Unpublished.
A. J. BATEMAN.
" CHEAP" DRUGS
F =female.
for by 4 compatibility alleles of equal frequency-but on his hypothesis double negatives indicate genetic identity of donor and recipient. Donors giving double negatives with the same recipient should be identical, as should recipients giving double negatives with the same donor-from table I, this is obviously untrue. Two recipients, both doubly negative with one donor behave differently with other donors, and vice versa. The non-identity of two persons giving double negative reactions with a third person is all the more striking when one takes into account the sign and size of primary and secondary reactions, as given in the original published data. The hypothesis is therefore untenable. Further, in the original records of these N.L.T. tests (to which I have had access by kind permission of Prof. P. M. Sheppard and Dr. C. A. Clarke of Liverpool University), the area of the weal and the total area of the reaction (weal and/or erythema) are shown separately, while in their paper 1 Moorhead and Patel give only the total areas. In about half the tests the erythema had an area greater than the weal, and in many of these cases no weal was recorded. In subsequent tests3 special efforts have been made to reduce the amount of red cells with the injected lymphocytes, and erythema is greatly reduced. It is obviously important in 1. 2. 3.
Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester, 20.
SIR,-We pleased to read your annotation (May 1) and of the doubts which are now being raised about the " efficacy of cheap " drugs. We have noticed a striking increase in the number of toxic were
reactions in patients treated with Italian chloramphenicol and tetracycline. Whereas, in the past, reactions to chloramphenicol and, particularly, tetracycline had been unusual in our experience, within three months of the changeover to foreignmanufactured antibiotics 10 cases were observed-mainly with skin rashes, at times amounting to exfoliative dermatitis.
We decided that the interests of economy in prescribing did not justify the exposure of seriously ill patients to an increased risk of reactions, and therefore insisted on supplies of British-made antibiotics. At the same time, we expressed our concern to the firm distributing the cheap antibiotics in this country, and asked for proof of their purity and safety, which they were unable to provide. We then received a warning from the Ministry that, although they could not prevent us using British antibiotics, we might be called upon to justify our action. Despite this threat we have continued to use proven products. S. Z. KALINOWSKI E. N. MOYES. Worcester Royal Infirmary.