2
940 lay in the men in the high cholesterol range. Similarly the diet appeared most effective in the men who were less than 65-5 years old at entry to the trial. DAYTON et al.3 admit that this trial, as with most of its predecessors, has fallen short of providing a definite answer. They suggest that at best it has shown that there may be retardation of the athero- matous process but not reversal. The main design of this trial and its double-blind technique were good, but results must be interpreted in the light of several weaknesses. First, the age of the men at entry pro- duced a selected population who had survived the toll of coronary thrombosis in the fourth and fifth decades of life. The mean age in each group was 65 years, but whereas only 3 were under 55, 12 were over 85. In fact, deaths from non-atherosclerotic events were greater in the experimental group towards the end of the trial. Secondly, more than 50% of the total food eaten by the men in the diet group was not the special diet, and little is known of the composition of the other food eaten. Thirdly, there was a ten- dency for those men who were well to leave the Center and be lost to the trial. Fourthly, there were more heavy cigarette smokers in the control group. This trial shows the immense difficulties investiga- tors face in planning and evaluating the effects of dietary change in a population. These men were in an institution; the unsaturated margarine, " filled " milk, imitation ice-cream, special sausage products, and " filled " cheese on which the diet was based were donated by industry; and separate canteen facilities were used which meant that the two groups were unable to compare meals directly. With all these advantages, strict dietary control was found to be far less successful than in those other trials 4-6 where men, having had an infarction, were highly motivated to cooperate fully 24 hours of each day, although living at home and pursuing their careers. " Strange English Pigs " IN this country CALNE and his colleagues ’-10 demonstrated that the pig will not readily reject liver homografts, whereas skin, kidney, and heart homo- grafts are rejected in a predictable way. Workers in Bristol 11 also noted that the pig’s liver was less readily rejected than other homografts; but others have failed 6. Bierenbaum, M. L., Green, D. P., Florin, A., Fleischmann, A. I., Caldwell, A. B. J. Am. med. Ass. 1967, 202, 1119. 7. Calne, R. Y., White, H. J. O., Yoffa, D. E., Binns, R. M., Maginn, R. R., Herbertson, R. M., Millard, P. R., Molina, V. P., Davis, D. R. Br. med. J. 1967, iv, 645. 8. Calne, R. Y., White, H. J. O., Yoffa, D. E., Maginn, R. R., Binns, R. M., Samuel, J. R., Molina, V. P. ibid. 1967, ii, 478. 9. Calne, R. Y., White, H. J. O., Binns, R. M., Herbertson, B. M., Millard, P. R., Pena, J., Salaman, J. R., Samuel, J. R., David, D. R. Transplantation Proceedings; vol. I, part 1, p. 321, New York, 1969. 10. Calne, R. Y., Sells, R. A., Pena, J. R., Davis, D. R., Millard, P. R., Herbertson, N. B., Binns, R. M., Davies, D. A. L. Nature, Lond. 1969, 223, 472. 11. Riddell, A. G., Terblanche, J., Peacock, J. H., Tierris, E. J., Hunt, A. C. in Advance in Transplantation (edited by J. Dausset, J. Hamburger, and G. Mathé); p. 639. Copenhagen, 1967. to confirm that it is an immunologically privileged organ. Some workers apparently find it hard to ac- cept the results of CALNE and his associates, and questions have been asked about these " strange English pigs ".12 Despite such scepticism, it is clear that CALNE and his colleagues have, within the strains of Large White and Landrace pigs, observed im- portant phenomena. The latest evidence 10 suggests that transplantation of orthotopic or accessory hepatic grafts induces a state of immunological tolerance in the pig; and a pig-liver homograft has been shown to prolong the survival of skin, renal, and cardiac homo- grafts from the same donor animal. In some experi- ments the survival of skin and renal homografts from different donor animals was prolonged by the pres- ence of a hepatic homograft, but less strikingly or consistently than when the donor was the same. Pro- tection of donor-specific skin-grafts was observed when skin-grafting was performed either on the day of liver grafting or delayed for 13-14 days thereafter. There are apparently no adverse effects on the hepa- tic grafts after the rejection of skin grafted either at the same time as or later than the hepatic graft. Sensitisation of the recipient by a previous renal homograft results in rejection of hepatic homografts,9 so a similar effect might be expected with a sensitising skin-graft. Thus the protective effect of porcine hepatic homografts is demonstrable only in a first-set reaction and not in animals sensitised by a previous graft. Furthermore, removal of an accessory liver two hours after it has been transplanted at the same time as skin and renal grafts resulted in no protection for these grafts; but if the liver was removed after twenty-four hours, survival of skin and kidney homo- grafts was prolonged. These experiments provide a reasonable basis for the view that the immunosup- pressive effect of pig-liver grafting acts during the recognition or perhaps central phase of the homograft response. The liver may release histocompatibility antigens which can induce partial tolerance in im- munologically mature animals. Such an explanation is supported by an experiment in which 2 out of 8 one-week-old litter mates who were given " soluble liver-antigen" extracts then showed modified rejec- tion of skin from the liver donor. These 2 pigs later accepted renal grafts from the original donor. These results are hard to evaluate, particularly since the observations concern recipient pigs whose genetic and histocompatibility relationship to donor or donors are unknown. Survival of pig hepatic homografts is apparently mainly an English pheno- menon : if pig livers do release antigens in a tolerance- inducing form, why do they not do so on both sides of the Atlantic ? Early work on immunological toler- ance or paralysis (the terms are interchangeable 13) indicated that it required the introduction of antigen 12. Surgical Research Society Summer Meeting, London, June 29 to July 2, 1969. 13. Dresser, D. W., Mitchison, N. A. Adv. Immun. 1968, 8, 129.

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Page 1: " Strange English Pigs "

940

lay in the men in the high cholesterol range. Similarlythe diet appeared most effective in the men who wereless than 65-5 years old at entry to the trial.DAYTON et al.3 admit that this trial, as with most of

its predecessors, has fallen short of providing a

definite answer. They suggest that at best it hasshown that there may be retardation of the athero-matous process but not reversal. The main design ofthis trial and its double-blind technique were good,but results must be interpreted in the light of severalweaknesses. First, the age of the men at entry pro-duced a selected population who had survived thetoll of coronary thrombosis in the fourth and fifthdecades of life. The mean age in each group was 65

years, but whereas only 3 were under 55, 12 were over85. In fact, deaths from non-atherosclerotic eventswere greater in the experimental group towards theend of the trial. Secondly, more than 50% of thetotal food eaten by the men in the diet group was notthe special diet, and little is known of the compositionof the other food eaten. Thirdly, there was a ten-dency for those men who were well to leave the Centerand be lost to the trial. Fourthly, there were moreheavy cigarette smokers in the control group.

This trial shows the immense difficulties investiga-tors face in planning and evaluating the effects ofdietary change in a population. These men were inan institution; the unsaturated margarine,

" filled "

milk, imitation ice-cream, special sausage products,and " filled " cheese on which the diet was basedwere donated by industry; and separate canteen

facilities were used which meant that the two groupswere unable to compare meals directly. With allthese advantages, strict dietary control was found tobe far less successful than in those other trials 4-6

where men, having had an infarction, were highlymotivated to cooperate fully 24 hours of each day,although living at home and pursuing their careers.

" Strange English Pigs "IN this country CALNE and his colleagues ’-10

demonstrated that the pig will not readily reject liverhomografts, whereas skin, kidney, and heart homo-grafts are rejected in a predictable way. Workers inBristol 11 also noted that the pig’s liver was less readilyrejected than other homografts; but others have failed6. Bierenbaum, M. L., Green, D. P., Florin, A., Fleischmann, A. I.,

Caldwell, A. B. J. Am. med. Ass. 1967, 202, 1119.7. Calne, R. Y., White, H. J. O., Yoffa, D. E., Binns, R. M., Maginn,

R. R., Herbertson, R. M., Millard, P. R., Molina, V. P., Davis,D. R. Br. med. J. 1967, iv, 645.

8. Calne, R. Y., White, H. J. O., Yoffa, D. E., Maginn, R. R., Binns,R. M., Samuel, J. R., Molina, V. P. ibid. 1967, ii, 478.

9. Calne, R. Y., White, H. J. O., Binns, R. M., Herbertson, B. M.,Millard, P. R., Pena, J., Salaman, J. R., Samuel, J. R., David, D. R.Transplantation Proceedings; vol. I, part 1, p. 321, New York,1969.

10. Calne, R. Y., Sells, R. A., Pena, J. R., Davis, D. R., Millard, P. R.,Herbertson, N. B., Binns, R. M., Davies, D. A. L. Nature, Lond.1969, 223, 472.

11. Riddell, A. G., Terblanche, J., Peacock, J. H., Tierris, E. J., Hunt,A. C. in Advance in Transplantation (edited by J. Dausset, J.Hamburger, and G. Mathé); p. 639. Copenhagen, 1967.

to confirm that it is an immunologically privilegedorgan. Some workers apparently find it hard to ac-cept the results of CALNE and his associates, andquestions have been asked about these " strangeEnglish pigs ".12 Despite such scepticism, it is clearthat CALNE and his colleagues have, within the strainsof Large White and Landrace pigs, observed im-portant phenomena. The latest evidence 10 suggeststhat transplantation of orthotopic or accessory hepaticgrafts induces a state of immunological tolerance inthe pig; and a pig-liver homograft has been shown toprolong the survival of skin, renal, and cardiac homo-grafts from the same donor animal. In some experi-ments the survival of skin and renal homografts fromdifferent donor animals was prolonged by the pres-ence of a hepatic homograft, but less strikingly orconsistently than when the donor was the same. Pro-tection of donor-specific skin-grafts was observedwhen skin-grafting was performed either on the dayof liver grafting or delayed for 13-14 days thereafter.There are apparently no adverse effects on the hepa-tic grafts after the rejection of skin grafted either atthe same time as or later than the hepatic graft.Sensitisation of the recipient by a previous renal

homograft results in rejection of hepatic homografts,9so a similar effect might be expected with a sensitisingskin-graft. Thus the protective effect of porcinehepatic homografts is demonstrable only in a first-setreaction and not in animals sensitised by a previousgraft. Furthermore, removal of an accessory livertwo hours after it has been transplanted at the sametime as skin and renal grafts resulted in no protectionfor these grafts; but if the liver was removed aftertwenty-four hours, survival of skin and kidney homo-grafts was prolonged. These experiments provide areasonable basis for the view that the immunosup-pressive effect of pig-liver grafting acts during therecognition or perhaps central phase of the homograftresponse. The liver may release histocompatibilityantigens which can induce partial tolerance in im-munologically mature animals. Such an explanationis supported by an experiment in which 2 out of 8one-week-old litter mates who were given " solubleliver-antigen" extracts then showed modified rejec-tion of skin from the liver donor. These 2 pigs lateraccepted renal grafts from the original donor.

These results are hard to evaluate, particularlysince the observations concern recipient pigs whosegenetic and histocompatibility relationship to donoror donors are unknown. Survival of pig hepatichomografts is apparently mainly an English pheno-menon : if pig livers do release antigens in a tolerance-inducing form, why do they not do so on both sides ofthe Atlantic ? Early work on immunological toler-ance or paralysis (the terms are interchangeable 13)indicated that it required the introduction of antigen12. Surgical Research Society Summer Meeting, London, June 29 to

July 2, 1969.13. Dresser, D. W., Mitchison, N. A. Adv. Immun. 1968, 8, 129.

Page 2: " Strange English Pigs "

941

into an immunologically immature animal. 14-20 Re-duction of the allogeneic cell dose required to inducetolerance in mice resulted in immunity 21; and fetalsheep were shown to respond to a variety of anti-gens.22 The idea of a special period of susceptibilityto tolerance was re-examined, and induction of toler-ance in adult life was demonstrable. 23-25 No systematicdifference 13 seems to exist between the dose of antigenrequired to induce tolerance in the newborn and thatrequired in the adult, providing the antigen is givenunder non-immunising conditions or in a non-

immunogenic form.13 In other words, if the animalcan be prevented from producing antibody against anantigen for a given period then a state of immuno-logical paralysis to subsequent challenge with thesame antigen may be induced. This, of course, is anover-simplification since immunity and tolerance cancoexist." 21

Several explanations for the pig-liver findings aretenable. The liver graft may interfere in a non-specificway with recognition of transplantation antigens,whether these are in the liver itself or in tissues or

organs transplanted at the same time: it may inhibitthe production of antibody to such antigens; or it mayrelease antigen in a form which is not recognised bythe recipient. The practice of transfusing donorblood at the time of liver transplantation may affectthe outcome; tolerance has been induced in puppies 28and human newborns 29-31 by massive transfusion.But 2 pigs who received liver-grafts without donorblood did not seem to reject their hepatic allograftsmore severely than transfused pigs Release of anti-gens by a liver homograft in a tolerance-inducingform cannot explain why a renal or skin homografttransplanted at the same time is protected from rejec-tion unless some additional mechanism preventsrecognition of renal and skin transplantation antigensor inhibits the sequence of events whereby the reci-pient produces antibody against these tissues. A renalor skin graft transplanted alone may be recognised14. Burnet, F. M., Fenner, F. The Production of Antibodies. New

York, 1949.15. Owen, R. D. Science, N. Y. 1945, 102, 400.16. Billingham, R. E., Brent, L., Medawar, P. B. Nature, Lond. 1953,

172, 603.17. Billingham, R. E., Brent, L., Medawar, P. B. Phil. Trans. R. Soc.

B. 1956, 239, 357.18. Hasek, M. Czechoslovak Biol. 1953, 2, 265.19. Hanan, R., Oyama, J. J. Immun. 1954, 73, 49.20. Cinader, B., Dubert, J. M. Br. J. exp. Path. 1955, 36, 515.21. Howard, J. G., Michie, D. Transplantn Bull. 1962, 29, 91.22. Silverstein, A. M., Uhr, J. W., Kraner, K. L., Lukes, R. J. J. exp.

Med. 1963, 117, 799.23. Mariani, T., Martinez, C., Smith, J. M., Good, R. A. Proc. Soc. exp.

Biol. Med. 1959, 101, 596.24. Brent, L., Gowland, G. Nature, Lond. 1962, 196, 1298.25. Good, R. A., Kelly, W. D., Martinez, C., Pollara, B., Homes, B. M.,

McKneally, M. F., Gabrielsen, A. E. in Immunopathology(edited by P. Graber and P. A. Miescher); p. 145. Basle, 1966.

26. Mitchison, N. A. Proc. R. Soc. Lond. B. 1964, 161, 275.27. Nossal, G. J. V., Austin, C. M. Aust. J. exp. Biol. med. Sci. 1966,

4, 327.28. Puza, A., Gombos, A. Transplantn Bull. 1958, 5, 30.29. Albert, F., Lejeune-Ledant, G., Moureau, P., Andre, A. in Biological

Problems of Grafting (edited by F. Albert and P. Medawar); p.369. Oxford, 1959.

30. Fowler, R., Schubert, W. K., West, C. D. Ann. N.Y. Acad. Sci.1960, 87, 403.

31. Maris, F. Folia biol., Praha, 1961, 7, 75.

because lymphocytes, or other cells, become sensitisedas they pass through the graft, because antigens arereleased from the graft and taken up by lymphoidorgans where sensitisation occurs. But a simultaneousliver homograft would not be expected to preventrelease of antigen from the kidney or skin or to pre-vent sensitisation within the grafts themselves, andany explanation must postulate a non-specific depres-sion of antigen-recognition factors, interference in thecentral phase of the immune response, or a selectiveuptake of antigen released from skin or kidney graftsby the accessory liver. Moreover, if the pigs used byCALNE et al. do prove to have a close histocompati-bility relationship, a non-specific depression of theinductive or central phase of the homograft responsemight be more likely to promote tolerance across minorhistocompatibility barriers than across wider barriers.The finding that accessory liver must be in position

for at least twenty-four hours before any protectiveeffect is demonstrable on renal grafts is in keepingwith the finding of MITCHISON 32 that two hours’ in-vivo exposure to protein antigens is required to para-lyse blood lymphocytes, whereas twenty-four hours isneeded to paralyse cells from lymphoid organs.32Thus, the liver’s presence for twenty-four hours mayallow tolerance to be induced throughout the entirelymphoid system of the pig. It is not known what

type of cell is the immediate target of antigen duringthe induction of tolerance, but the cell finally affectedhas been identified as the lymphocyte,33,34 so perhapsa defect should be sought in the activity of the lym-phocyte population of these pigs. Adoptive transferexperiments are not possible in pigs, and CALNE andhis colleagues 10 are investigating this point by meas-uring the response of pig peripheral blood-lympho-cytes to donor antigen in vitro.

Annotations

BAN ON CYCLAMATE SWEETENERS

CYCLAMIC acid and its sodium and calcium saltsare synthetic sweetening agents which have beenused in food in the United States since 1950 and in

many other countries. In Britain their addition to

soft drinks was permitted in 1965 and in all foodswithout limitation, except for soft drinks and ice-

cream, in 1967. All along, there has been uneasinessabout their safety,35 largely because a derivative,cyclohexylamine, can in certain experimental situa-tions be carcinogenic in animals. At least two largecompanies selling food in the United Kingdom donot use cyclamates in their own products.A fortnight ago the United States Government

announced its intention to forbid the sale of productscontaining cyclamates after the end of 1969. Sweden,32. Mitchison, N. A. Immunology, 1968, 15, 541.33. Gowans, J. L., McGregor, D. D., Cowen, D. M., Ford, C. E.

Nature, Lond. 1962, 196, 651.34. Billingham, R. E., Silvers, W. K., Wilson, D. B. J. exp. Med. 1963,

118, 397.35. See Lancet, 1966, i, 134.