THE LANCET LONDON
Graft Survival and Immunological Enhancement THE ideal solution for circumventing a homograft response would be to induce specific tolerance to the graft antigens. At present, however, there is no
clinically applicable regimen for inducing tolerance. Another highly specific means of protecting a graft is immunological enhancement-a phenomenon which has been studied in great detail, chiefly by the use of grafts of incompatible transplantable mouse tumours. Immunological enhancement can be a misleading term; it refers to the enhanced survival of an incompatible graft, not to an enhanced immune response. The enhanced survival is caused, paradoxically, by contact of the graft with humoral antibody directed against graft antigens.1 Before going into the question of the mechanisms of enhancement, it is necessary to consider some of the effects of humoral antibody upon grafted cells. Different types of cells are known to have different susceptibilities to the cytotoxic action of alloantibody and complement.2-4
(for example, dissociated lymphoid or myeloid cells) are readily lysed both in vitro and in vivo, while others such as dissociated sarcomas or carcinomas can be lysed only if there is a considerable excess of antibody and complement present.5.6 The cause of this variation in susceptibility to antibody is the different amounts of transplantation antigens on the cell surface. 7 . 8 Those cells having large amounts of antigen on their surface combine with large numbers of antibody molecules, and a corresponding amount of complement fixation occurs. Cell lysis depends, of course, on complement fixation, and cells bearing numerous antigen sites on their surface are therefore vulnerable to humoral antibody and complement. Conversely, cells which carry only sparse numbers of antigen sites on their surface absorb small amounts of antibody, thereby reducing the opportunity for complement-mediated
lysis. 1. 2. 3. 4. 5.
Kaliss, N. Cancer Res. 1958, 18, 992. Gorer, P. A., O’Gorman, P. Transplant Bull. 1956, 3, 142. Gorer, P. A., Boyse, E. A. in Biological Problems of Grafting (edited by F. Albert and P. B. Medawar); p. 193. Oxford, 1959. Hellström, K. E. Transplant Bull. 1959, 6, 411. Boyse, E. A., Old, L. J., Stockert, E. Ann. N.Y. Acad. Sci. 1962, 99,
Chouroulinkov, I., Boyse,
E. A., Old, L. J. Proc. Soc. exp. Biol. Med. 1962, 111, 263. 7. Winn, H. J. Ann. N. Y. Acad. Sci. 1962, 101, 23. 8. Möller, E., Möller, G. J. exp. Med. 1962, 115, 527.
Another factor which influences the effect of antibody upon graft cells is the complement-fixing potency of the antibody involved. Some immunoglobulins fix little or no complement,9 and presumably this accounts for the non-cytotoxic antibodies which have been detected in alloantisera 10,11. The capacity of IgG to fix complement depends upon the integrity of that part of the molecule known as the Fc fragment.9 Controlled digestion of IgG with papain or pepsin removes the complement-fixing portion of the molecule without destroying its antigen-combining power. Antibody fragments can therefore be produced by enzyme digestion which combine specifically with antigen on a cell surface, but do not cause cytolysis even in the presence of complement.10,12 Apart from these strictly immunological considerations, there are physical factors which affect the diffusion of antibodies and complement components through a graft. Since most grafts consist of solid tissues rather than dissociated cells, diffusion gradients through these tissues are likely to have a major effect upon graft susceptibility.
Thus, when humoral antibody combines with graft cells, cell lysis does not always follow; and it is in these circumstances that
immunological enhanceAlthough most of the early work
may be seen. and the analysis of mechanisms of enhancement has been carried out using transplantable tumour grafts, normal tissue grafts may also be enhanced.1,13,14 On p. 1103 this week Dr. FRENCH and Professor BATCHELOR describe experiments showing that immunological enhancement can procure the survival of incompatible rat-kidney grafts for an indefinite period. They found that inbred AS rats transplanted with (August strain X AS) hybrid kidneys survived with functioning grafts if the AS recipients were injected with AS anti-August antiserum at the time of transplantation and on the succeeding four days. They point out that this has obvious implications not only for human renal transplantation but possibly also for other grafts, particularly where heavy immunosuppression is undesirable, as with pulmonary
allografts. the mechanisms of enhancement ? There be at least two important ones. Firstly, if antibody is given to a subject at the same time as antigen, the development of active immunity to that antigen is reduced or completely inhibited. This effect has been demonstrated using transplantation antigens 15 and other more conventional antigens.16
Cohen, S., Porter, R. R. Adv. Immunol. 1964, 4, 287. Chard, T. Immunology, 1968, 14, 583. Voisin, G. A., Kinsky, R., Jansen, F., Bernard, C. Transplantation (in the press). 12. Chard, T., French, M. E., Batchelor, J. R. ibid. 1967, 5, 1266. 13. Nelson, D. S. Br. J. exp. Path. 1962, 43, 1. 14. Chutna, J. Nature, Lond. 1968, 217, 175. 15. Snell, G. D., Winn, H. J., Stimpfling, J. H., Parker, S. J. J. exp. Med. 1960, 112, 293. 16. Uhr, J. W., Baumann, J. B. ibid. 1961, 113, 935.
9. 10. 11.
It is the basis of treatment of rhesus-negative mothers with anti-D antiserum to prevent their becoming sensitised against rhesus-positive cells of their offspring. BILLINGHAM et al.17 referred to the" inhibition of active immunisation by antibody as an afferent " block of the immune response. Presumably the administered antibody combines with antigen, partially or wholly abolishing its power to immunise. It is of course necessary in the context of graft enhancement that the injected antibody does not cause an irreversible state of damage to the graft, and it is interesting that the longest enhancement observed by FRENCH and BATCHELOR was when heterozygous rat donors were used. Such donors would be expected to have quantitatively less antigen on their cells than would homozygotes, and therefore their organs would be less vulnerable to immune damage. The second mechanism believed to be important in enhancement is the competition for antigen sites that is postulated to exist between humoral antibody and immunologically committed lymphocytes which mediate cellular immunity.18-2o Since immunological enhancement can follow active immunisation, inhibition of immunisation (the first mechanism) cannot be a complete explanation. There is considerable evidence in support of the idea that antibody and immune cells compete for the same antigenic recep" tors-i.e., an efferent " block in the immune response. 17 It has been shown that anti-graft antibody can prevent immune lymphocytes from destroying target graft cells both in vivo 18,19 and in vitro.21,22 In the experiments of FRENCH and BATCHELOR the antibody-treated rats did develop an active antibody response; therefore the prolonged survival of the kidney grafts cannot be attributed solely to an inhibition of immunisation. FRENCH and BATCHELOR believe that the injected antibody covered a sufficient number of antigen sites on the transplanted kidney to protect it from irreversible damage by immune lymphocytes, but, on the other hand, sufficient antigen remained uncombined with antibody to permit some active immunisation of the recipient. Subsethe quently antibody actively synthesised by recipient continued to protect the graft-that is, a state of autoenhancement had been reached. These findings and those of STUART et al. 23 and HILDEMANN et al. 24 show that there is a good prospect of immunological enhancement being put to clinical use. 17. 18.
Billingham, R. E., Brent, L., Medawar, P. B. Transplant. Bull. 1956, 3, 84. Batchelor, J. R., Silverman, M. S. in Transplantation (edited by G. E. W. Wolstenholme and M. Cameron); p. 216. London,
1962. 19. Moller, G. J. natn. Cancer Inst. 1963, 30, 1205. 20. Batchelor, J. R. Cancer Res. 1968, 28, 1410. 21. Brunner, K. T., Mauel, J., Cerottini, J. C., Chapuis, B. 22.
Immunology, 1968, 14, 181. Hellström, I., Hellström, K. E., Evans, C. A., Heppner, G. H., Pierce, G. E., Yang, J. P. S. Proc. natn. Acad. Sci. 1969, 62, 362.
Stuart, F. P., Saitoh, T., Fitch, F. W. Science, N. Y. 1968, 160,
1463. 24. Hildemann, W. H.
Transplant. Revs (in the press).
The Irritable Bowel ONE of the commonest causes of abdominal pain is what has been called the " irritable colon" or " spastic colon " syndrome; but, despite excellent descriptions of the characteristic symptoms, many
patients undergo biochemical and radiological investigations1 of all accessible abdominal viscera before the diagnosis is reluctantly accepted. This situation arises partly because insufficient attention is paid to the details of the symptoms and signs, and partly because the mechanism of symptom production is ill understood and visible or tangible evidence of pathological change is lacking. One consequence of the lack of objective " evidence is the doctor’s continuing anxiety about the diagnosis, and another is the purposive use of synonyms such as " colon neurosis " functional colon ", and " psychogenic "
diarrhoea ". CONNELL et al.demonstrated, in a selected group subjects, that after a meal the sigmoid colon responded with recurring peaks of high pressure in tubes placed within it. They recorded this manifestation of gut activity in the colon of three groups: (1) those with a duodenal ulcer in remission and no bowel symptoms; (2) those with " spastic colon"" whose abdominal pain was not brought on by eating during the investigation; and (3) those with " spastic colon " whose symptoms were brought on or aggravated by a meal eaten during the study. Those who had pain after eating produced waves of higher pressure and for a greater proportion of the recording time, both before and after a meal, than did the other groups. Hypermotility usually began some minutes before discomfort was noticed, but the conclusion was that the hypermotility was in some way related to the development of abdominal pain. The pain was not felt in the region of the sigmoid, and it did not correspond in its time-intensity pattern with the change in pressure within. the recording system. Indeed, each of three recording tubes, spaced 5 cm. apart, registered independent changes of pressure so that, if the high peak of pressure was responsible for pain, then a very large number of sites of production of "pain" impulses must exist. In one subject a similar pattern of hypermotility was recorded by telemetering capsule in the terminal ileum after a meal. of
HOLDSTOCK et al. have extended the investigations to another group of patients with severe abdominal pain for which no cause was found after a variety of investigations, but in whom unusually high peaks of pressure were recorded from the colon or small intestine. As in the previous inquiry, the patients included were those with an abnormal pattern in the pressure record. What is particularly interesting in 1. 2. 3.
Waller, S. L., Misiewicz, J. J. Lancet, Oct. 11, 1969, p. 753. Connell, A. M., Jones, F. A., Rowlands, E. N. Gut, 1965, 6, 105. Holdstock, D. J., Misiewicz, J. J., Waller, S. L. ibid. 1969, 10,