THE LYMPHOCYTE IN THE GUT

of 2 /2
31 Cattle leukaemia came under close investigation when, around the turn of the century, the disease entered East Prussia from the east and spread west- wards in Germany. 3 Though called a leukaemia, in terms of human disease it is more properly regarded as a lymphosarcoma; it was easily recognised in abattoirs, and in Europe, the U.S.S.R., and the U.S.A. meat was commonly condemned because of it. By 1918 it had reached the Elbe, and thereafter it seemed to spread westward with increasing speed. Epidemio- logical investigations were mounted, especially in Denmark where in 1953 the annual incidence was 41 per 100,000 as opposed to 100 per 100,000 in Germany. Cattle leukaemia was not distributed evenly in Denmark, and Bendixen’s work ’’’" suggested that it spread from herd to herd by purchase of cattle. The disease affected all races of bovines, and large herds were worse affected than the smaller herds. Bendixen concluded that the disease was infectious and potentially controllable by slaughter of infected cattle; these, it seemed, might be identified at a pre- leukosis phase by their peripheral lymphocytosis. In the U.S.A., Marshak and his co-workers’7 took up these investigations and continued them over a long period. They did not agree that peripheral lymphocytosis was a constant feature in animals that were to acquire the disease. 8 They found an apparent genetic influence: the progeny of certain cows and bulls acquired the lymphosarcoma over several generations. But evidence for involvement of an infectious virus mounted steadily. Dutcher et al. 9 found structures in milk which may have been viruses; and later a C-type virus was found in cell-line cultures of lymphocytes from lymphosarcomatous cattle.1o Its antigenic structure has been examined 11 and com- pared 12 with that of murine and feline leukaemia viruses, and infection can be detected by fluorescent and precipitin antibody tests. 13 s Olsen et al. 14 noted that 5 of 13 sheep injected with virus-containing cultured lymphocytes from a case of bovine lymphosarcoma died of lymphosarcoma; and the cultured lymphocytes of the dead animals contained C-type particles. All these findings were discussed at an international conference in Argentina, the proceedings of which have just been published." In the experiments with infant chimpanzees, unpasteurised milk was used in all cases. 6 controls received milk from non-affected 3. Clemmesen, J. Statistical Studies in the Aetiology of Malignant Neoplasms; vol. i. Copenhagen, 1965. 4. Bendixen, H. J. Thesis, University of Copenhagen, 1962. Cited by Clemmesen.3 5. Bendixen, H. J. Ann. N.Y. Acad. Sci. 1963, 108, 1241. 6. Marshak, R. R., Hare, W. C., Abt, D. A., et al. ibid. p. 1284. 7. Abt, D. A., Marshak, R. R., Kulp, H. W., Pollock, R. J., Jr. Com- parative Leukemia Research 1969 (Bibl. hœmat. no. 36) (edited by R. M. Dutcher); p. 527. Basle, 1970. 8. Croshaw, J. E., Jr., Abt, D. A., Marshak, R. R., Hare, W. C. D., Switzer, J., Ipsen, J., Dutcher, R. M. Ann. N.Y. Acad. Sci. 1963, 108, 1193. 9. Dutcher, R. M., Larkin, E. P., Marshak, R. R. J. natn. Cancer Inst. 1964, 33, 1055. 10. Ferrer, J. F., Stock, N. D., Lin, P. S. ibid. 1971, 47, 613. 11. Ferrer, J. F., Avila, L. A., Stock, N. D. ibid. p. 1864. 12. Ferrer, J. F. Cancer Res. 1972, 32, 1871. 13. Ferrer, J. F., Bhatt, D. M. Proc. Am. Ass. Cancer Res. 1973, 14, 18. 14. Olsen, C., Miller, L. D., Miller, J. M., Hoss, H. E. J. natn. Cancer Inst. 1972, 49, 1463. 15. Pasqualini, C. D. (editor). Zoonosis and its Possible Relation to Human Lymphomas and Leukaemias. Argentine Society of Clinical Investigation. Medicina (Buenos Aires), 1974, suppl. 1, (English and Spanish). cows; and 6 had milk from infected cows, two of them from fcow believed to be a reliable and abundant source of virus. These last two died at 34 and 45 weeks of age after a 5-6-week illness in which leukaemia was accompanied by progressive pneumonia due to Pneumocystis carinii. Since neither this pneumonia nor leukaemia has ever previously been reported in chimpanzees, these findings are very disturbing. In view of their public-health importance they urgently need confirmation. THE LYMPHOCYTE IN THE GUT LYMPHOCYrES are predominant in Peyer’s patches and form a large proportion of the cells in the small- intestinal lamina propria. Their involvement in immunological reactions in the gut is certain, but the fundamental mechanisms and how their dysfunction plays a part in intestinal disease remain obscure. Some of the current work in this area was discussed last month at St Bartholomew’s Hospital. It has been proposed that the Peyer’s patch of the mammalian small intestine is the equivalent of the avian bursa of Fabricius. Prof. Delphine Parrott pointed out, however, that in animals B and T lym- phocytes are found in Peyer’s patches within three days of birth, and furthermore prenatal resection of the small bowel does not impair subsequent immuno- logical function 2-both arguments against the Peyer’s patch being a primary lymphoid organ. Her work in Glasgow shows that the predominant lymphocyte in a Peyer’s patch is a B cell, but that the areas between nodules, and the region underlying the epithelial cells, the " dome ", are both populated mainly by thymus- dependent cells, T lymphocytes. The mucosa over the dome has no villi, its epithelial cells are reduced in height, and numbers of intraepithelial lymphocytes are increased. She suggested these areas might facilitate contact with antigen from the gut lumen before anti- bodies are produced by T and B cell cooperation in the lamina propria. The factors which lead to population of the small intestine by lymphoid cells are not known, but Dr Joseph Hall, at the Chester Beatty Institute, had shown in mice that labelled immunoblasts preferen- tially migrate to the small intestine within 21 hours of injection and that the migration is independent of antigen, being demonstrable in fasting germ-free animals. This, together with the fact that grafts of antigen-free small intestine in ectopic sites develop normal lymphoid areas, suggests that lymphocytes are attracted by a powerful intrinsic small-intestinal mucosal factor. How, if at all, lymphocyte dysfunction is implicated in small-intestinal disease remains obscure. Dr Anne Ferguson had produced in mice lesions similar to those of coeliac disease in small-intestinal allografts under- going rejection, and had demonstrated specific pro- duction of migration-inhibition factor, both these phenomena being prevented by previous thymectomy. She suggests that the lesion in coeliac disease may therefore be dependent upon T lymphocytes rather 1. Ferguson, A., Parrott, D. M. V. Clin. exp. Immun. 1972, 12, 477. 2. Cooper, M., Daws, G. Unpublished.

Transcript of THE LYMPHOCYTE IN THE GUT

31

Cattle leukaemia came under close investigationwhen, around the turn of the century, the diseaseentered East Prussia from the east and spread west-wards in Germany. 3 Though called a leukaemia, interms of human disease it is more properly regardedas a lymphosarcoma; it was easily recognised in

abattoirs, and in Europe, the U.S.S.R., and the U.S.A.meat was commonly condemned because of it. By1918 it had reached the Elbe, and thereafter it seemedto spread westward with increasing speed. Epidemio-logical investigations were mounted, especially inDenmark where in 1953 the annual incidence was41 per 100,000 as opposed to 100 per 100,000 inGermany. Cattle leukaemia was not distributedevenly in Denmark, and Bendixen’s work ’’’" suggestedthat it spread from herd to herd by purchase of cattle.The disease affected all races of bovines, and largeherds were worse affected than the smaller herds.Bendixen concluded that the disease was infectiousand potentially controllable by slaughter of infectedcattle; these, it seemed, might be identified at a pre-leukosis phase by their peripheral lymphocytosis.

In the U.S.A., Marshak and his co-workers’7 tookup these investigations and continued them over along period. They did not agree that peripherallymphocytosis was a constant feature in animalsthat were to acquire the disease. 8 They found anapparent genetic influence: the progeny of certaincows and bulls acquired the lymphosarcoma overseveral generations. But evidence for involvement ofan infectious virus mounted steadily. Dutcher et al. 9

found structures in milk which may have been viruses;and later a C-type virus was found in cell-line culturesof lymphocytes from lymphosarcomatous cattle.1o Itsantigenic structure has been examined 11 and com-pared 12 with that of murine and feline leukaemia viruses,and infection can be detected by fluorescent and

precipitin antibody tests. 13 s Olsen et al. 14 noted that5 of 13 sheep injected with virus-containing culturedlymphocytes from a case of bovine lymphosarcomadied of lymphosarcoma; and the cultured lymphocytesof the dead animals contained C-type particles.

All these findings were discussed at an internationalconference in Argentina, the proceedings of whichhave just been published." In the experiments withinfant chimpanzees, unpasteurised milk was used inall cases. 6 controls received milk from non-affected

3. Clemmesen, J. Statistical Studies in the Aetiology of MalignantNeoplasms; vol. i. Copenhagen, 1965.

4. Bendixen, H. J. Thesis, University of Copenhagen, 1962. Citedby Clemmesen.3

5. Bendixen, H. J. Ann. N.Y. Acad. Sci. 1963, 108, 1241.6. Marshak, R. R., Hare, W. C., Abt, D. A., et al. ibid. p. 1284.7. Abt, D. A., Marshak, R. R., Kulp, H. W., Pollock, R. J., Jr. Com-

parative Leukemia Research 1969 (Bibl. hœmat. no. 36) (editedby R. M. Dutcher); p. 527. Basle, 1970.

8. Croshaw, J. E., Jr., Abt, D. A., Marshak, R. R., Hare, W. C. D.,Switzer, J., Ipsen, J., Dutcher, R. M. Ann. N.Y. Acad. Sci.1963, 108, 1193.

9. Dutcher, R. M., Larkin, E. P., Marshak, R. R. J. natn. Cancer Inst.1964, 33, 1055.

10. Ferrer, J. F., Stock, N. D., Lin, P. S. ibid. 1971, 47, 613.11. Ferrer, J. F., Avila, L. A., Stock, N. D. ibid. p. 1864.12. Ferrer, J. F. Cancer Res. 1972, 32, 1871.13. Ferrer, J. F., Bhatt, D. M. Proc. Am. Ass. Cancer Res. 1973, 14, 18.14. Olsen, C., Miller, L. D., Miller, J. M., Hoss, H. E. J. natn. Cancer

Inst. 1972, 49, 1463.15. Pasqualini, C. D. (editor). Zoonosis and its Possible Relation to

Human Lymphomas and Leukaemias. Argentine Society ofClinical Investigation. Medicina (Buenos Aires), 1974, suppl. 1,(English and Spanish).

cows; and 6 had milk from infected cows, two ofthem from fcow believed to be a reliable and abundantsource of virus. These last two died at 34 and 45weeks of age after a 5-6-week illness in which leukaemiawas accompanied by progressive pneumonia due toPneumocystis carinii. Since neither this pneumonianor leukaemia has ever previously been reported inchimpanzees, these findings are very disturbing. Inview of their public-health importance they urgentlyneed confirmation.

THE LYMPHOCYTE IN THE GUT

LYMPHOCYrES are predominant in Peyer’s patchesand form a large proportion of the cells in the small-intestinal lamina propria. Their involvement in

immunological reactions in the gut is certain, but thefundamental mechanisms and how their dysfunctionplays a part in intestinal disease remain obscure. Someof the current work in this area was discussed lastmonth at St Bartholomew’s Hospital.

It has been proposed that the Peyer’s patch of themammalian small intestine is the equivalent of theavian bursa of Fabricius. Prof. Delphine Parrott

pointed out, however, that in animals B and T lym-phocytes are found in Peyer’s patches within threedays of birth, and furthermore prenatal resection ofthe small bowel does not impair subsequent immuno-logical function 2-both arguments against the Peyer’spatch being a primary lymphoid organ. Her work in

Glasgow shows that the predominant lymphocyte in aPeyer’s patch is a B cell, but that the areas betweennodules, and the region underlying the epithelial cells,the " dome ", are both populated mainly by thymus-dependent cells, T lymphocytes. The mucosa overthe dome has no villi, its epithelial cells are reduced inheight, and numbers of intraepithelial lymphocytes areincreased. She suggested these areas might facilitatecontact with antigen from the gut lumen before anti-bodies are produced by T and B cell cooperation inthe lamina propria.The factors which lead to population of the small

intestine by lymphoid cells are not known, but DrJoseph Hall, at the Chester Beatty Institute, hadshown in mice that labelled immunoblasts preferen-tially migrate to the small intestine within 21 hours ofinjection and that the migration is independent ofantigen, being demonstrable in fasting germ-freeanimals. This, together with the fact that grafts ofantigen-free small intestine in ectopic sites developnormal lymphoid areas, suggests that lymphocytesare attracted by a powerful intrinsic small-intestinalmucosal factor.

How, if at all, lymphocyte dysfunction is implicatedin small-intestinal disease remains obscure. Dr Anne

Ferguson had produced in mice lesions similar to thoseof coeliac disease in small-intestinal allografts under-going rejection, and had demonstrated specific pro-duction of migration-inhibition factor, both thesephenomena being prevented by previous thymectomy.She suggests that the lesion in coeliac disease maytherefore be dependent upon T lymphocytes rather

1. Ferguson, A., Parrott, D. M. V. Clin. exp. Immun. 1972, 12, 477.2. Cooper, M., Daws, G. Unpublished.

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than upon complement activation3 or lymphocyte-dependent antibodies.4 Nevertheless, her experi-mentally induced lesions show differences from thoseof coeliac disease, in that plasma cells in the intestinalinfiltrate are fewer and epithelial-cell changes lesssevere. Thus it seems that cell-mediated reactions

may be involved in the pathogenesis of coeliac disease,but the exact mechanisms remain to be revealed.

CHLORPROPAMIDE IN DIABETIC PREGNANCY

PREGNANCY in the insulin-independent diabetic

may pose a difficult therapeutic problem. Increasingimpairment of carbohydrate tolerance is likely as

pregnancy progresses, simple dietary measures mayfail to control hyperglycsemia, and yet physician andpatient alike are reluctant to start insulin injections if asafe alternative exists in tablet form. The temptationto prescribe a sulphonylurea (either de novo or byincreasing the dose in pregnancy) must be weighedagainst the adequacy of control that these drugs canachieve and the potential hazards for fetal healthinherent in a substance which crosses the placentawith ease and is a potent stimulant of pancreatic islettissue. How safe is chlorpropamide for the fetus ?Early reports from South Africa suggested particulardangers in this context: Jackson et al. reported anoverall fetal/infant mortality of 64% in a series of 25chlorpropamide-treated pregnancies, the mortalitybeing more than double that in pregnancies where thematernal diabetes was controlled with tolbutamide,diet, or insulin; and Campbell 6 raised the question ofdrug-induced malformation among surviving infants.These frightening figures were not, however, repro-duced by clinicians in Britain (overall mortality 15%in 26 chlorpropamide-treated pregnancies 7), in Jam-aica (mortality 12% in 34 pregnancies 8), or indeed bya later study from South Africa (mortality 14% in 58pregnancies 9). None of these reports suggests a

teratogenic effect of chlorpropamide : all lead to the

suspicion that the outcome of pregnancy has beengoverned by the severity of maternal diabetes (whichdetermines the dose of sulphonylurea), rather than byany specific morbid effect of chlorpropamide itself.

This suspicion seems to be confirmed by a reportfrom Aberdeen. 10 Sutherland and his colleaguesreview their experience with chlorpropamide, in dailydosage of at least 200 mg., in 19 pregnant diabetics, andcorrelate drug usage with diabetic control and fetaloutcome. Good control of maternal diabetes wasdefined strictly as a mid-afternoon blood-glucosebelow 135 mg. per 100 ml. at all stages of pregnancy,and bad control likewise as a blood-glucose above170 mg. per 100 ml. No constant relation was found

3. Ballard, J., Shiner, M. Lancet, 1972, i, 1202.4. Fakhri, O., Hobbs, J. R. ibid. 1972, ii, 403.5. Jackson, W. P. U., Campbell, G. D., Notelovitz, M., Blumsohn, D.

Diabetes, 1962, 11, suppl. p. 98.6. Campbell, G. D. Br. med. J. 1963, i, 59.7. Malins, J. M., Cooke, A. M., Pyke, D. A., Fitzgerald, M. G.

ibid. 1964, ii, 187.8. Douglas, C. P., Richards, R. Diabetes, 1967, 16, 60.9. Notelovitz, M. S. Afr. med. J. 1971, 45, 226.

10. Sutherland, H. W., Bewsher, P. D., Cormack, J. D., Hughes,C. R. T., Reid, A., Russell, G., Stowers, J. M. Archs Dis. Childh.1974, 49, 283.

between the daily dose of chlorpropamide, the totalingested during pregnancy, and the fetal outcome; thetwo intrauterine deaths were in badly controlled preg-nancies where increased doses of chlorpropamide(500 mg. a day) had been used in the third trimester.The condition of the newborn infants reflected thecontrol of diabetes during pregnancy: all infantsfrom badly controlled pregnancies showed clinical orbiochemical abnormalities, whereas half those fromwell controlled pregnancies showed no abnormalityother than the plump and plethoric appearance typicalin the infant of a diabetic mother. Intravenousglucose-tolerance tests were performed on 6 infantsshortly after birth, and showed a brisker insulin res-ponse and rate of glucose disposal than in infants ofuntreated mothers with less severe diabetes.

The Aberdeen findings provide strong evidence thatchlorpropamide in pregnancy is harmless to the fetusor infant and that good control of maternal diabetes,however this is achieved, is the most important con-tribution towards a successful outcome. A similarconclusion was drawn by White at the Joslin Clinic 11in the pre-sulphonylurea era. But it would be unwiseto suggest, merely because the drug is safe, that high-dose chlorpropamide is an appropriate treatment indiabetic pregnancy: very high blood-sugar in suchwomen is much better controlled with insulin. Chlor-

propamide therapy is best confined to pregnantwomen with mild diabetes, in whom good controlcan be attained with small doses; and Sutherlandet all have already documented its value in the treat-ment of " chemical " diabetes in pregnancy. Chlor-

propamide in this context seems sensible and worthy ofwider usage, provided it is combined with strictattention to other aspects of diabetic control and expertobstetric management.

tcPo2HAVING to measure various blood-levels repeatedly

in the care of certain critically ill patients is a nightmarefor all concerned, and non-invasive techniques are acherished dream. The blood-gases are a good case inpoint. To be valuable, arterial sampling usually hasto be frequent, and the lot of patients on ventilatorysupport can undoubtedly be made easier if end-tidalPco2 can be monitored instead of PaC02. The newbornbaby with respiratory distress poses special difficulties.Carbon dioxide takes second place to oxygen, whichmust be maintained within normal limits. Either toolittle or too much may do permanent damage, and theonly arbiter of what is right is the oxygen tension inthe arterial blood. Frequent sampling is technicallydifficult and not without risk. The Clark electrodeand micro-methods were great advances, but heel

stabs, arterial punctures, and umbilical-artery cannula-tion-the neonatologist’s present stock-in-trade-are all invasive methods with their disadvantages.Capillary Po2 is not necessarily a good indication ofPao2; crying distorts the findings in samples obtained

11. White, P. Am. J. Med. 1949, 7, 609.12. Sutherland, H. W., Stowers, J. M., Cormack, J. D., Bewsher,

P. D. Br. med. J. 1973, iii, 9.