enhanced antibody responses in active chronic hepatitis
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gress to examine the effect of intrapleural B.C.G. in macro-phage depleted and immunosuppressed animals.Cancer Research Campaign Laboratories,University of Nottingham,University Park,Nottingham NG7 2RD M. V. PIMM
PLASMAPHERESIS AND IMMUNOSTIMULATION
SIR,-We were very interested in your editorial’ on theclinical applications of plasmapheresis and in particular of itsuse by Hersey and his colleagues to remove serum blockingfactors of cell-mediated immunity in patients with malignantmelanoma.We have shown that T-lymphocyte activity can be enhanced
in patients with malignant disease, including melanoma, by in-travenous infusion of proteolytic enzymes (i.e., ’Brinase’2 andstreptokinase3) or by washing of lymphocytes removed by anI.B.M./N.C.I. continuous-flow cell separator.’ The enhance-ment of T-cell activity by these measures, however, lasts onlyabout four to seven days in advanced malignancy. The re-blocking of activity, we presume, is due to serum blocking fac-tors.
We found that the use of the cell separator alone withoutwashing of the lymphocytes enhanced T-cell activity in
patients. We then demonstrated (unpublished) that simplemechanical agitation of blocked T cells from patients withmalignant disease increases their capacity to bind sheep eryth-rocytes (E rosettes) and that the material shaken off the lym-phocytes when incubated with normal control T cells inhibitstheir binding capacity:
T cells (%) ’’Shakings’’ added to control T cellsCancer Before shaking After shaking Control (%) Reduced to (%)Breast 18 62 50 35
Qaecum 48 58 74 67
Lymphosar-coma 54 70 70 59
The T-cell counts of healthy controls were unaffected by shaking.Because of the blocking effect of serum factors on T cells in
malignancy we subjected two patients with advanced malig-nant disease to plasmapheresis using the I.B.M. continuous-flow cell separator, 2 litres of patient’s plasma being exchangedfor a similar amount of fresh-frozen pooled human plasma.The patient’s T-cell counts rose from 30% to 58% (case 1) andfrom 34% to 75% (case 2) following the procedure. The serumblocking effect on control normal T cells fell appreciably im-mediately after plasmapheresis and remained at a low level ineach case for about 4 weeks. Normal control T cells were incu-bated in patient’s serum for 30 min at 18°C. The serum block-
ing effect was then expressed as the percentage reduction in Erosetting:
% reduction in E rosettingCase 1 Case 2
Time (osteosarcoma) (bronchogemc carcinoma)Before plasmapheresis 34 50After plasmapheresis: 7 24
1 wk 3 172 wk 4 183 wk 2 164 wk 22 15
Repeat plasmapheresis:1 wk later 6 42 wk later 16 11
Skin hypersensitivity to dmitrochlorobenzene and punfied protein derivative butnot to streptokinase was restored in both patients.
In these two cases the relatively small exchange of 2 litreswas sufficient to produce a prolonged effect. If this experienceis confirmed in a larger series of patients which we are now in-vestigating then plasmapheresis could have a practical part toplay in immunotherapy.
1. Lancet, 1976, i, 1113.2. Thornes, R. D., Smyth, H., Brown, O., Holland, P. D. J. ibid. 1973, i, 1386.3. Thornes, R. D. ibid. 1974, ii, 382.4. Doyle, J. S., Bell, J., Deasy, P., Thornes, R. D. ibid. p. 959.
We believe that restoration of immune competence should,if possible, precede specific or non-specific treatment.
Institute of Clinical Science and Research,Royal College of Surgeons in Ireland,Dublin, Eire
ORLA BROWNEJ. BELLP. D. J. HOLLANDR. D. THORNES
ENHANCED ANTIBODY RESPONSES IN ACTIVECHRONIC HEPATITIS
SIR,—We read the paper by Galbraith et al.’ with interest.We have done similar studies but our results differ in several
respects.Galbraith et al. found a significant correlation between
raised antibody titres to rubella and to measles and the posses-sion of HLA-B8 in patients with HBsAg-negative chronicactive hepatitis, but not in their relatives. We have studiedantibodies to a variety of antigens including rubella andmeasles in individually matched HLA-B8 positive and negativesubjects-mainly patients with HBsAg-negative chronic liverdisease, including many with chronic active hepatitis-andfound no correlation between HLA-B8 and any antibody titreexcept gluten.2 Furthermore, in a separate unpublished studyof 33 patients with HBsAg-negative chronic active hepatitis wefound no correlation between HLA-B8 and rubella or measlesantibody titres. We were careful in our published study2 tomatch individually the HLA-B8 positive and negative subjects,especially for age, since we find in adult controls an inversecorrelation between these antibody titres (notably rubella,P<0.05) and age. Even with satisfactory matching the conclu-sion that the findings suggest a generalised, non-specific in-crease in immunological responsiveness associated withHLA-B8 is premature, especially since Galbraith et al. and wefind no correlation between HLA-B8 and viral antibody titresin people without chronic active hepatitis.
Galbraith et al. also conclude that Escherichia coli antibodytitres "correlated closely with the degree of porto-systemicshunting". However, the presence of shunting was not assesseddirectly (e.g., by the presence of a patent surgical shunt oroesophageal varices) but by the counts of radioactive techne-tium colloid over the spleen. Evidence that splenic uptake ofcolloid correlates with other manifestations of shunting is notvery good. Although related to some extent to shunting, splenicuptake also depends on splenic size3 and the spleen may beenlarged for other reasons in liver disease. We have studiedviral antibodies4 and antibodies to 11 common strains of E.coli (unpublished) in patients with various chronic liver dis-eases, including 33 with HBsAg-negative chronic active hepa-titis, and found no correlation between antibody titres and thepresence of portal-systemic shunts, as evidenced by a patentsurgical shunt or oesophageal varices seen radiologically or atendoscopy. Furthermore, in 4 patients with surgical shunts butno evidence of liver disease only 7% of 44 E. coli antibody testswere positive compared with 31% of 341 tests in 31 controls.We, therefore, conclude that raised E. coli antibody titres (andalso viral antibody titres) are not related to portal-systemicshunting per se. However, the possibility remains, as impliedby Galbraith et al., that E. coli antibody titres are related tosome abnormal or exaggerated function of the spleen in pa-tients with chronic active hepatitis.University Department of Medicine,St James’s Hospital,Leeds LS9 7TF
BRIAN B. SCOTTM. S. LOSOWSKY
1. Galbraith, R. M., and others. Lancet, 1976, i, 930.2. Scott, B. B., Cooke, E. M., Hambling, M. H., Rajah, S. M., Swinburne, M.
L., Losowsky, M. S. J. Immunogenet. 1976, 3, 185.3. Eddleston, A. L. W. F., Blendis, L. M., Osborn, S. B., Williams, R. Gut,
1969, 10, 711.4. Scott, B. B., Hambling, M. H., Losowsky, M. S. Biomedicine (in the press)