enhanced antibody responses in active chronic hepatitis

1
96 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 the clinical applications of plasmapheresis and in particular of its use by Hersey and his colleagues to remove serum blocking factors of cell-mediated immunity in patients with malignant melanoma. 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 and streptokinase3) or by washing of lymphocytes removed by an I.B.M./N.C.I. continuous-flow cell separator.’ The enhance- ment of T-cell activity by these measures, however, lasts only about 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 without washing of the lymphocytes enhanced T-cell activity in patients. We then demonstrated (unpublished) that simple mechanical agitation of blocked T cells from patients with malignant disease increases their capacity to bind sheep eryth- rocytes (E rosettes)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 inhibits their binding capacity: T cells (%) ’’Shakings’’ added to control T cells Cancer 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 exchanged for a similar amount of fresh-frozen pooled human plasma. The patient’s T-cell counts rose from 30% to 58% (case 1) and from 34% to 75% (case 2) following the procedure. The serum blocking effect on control normal T cells fell appreciably im- mediately after plasmapheresis and remained at a low level in each case for about 4 weeks. Normal control T cells were incu- bated in patient’s serum for 30 min at 18&deg;C. The serum block- ing effect was then expressed as the percentage reduction in E rosetting: % reduction in E rosetting Case 1 Case 2 Time (osteosarcoma) (bronchogemc carcinoma) Before plasmapheresis 34 50 After plasmapheresis: 7 24 1 wk 3 17 2 wk 4 18 3 wk 2 16 4 wk 22 15 Repeat plasmapheresis: 1 wk later 6 4 2 wk later 16 11 Skin hypersensitivity to dmitrochlorobenzene and punfied protein derivative but not to streptokinase was restored in both patients. In these two cases the relatively small exchange of 2 litres was sufficient to produce a prolonged effect. If this experience is confirmed in a larger series of patients which we are now in- vestigating then plasmapheresis could have a practical part to play 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 BROWNE J. BELL P. D. J. HOLLAND R. D. THORNES ENHANCED ANTIBODY RESPONSES IN ACTIVE CHRONIC HEPATITIS SIR,&mdash;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 chronic active hepatitis, but not in their relatives. We have studied antibodies to a variety of antigens including rubella and measles in individually matched HLA-B8 positive and negative subjects-mainly patients with HBsAg-negative chronic liver disease, including many with chronic active hepatitis-and found no correlation between HLA-B8 and any antibody titre except gluten.2 Furthermore, in a separate unpublished study of 33 patients with HBsAg-negative chronic active hepatitis we found no correlation between HLA-B8 and rubella or measles antibody titres. We were careful in our published study2 to match individually the HLA-B8 positive and negative subjects, especially for age, since we find in adult controls an inverse correlation 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 with HLA-B8 is premature, especially since Galbraith et al. and we find no correlation between HLA-B8 and viral antibody titres in people without chronic active hepatitis. Galbraith et al. also conclude that Escherichia coli antibody titres "correlated closely with the degree of porto-systemic shunting". However, the presence of shunting was not assessed directly (e.g., by the presence of a patent surgical shunt or oesophageal varices) but by the counts of radioactive techne- tium colloid over the spleen. Evidence that splenic uptake of colloid correlates with other manifestations of shunting is not very good. Although related to some extent to shunting, splenic uptake also depends on splenic size3 and the spleen may be enlarged for other reasons in liver disease. We have studied viral 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 the presence of portal-systemic shunts, as evidenced by a patent surgical shunt or oesophageal varices seen radiologically or at endoscopy. Furthermore, in 4 patients with surgical shunts but no evidence of liver disease only 7% of 44 E. coli antibody tests were positive compared with 31% of 341 tests in 31 controls. We, therefore, conclude that raised E. coli antibody titres (and also viral antibody titres) are not related to portal-systemic shunting per se. However, the possibility remains, as implied by Galbraith et al., that E. coli antibody titres are related to some 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. SCOTT M. 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)

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Page 1: ENHANCED ANTIBODY RESPONSES IN ACTIVE CHRONIC HEPATITIS

96

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&deg;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,&mdash;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)