824 INHIBITION OF LYMPHOCYTE-P.P.D. REACTIVITY BY PLASMA
anti-H.A.v. ELISA, titres up to 1 :2x106 were found in a strongly positive serum from a patient a few months after jaundice. Chimpanzee convalescent serum (no. V811-501-573 from N.I.A.I.D.) was used as a control and had a titre in our ELISA of 1:8000. Commercial human immune-serum-globulin preparations had anti-H.A.v. titres of about 1:100 000. In seronegative people given a prophylactic dose of such a preparation, seroconversion was found, with anti-H.A.v. titres ranging our
from 1:20 to 1:40. 500 blood-donor sera obtained from Dr H. Reesink (Central Laboratory of the Blood Transfusion Service, Amsterdam) were tested for anti-H.A.v. in our ELISA and in radioimmunoassay by Dr G. Frosner; 52% were positive in both tests. The anti-H.A.v. incidence was correlated with age, up to 80% for donors aged 40-50 years. WILLEM DUERMEYER Organon Scientific Development Group, JOKE VAN DER VEEN P.O. Box 20, BERNARD KOSTER Oss, Netherlands
BLOOD-TRANSFUSION AND RENAL TRANSPLANTATION
SIR,-A number of reports, including two from this centre, show improved survival of renal grafts in patients given bloodtransfusions before transplantation.-’ Earlier we found that lymphocyte reactivity to purified protein derivation (P.P.D.) of Mycobacterium tuberculosis was diminished in patients who had received multiple blood-transfusions5 and we have now titrated the lymphocyte-depressing factor6in the plasma of patients with chronic renal failure who were in end-stage renal failure. To examine the effect of plasma from transfused patients on lymphocyte-antigen reaction we used the tanned erythrocyte electrophoretic mobility (T.E.E.M.) test’ which has been used successfully in a number of laboratories to assess lymphocyte sensitisation.8-11 The interaction between sensitised lymphocytes and P.P.D. generates a factor which slows the mobility of tanned erythrocytes in an electric field" determined as in the
macrophage electrophoretic mobility test. Lymphocytes were incubated for 30 min with dilutions of test plasma before the addition of P.P.D. and the dilution of plasma producing 50% inhibition of lymphocyte-p.p.D. response was determined by extrapolation from the graphically expressed results. All test plasmas were examined in this way and the mean ±1 S.D. was calculated for each group of patients studied (see table). Normal plasma partially inhibited lymphocyte-p.p.D. reactivity (also described by Field12) but a significantly greater inhibitory activity was found in plasma from multitransfused renal patients (see table). These results suggest that multiple blood transfusions may reduce the lymphocyte response to specific antigen and may generally suppress lymphocyte reactivity.’3 The suppressive factors in plasma have yet to be fully characterised but our initial findings suggest that both macroglobulins and immunoglobins are involved. The beneficial 1.
Murray, S., Dewar, P. J., Uldall, P. R., Wilkinson, R., Kerr, D. N. S., Taylor, R. M. R., Swinney, J. Tissue Antigens, 1974, 4, 548. 2. Opelz, G., Terasaki, P. I. Dialy. Transplant. 1977, 6, 46. 3. Uldall, P. R., Wilkinson, R., Dewar, P. J., Murray, S., Morley, A., Baxby, K., Hall, R. R., Taylor, R. M. R. Lancet, 1977, i, 316. 4. Blarney, R. W., Knapp, M. S., Burden, R. P., Salisbury, M. Br. med. J. 1978, i, 138. K., Uldall, P. R., Swinney, J., Field, E. J. I.R.C.S. Med. Sci.
5. Shenton, B.
1974, 8, 1564. Field, E. J., Caspary, E. A. Br. J. Cancer, 1972,26, 164. Porzsolt, F., Tautz, R., Schmidtberger, R., Ax, W. Z. Immunitatsforsch. 1974, 147, 352. 8. Lampert, F., Nitsche, U., Zwergel, T., Abiodun, P. Lancet, 1977, ii, 141. 9. Douwes, F. R., Hutteman, U., Mross, K. Dt. med. Wschr. 1977, 102, 419. 10. Jenssen, H. L., Shenton, B. K. Acta biol. med. germ. 1975, 34, 29. 11. Shenton, B. K., Jenssen, H. L., Werner, H., Field, E. J. J. immun. Methods, 1977, 14, 123. 12. Field, E. J., Caspary, E. A. Lancet, 1971, i, 95. 13. Sengar, D. P. S., Opelz, G., Terasaki, P. I. Transplant. Proc. 1973, 5, 641. 6. 7.
* One transfusion comprised one unit of blood or packed cells. In t tests, differences between all groups except between multiply transfused renal
significant (r=0001) patients and haamophiliacs
were
(p=0.165). effects of transfusion may derive from the suppression of developing lymphocyte sensitisation after transplantation. We have found the T.E.E.M. test to be reproducible in blind studies; tanned erythrocytes are homogeneous indicator particles, the investigation is complete in less than 4 h and is therefore suitable for both clinical and experimental investigations. B. K. SHENTON Department of Surgery, Royal Victoria Infirmary, Newcastle upon Tyne NE1
CIMETIDINE
4LP
G. PROUD B. M. SMITH R. M. R. TAYLOR
AND RENAL-ALLOGRAFT REJECTION
SiR,-Cimetidine is effective in the treatment! and prevention2 of stress ulcer. In our experience with forty-six cadaveric renal transplants in children, stress ulcers developed in three with fatal outcome in two, a frequency and mortality similar to those reported in adults.’ The use of cimetidine for treatment of stress ulcers or prophylactically in kidney transplant recipients thus seemed attractive. Our group gave cimetidine to two consecutive children after renal transplantation. Both had severe, irreversible graft rejections 4-5 days after the introduction of this drug. The similarity in timing and severity of these rejection episodes suggest an association with the cimetidine therapy. Perhaps this is the clinical manifestation4.5 of the immunological disturbances caused by histamine Hz receptor antagonists. The first case was a 13-year-old, 32 kg, girl with a stress ulcer 13 days after renal transplantation. Her course had been uncomplicated until this episode. She was receiving prednisone 2 mg/kg daily and had a serum-creatinine of 0.9 mg/dl. Intermittent bleeding persisted despite anatacids and saline lavage. On day 17, when the administration of cimetidine, 150 mg every 6 h intravenously was started, her serum-creatinine was 0-83 mg/dl. On day 21, urine volume dropped precipitously, and creatinine clearance fell from 45.0 to 12.0 ml/min. 2 days later, despite anti-rejection therapy, creatinine clearance was below 2 ml/min and never improved. Bleeding continued, and the child died from complications associated with the stress ulcer. Because of this experience, the next transplant patient, a 5-year-old, 11 kg boy, was put on cimetidine 150 mg every 12 h intravenously as prophylaxis at the time of the transplant. He had good early graft function with a creatinine clearance of 20 ml/min by day 4. During day 5, severe oliguria developed without evidence of obstruction or major vessel thrombosis, and creatinine clearance plummeted to 3 ml/min. The immunological characteristics of allograft rejection are 1. 2. 3. 4. 5.
MacDonald, A. S., Steele, B. J., Bottomley, M. G. Lancet, 1977, i, 68. MacDougall, B. R. D., Bailey, R. J., Williams, R. ibid. p. 617. Moore, T. C., Hume, D. M. Ann. Surg. 1969, 170,1 Malagelada, J. R., Cortot, A. Mayo Clin. Proc. 1978, 53, 184. Moulias, R., Congy, F. Nouv. Presse méd. 1976, 5, 149.
825
largely those of delayed hypersensitivity,6 in which T lymphocytes, many possessing histamine H2 receptors,4,5 play an important role. Histamine intradermally can reduce the delayedhypersensitivity reaction in vivo in guineapigs and H2 receptor antagonists prevent this suppression.’ An analogous situation in man is the cimetidine-induced reversal of acquired tolerance
TABLE II-HLA-DR INCOMPATIBILITY AND GRAFT FUNCTION AND
3
1
MONTHS AFTER TRANSPLANTATION
dinitrochlorobenzenê.8 In-vitro data show that histamine suppression of delayed hypersensitivity is, in part, mediated by to
H2-receptor-induced inhibition of migratory inhibitory factor (M.I.F.) release.’ M.I.F. is postulated to have an important role in
transplant rejection.6 Thus, H2-receptor antagonists such as
cimetidine may stimulate elements of the immune system involved in allograft rejection, an effect clearly not desired in renal transplantation. The temptation to use cometidine to treat or prevent the often fatal complication of stress ulcer is great. However, our experience and published laboratory work suggest that the potential deleterious effects of this class of drugs in trans-
planted patients must be borne in mind. Children’s Kidney Center, Albert Einstein College of Medicine, Bronx, N.Y. 10461, U.S.A.
WILLIAM A. PRIMACK
No
vs. 1-2 antigen after 3 months.
incompatibility
month, p
anti-H.A.v. ELISA, titres up to 1 :2x106 were found in a strongly positive serum from a patient a few months after jaundice. Chimpanzee convalescent serum (no. V811-501-573 from N.I.A.I.D.) was used as a control and had a titre in our ELISA of 1:8000. Commercial human immune-serum-globulin preparations had anti-H.A.v. titres of about 1:100 000. In seronegative people given a prophylactic dose of such a preparation, seroconversion was found, with anti-H.A.v. titres ranging our
from 1:20 to 1:40. 500 blood-donor sera obtained from Dr H. Reesink (Central Laboratory of the Blood Transfusion Service, Amsterdam) were tested for anti-H.A.v. in our ELISA and in radioimmunoassay by Dr G. Frosner; 52% were positive in both tests. The anti-H.A.v. incidence was correlated with age, up to 80% for donors aged 40-50 years. WILLEM DUERMEYER Organon Scientific Development Group, JOKE VAN DER VEEN P.O. Box 20, BERNARD KOSTER Oss, Netherlands
BLOOD-TRANSFUSION AND RENAL TRANSPLANTATION
SIR,-A number of reports, including two from this centre, show improved survival of renal grafts in patients given bloodtransfusions before transplantation.-’ Earlier we found that lymphocyte reactivity to purified protein derivation (P.P.D.) of Mycobacterium tuberculosis was diminished in patients who had received multiple blood-transfusions5 and we have now titrated the lymphocyte-depressing factor6in the plasma of patients with chronic renal failure who were in end-stage renal failure. To examine the effect of plasma from transfused patients on lymphocyte-antigen reaction we used the tanned erythrocyte electrophoretic mobility (T.E.E.M.) test’ which has been used successfully in a number of laboratories to assess lymphocyte sensitisation.8-11 The interaction between sensitised lymphocytes and P.P.D. generates a factor which slows the mobility of tanned erythrocytes in an electric field" determined as in the
macrophage electrophoretic mobility test. Lymphocytes were incubated for 30 min with dilutions of test plasma before the addition of P.P.D. and the dilution of plasma producing 50% inhibition of lymphocyte-p.p.D. response was determined by extrapolation from the graphically expressed results. All test plasmas were examined in this way and the mean ±1 S.D. was calculated for each group of patients studied (see table). Normal plasma partially inhibited lymphocyte-p.p.D. reactivity (also described by Field12) but a significantly greater inhibitory activity was found in plasma from multitransfused renal patients (see table). These results suggest that multiple blood transfusions may reduce the lymphocyte response to specific antigen and may generally suppress lymphocyte reactivity.’3 The suppressive factors in plasma have yet to be fully characterised but our initial findings suggest that both macroglobulins and immunoglobins are involved. The beneficial 1.
Murray, S., Dewar, P. J., Uldall, P. R., Wilkinson, R., Kerr, D. N. S., Taylor, R. M. R., Swinney, J. Tissue Antigens, 1974, 4, 548. 2. Opelz, G., Terasaki, P. I. Dialy. Transplant. 1977, 6, 46. 3. Uldall, P. R., Wilkinson, R., Dewar, P. J., Murray, S., Morley, A., Baxby, K., Hall, R. R., Taylor, R. M. R. Lancet, 1977, i, 316. 4. Blarney, R. W., Knapp, M. S., Burden, R. P., Salisbury, M. Br. med. J. 1978, i, 138. K., Uldall, P. R., Swinney, J., Field, E. J. I.R.C.S. Med. Sci.
5. Shenton, B.
1974, 8, 1564. Field, E. J., Caspary, E. A. Br. J. Cancer, 1972,26, 164. Porzsolt, F., Tautz, R., Schmidtberger, R., Ax, W. Z. Immunitatsforsch. 1974, 147, 352. 8. Lampert, F., Nitsche, U., Zwergel, T., Abiodun, P. Lancet, 1977, ii, 141. 9. Douwes, F. R., Hutteman, U., Mross, K. Dt. med. Wschr. 1977, 102, 419. 10. Jenssen, H. L., Shenton, B. K. Acta biol. med. germ. 1975, 34, 29. 11. Shenton, B. K., Jenssen, H. L., Werner, H., Field, E. J. J. immun. Methods, 1977, 14, 123. 12. Field, E. J., Caspary, E. A. Lancet, 1971, i, 95. 13. Sengar, D. P. S., Opelz, G., Terasaki, P. I. Transplant. Proc. 1973, 5, 641. 6. 7.
* One transfusion comprised one unit of blood or packed cells. In t tests, differences between all groups except between multiply transfused renal
significant (r=0001) patients and haamophiliacs
were
(p=0.165). effects of transfusion may derive from the suppression of developing lymphocyte sensitisation after transplantation. We have found the T.E.E.M. test to be reproducible in blind studies; tanned erythrocytes are homogeneous indicator particles, the investigation is complete in less than 4 h and is therefore suitable for both clinical and experimental investigations. B. K. SHENTON Department of Surgery, Royal Victoria Infirmary, Newcastle upon Tyne NE1
CIMETIDINE
4LP
G. PROUD B. M. SMITH R. M. R. TAYLOR
AND RENAL-ALLOGRAFT REJECTION
SiR,-Cimetidine is effective in the treatment! and prevention2 of stress ulcer. In our experience with forty-six cadaveric renal transplants in children, stress ulcers developed in three with fatal outcome in two, a frequency and mortality similar to those reported in adults.’ The use of cimetidine for treatment of stress ulcers or prophylactically in kidney transplant recipients thus seemed attractive. Our group gave cimetidine to two consecutive children after renal transplantation. Both had severe, irreversible graft rejections 4-5 days after the introduction of this drug. The similarity in timing and severity of these rejection episodes suggest an association with the cimetidine therapy. Perhaps this is the clinical manifestation4.5 of the immunological disturbances caused by histamine Hz receptor antagonists. The first case was a 13-year-old, 32 kg, girl with a stress ulcer 13 days after renal transplantation. Her course had been uncomplicated until this episode. She was receiving prednisone 2 mg/kg daily and had a serum-creatinine of 0.9 mg/dl. Intermittent bleeding persisted despite anatacids and saline lavage. On day 17, when the administration of cimetidine, 150 mg every 6 h intravenously was started, her serum-creatinine was 0-83 mg/dl. On day 21, urine volume dropped precipitously, and creatinine clearance fell from 45.0 to 12.0 ml/min. 2 days later, despite anti-rejection therapy, creatinine clearance was below 2 ml/min and never improved. Bleeding continued, and the child died from complications associated with the stress ulcer. Because of this experience, the next transplant patient, a 5-year-old, 11 kg boy, was put on cimetidine 150 mg every 12 h intravenously as prophylaxis at the time of the transplant. He had good early graft function with a creatinine clearance of 20 ml/min by day 4. During day 5, severe oliguria developed without evidence of obstruction or major vessel thrombosis, and creatinine clearance plummeted to 3 ml/min. The immunological characteristics of allograft rejection are 1. 2. 3. 4. 5.
MacDonald, A. S., Steele, B. J., Bottomley, M. G. Lancet, 1977, i, 68. MacDougall, B. R. D., Bailey, R. J., Williams, R. ibid. p. 617. Moore, T. C., Hume, D. M. Ann. Surg. 1969, 170,1 Malagelada, J. R., Cortot, A. Mayo Clin. Proc. 1978, 53, 184. Moulias, R., Congy, F. Nouv. Presse méd. 1976, 5, 149.
825
largely those of delayed hypersensitivity,6 in which T lymphocytes, many possessing histamine H2 receptors,4,5 play an important role. Histamine intradermally can reduce the delayedhypersensitivity reaction in vivo in guineapigs and H2 receptor antagonists prevent this suppression.’ An analogous situation in man is the cimetidine-induced reversal of acquired tolerance
TABLE II-HLA-DR INCOMPATIBILITY AND GRAFT FUNCTION AND
3
1
MONTHS AFTER TRANSPLANTATION
dinitrochlorobenzenê.8 In-vitro data show that histamine suppression of delayed hypersensitivity is, in part, mediated by to
H2-receptor-induced inhibition of migratory inhibitory factor (M.I.F.) release.’ M.I.F. is postulated to have an important role in
transplant rejection.6 Thus, H2-receptor antagonists such as
cimetidine may stimulate elements of the immune system involved in allograft rejection, an effect clearly not desired in renal transplantation. The temptation to use cometidine to treat or prevent the often fatal complication of stress ulcer is great. However, our experience and published laboratory work suggest that the potential deleterious effects of this class of drugs in trans-
planted patients must be borne in mind. Children’s Kidney Center, Albert Einstein College of Medicine, Bronx, N.Y. 10461, U.S.A.
WILLIAM A. PRIMACK
No
vs. 1-2 antigen after 3 months.
incompatibility
month, p
