509
that sharing of B-locus. and blood-donors couldl beneficial influence on kidney graft survivall
tigation one might conclude antigens between recipients have
a
(table i). The capacity of the recipients to respond immunologically to the blood-transfusions might also influence graft: survival. Table n shows that sera of 2 animals of the: transfused group contained cytotoxic antibodies against: more than 50% of the cell samples tested. This "broad" ’
reactivity pattern could not be attributed to a greater disparity for s.D. antigens between blood-donors and recipients, only. In human kidney grafting, a distinction is made between high and low responders on the basis of the "broadness" of the cytotoxic reactivity pattern of the recipients’ sera and high responders were shown to 11 .
i
have the least favourable graft survival times. 10 This; may also be true for the monkey model. Table n shows that the recipient reacting against 72% of the samples (a "poor risk" according to clinical criteria) rejected its kidney relatively fast, especially considering the "favourable" time interval (fourteen days) between the last transfusion and transplantation in this case. The high immunological responsiveness of that animal may explain the comparatively short survival time and thus a bad fit with the regression line shown in fig. 2. Human recipients with a positive cross-match, usually reject their graft in a hypercute fashion.12 Surprisingly, the 2 monkeys with a positive cross-match did not reject their kidneys hyperacutely; in fact, they showed a prolongation of graft survival and histology similar to those of the animals with a negative cross-match. When absorption studies were done to determine the nature of the antibodies in the recipients’ sera, most of the antibodies were removable with platelets and are therefore directed against "conventional" A or B locus antigens. Unfortunately, we could not ascertain whether the 2 positive cross-matches were the effect of antibodies against la-like or B-cell alloantigens, since the kidneydonors had already been killed. The immunosuppressive effect of the azathioprine/ prednisolone regimen was unexpectedly low. This may be because the drugs were not given daily but every other day (for reasons of expediency). In previous experiments, daily doses of 4 mg/kg azothioprine alone produced a mean kidney allograft survival of 19-6 days.13 Whether the immunosuppressive treatment given in our experiments had a potentiating influence on the effect of the blood-transfusions remains to be proved. One can only speculate about the mode of action by which pretreatment with blood-transfusions produces prolonged kidney allograft survival. Less than optimally matched blood-transfusions invariably induced a positive effect on kidney allograft survival in less than optimally matched host/donor combinations. The phenomenon is therefore not likely to be immunologically specific because, for the induction of specific anti-donor type antibodies, as in immunological enhancement (I.E.), more sharing of RhLA products between blood and kidney donors would be expected. Another argument against I.E. is the previous finding that it is very difficult to induce active or passive enhancement in rhesus monkeys by pretreatment of recipients with donor blood or by the administration of various kinds of alloantisera, including B-cell alloantisera (unpublished ,
’
.
observations). To elucidate the mechanism by
which the
impressive prolongation of graft survival was achieved, numerous variations of the experimental protocol are required. Already, evidence has been obtained that even a single transfusion, given three weeks before transplantation, can lead to significant prolongation of kidney allograft survival in unrelated rhesus monkeys. Other experiments currently in progress should reveal whether host-donor matching for B-cell alloantigens can
increase the observed effect of pretreatment with transfusions and whether B-cell alloantibodies produced by
the
recipients may after all play a decisive role in longing graft survival.
pro-
We gratefully acknowledge the surgical assistance given by Mr G. A. Heystek, Mr R. H. van Leersum, and Mr H. D. Wiersema; Mr D. van Harte for postoperative care, Dr C. Zurcher for performing the histopathological examinations and Dr W. van Vreeswijk for histocompatibility testing. Part of the research was supported by a contract from the Dutch Kidney Foundation and contract no. 088-72-1BIAC of the Commission of the European Communities (contribution no. 1088 of the Euratom Biology Division).
Requests for reprints should be addressed to A. A. van E., Primate Centre TNO, 151 Lange Kleiweg, Rijswijk (ZH), The Netherlands. REFERENCES
Rood, J. J., van Leeuwen, A., Persijn, G., Lansbergen, Q, Goulmy, E., Termijtelen, A., Bradley, B. Transpl. Proc. (in the press). 2. Festenstein, H., Sachs, J. A., Paris, A. M. I. Lancet, 1976, i, 157. 3. van Hooff, J. P., Kalff, M. W., van Poelgeeste, A. E. Transplantation, 1976, 22, 306. 4. Persijn, G., van Hooff, J. P., Kalff, M. W., Lansbergen, Q., van Rood, J. J. Transpl. Proc. (in the press). 5. Opelz, G., Terasaki, P. I. Lancet, 1976, ii, 380. 6. Opelz, G., Terasaki, P. I. Transplantation, 1976, 22, 380. 7. Balner, H. Transpl. Rev. 1973, 15, 50. 8. Marquet, R. L., Heystek, G. A., van Bekkum, D. W. in Medical Primatology 1972, Proceedings of the 3rd Conference on Experimental Surgery in Primates, Lyon 1972, part II; p. 125. Basle, 1972. 9. van Es, A. A., Marquet, R. L., van Vreeswijk, W., Tank, B., Balner, H. Transpl. Proc. (in the press). 10. Myburgh, J. A., Maier, G., Smit, J. A., Shapiro, M., Meyers, A. M., Rablin, R., van Blerk, P. J. P., Jersky, J. Transplantation, 1974, 18, 3, 206. 11. Opelz, G., Mickey, M. R., Terasaki, P. I. ibid. 1974, 17, 371. 12. Terasaki, P. I., Marchioro, T. L., Starzl, T. E. Histocompatibility Testing. 1965. National Academy of Sciences, National Research Council, Washington, D.C., 1965. 13. Dicke, H. W., Heystek, G. A., Marquet, R. L., van der Ven, M. G. Transpl. Proc. 1971, 3, 484. 1.
van
ASSOCIATION BETWEEN LEUCOCYTE GROUP-5a ANTIGEN AND ACUTE LYMPHOBLASTIC LEUKÆMIA R. P. WARREN D. D. NGUYEN
R. STORB E. D. THOMAS
Fred Hutchinson Cancer Research Center, Seattle, and Department of Medicine, Division of Oncology, University of Washington School of Medicine, Seattle, Washington, U.S.A.
Leucocyte group 5 has two dominant alleles (5a and 5b) which segregate indeof the pendently major histocompatibility complex. The was studied in a Caucasian population group-5 system of controls and patients with acute lymphoblastic leukæmia. The 5a gene frequency was 0·09 in 72 controls and 0·38 in 39 patients with acute lymphoblastic leukæmia (p
that sharing of B-locus. and blood-donors couldl beneficial influence on kidney graft survivall
tigation one might conclude antigens between recipients have
a
(table i). The capacity of the recipients to respond immunologically to the blood-transfusions might also influence graft: survival. Table n shows that sera of 2 animals of the: transfused group contained cytotoxic antibodies against: more than 50% of the cell samples tested. This "broad" ’
reactivity pattern could not be attributed to a greater disparity for s.D. antigens between blood-donors and recipients, only. In human kidney grafting, a distinction is made between high and low responders on the basis of the "broadness" of the cytotoxic reactivity pattern of the recipients’ sera and high responders were shown to 11 .
i
have the least favourable graft survival times. 10 This; may also be true for the monkey model. Table n shows that the recipient reacting against 72% of the samples (a "poor risk" according to clinical criteria) rejected its kidney relatively fast, especially considering the "favourable" time interval (fourteen days) between the last transfusion and transplantation in this case. The high immunological responsiveness of that animal may explain the comparatively short survival time and thus a bad fit with the regression line shown in fig. 2. Human recipients with a positive cross-match, usually reject their graft in a hypercute fashion.12 Surprisingly, the 2 monkeys with a positive cross-match did not reject their kidneys hyperacutely; in fact, they showed a prolongation of graft survival and histology similar to those of the animals with a negative cross-match. When absorption studies were done to determine the nature of the antibodies in the recipients’ sera, most of the antibodies were removable with platelets and are therefore directed against "conventional" A or B locus antigens. Unfortunately, we could not ascertain whether the 2 positive cross-matches were the effect of antibodies against la-like or B-cell alloantigens, since the kidneydonors had already been killed. The immunosuppressive effect of the azathioprine/ prednisolone regimen was unexpectedly low. This may be because the drugs were not given daily but every other day (for reasons of expediency). In previous experiments, daily doses of 4 mg/kg azothioprine alone produced a mean kidney allograft survival of 19-6 days.13 Whether the immunosuppressive treatment given in our experiments had a potentiating influence on the effect of the blood-transfusions remains to be proved. One can only speculate about the mode of action by which pretreatment with blood-transfusions produces prolonged kidney allograft survival. Less than optimally matched blood-transfusions invariably induced a positive effect on kidney allograft survival in less than optimally matched host/donor combinations. The phenomenon is therefore not likely to be immunologically specific because, for the induction of specific anti-donor type antibodies, as in immunological enhancement (I.E.), more sharing of RhLA products between blood and kidney donors would be expected. Another argument against I.E. is the previous finding that it is very difficult to induce active or passive enhancement in rhesus monkeys by pretreatment of recipients with donor blood or by the administration of various kinds of alloantisera, including B-cell alloantisera (unpublished ,
’
.
observations). To elucidate the mechanism by
which the
impressive prolongation of graft survival was achieved, numerous variations of the experimental protocol are required. Already, evidence has been obtained that even a single transfusion, given three weeks before transplantation, can lead to significant prolongation of kidney allograft survival in unrelated rhesus monkeys. Other experiments currently in progress should reveal whether host-donor matching for B-cell alloantigens can
increase the observed effect of pretreatment with transfusions and whether B-cell alloantibodies produced by
the
recipients may after all play a decisive role in longing graft survival.
pro-
We gratefully acknowledge the surgical assistance given by Mr G. A. Heystek, Mr R. H. van Leersum, and Mr H. D. Wiersema; Mr D. van Harte for postoperative care, Dr C. Zurcher for performing the histopathological examinations and Dr W. van Vreeswijk for histocompatibility testing. Part of the research was supported by a contract from the Dutch Kidney Foundation and contract no. 088-72-1BIAC of the Commission of the European Communities (contribution no. 1088 of the Euratom Biology Division).
Requests for reprints should be addressed to A. A. van E., Primate Centre TNO, 151 Lange Kleiweg, Rijswijk (ZH), The Netherlands. REFERENCES
Rood, J. J., van Leeuwen, A., Persijn, G., Lansbergen, Q, Goulmy, E., Termijtelen, A., Bradley, B. Transpl. Proc. (in the press). 2. Festenstein, H., Sachs, J. A., Paris, A. M. I. Lancet, 1976, i, 157. 3. van Hooff, J. P., Kalff, M. W., van Poelgeeste, A. E. Transplantation, 1976, 22, 306. 4. Persijn, G., van Hooff, J. P., Kalff, M. W., Lansbergen, Q., van Rood, J. J. Transpl. Proc. (in the press). 5. Opelz, G., Terasaki, P. I. Lancet, 1976, ii, 380. 6. Opelz, G., Terasaki, P. I. Transplantation, 1976, 22, 380. 7. Balner, H. Transpl. Rev. 1973, 15, 50. 8. Marquet, R. L., Heystek, G. A., van Bekkum, D. W. in Medical Primatology 1972, Proceedings of the 3rd Conference on Experimental Surgery in Primates, Lyon 1972, part II; p. 125. Basle, 1972. 9. van Es, A. A., Marquet, R. L., van Vreeswijk, W., Tank, B., Balner, H. Transpl. Proc. (in the press). 10. Myburgh, J. A., Maier, G., Smit, J. A., Shapiro, M., Meyers, A. M., Rablin, R., van Blerk, P. J. P., Jersky, J. Transplantation, 1974, 18, 3, 206. 11. Opelz, G., Mickey, M. R., Terasaki, P. I. ibid. 1974, 17, 371. 12. Terasaki, P. I., Marchioro, T. L., Starzl, T. E. Histocompatibility Testing. 1965. National Academy of Sciences, National Research Council, Washington, D.C., 1965. 13. Dicke, H. W., Heystek, G. A., Marquet, R. L., van der Ven, M. G. Transpl. Proc. 1971, 3, 484. 1.
van
ASSOCIATION BETWEEN LEUCOCYTE GROUP-5a ANTIGEN AND ACUTE LYMPHOBLASTIC LEUKÆMIA R. P. WARREN D. D. NGUYEN
R. STORB E. D. THOMAS
Fred Hutchinson Cancer Research Center, Seattle, and Department of Medicine, Division of Oncology, University of Washington School of Medicine, Seattle, Washington, U.S.A.
Leucocyte group 5 has two dominant alleles (5a and 5b) which segregate indeof the pendently major histocompatibility complex. The was studied in a Caucasian population group-5 system of controls and patients with acute lymphoblastic leukæmia. The 5a gene frequency was 0·09 in 72 controls and 0·38 in 39 patients with acute lymphoblastic leukæmia (p
