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. 1976 Sep;184(3):352–368. doi: 10.1097/00000658-197609000-00013

Seven years' experience with antilymphoblast globulin for renal transplantation from cadaver donors.

J S Najarian, R L Simmons, R M Condie, E J Thompson, D S Fryd, R J Howard, A J Matas, D E Sutherland, R M Ferguson, J R Schmidtke
PMCID: PMC1344397  PMID: 786192

Abstract

Antibody of the IgGab type can be isolated from horses immunized with cultured human lymphoblasts plus complete Freund's adjuvant. The essential steps for the production of a safe, potent anti-human lymphoblast globulin (ALG) are: A) the use of early bleedings after immunization to reduce the titer of antibodies which react with red blood cells and platelets; B) careful absorption with human red blood cell stroma and platelets; C) stabilization with non-crystalline silica dioxide; D) chromatography through QAE sephadex to remove pyrogens, microaggregates and possible inhibitors of ALG activity; E) careful safety testing in animals for toxicity and pyrogenicity; and F) testing in vitro for sterility. Such a purified horse ALG (IgGab) can be administered safely intravenously to patients to supplement a standardized immunosuppressive regimen incorporating azathioprine and prednisone. Under these circumstances, allergic reactions are very rare, antibodies to horse IgG do not develop, skin tests to horse IgG remain negative, and immune elimination of circulating horse IgG from the human circulation cannot be demonstrated. The overall results of ALG patient survival and transplant function after 184 consecutive first cadaver transplants at the University of Minnesota demonstrate a statistically significant improvement in both parameters accompanying increases in ALG dose while rigidly utilizing standardized doses of azathioprine and prednisone. There is a significant reduction in the number of grafts lost to rejection; significant reduction in the number of rejection episodes; significant delay in the onset of rejection episodes; but there is no increase in septic loss of patients or kidneys. These efforts could be seen in the gross data or when subgroups controlling for patient age, tissue typing were analyzed. Excluding patients at high risk did not alter the results. The beneficial effects of ALG were particularly striking in good matches. In the highest doses, ALG may be dangerous for older patients with poor matches who develop an increased incidence of septic loss of kidney and/or life. Thus, ALG appears to be a useful adjunct in the early management of cadaver transplants by reducing the incidence and frequency of rejection episodes. The dose should probably be reduced in the older patients who receive kidneys from badly mismatched donors. One cannot conclude from this study that ALG manufactured in other centers by this or other techniques, will accomplish the same results since the multiplicity of factors involved in the success and failure of transplants must be controlled so that the influence of intravening variables in the assessment of ALG effectiveness can be assessed.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Amos D. B., Bashir H., Boyle W., MacQueen M., Tiilikainen A. A simple micro cytotoxicity test. Transplantation. 1969 Mar;7(3):220–223. doi: 10.1097/00007890-196903000-00023. [DOI] [PubMed] [Google Scholar]
  2. Bach J. F., Dormont J. Further developments of the rosette inhibition test for the testing of antihuman lymphocyte serum. Transplantation. 1971 Jan;11(1):96–100. doi: 10.1097/00007890-197101000-00016. [DOI] [PubMed] [Google Scholar]
  3. Buselmeier T. J., Simmons R. L., Najarian J. S., Duncan D. A., von Hartitzsch B., Kjellstrand C. M. The clinical application of a new prosthetic arteriovenous shunt. Characteristics and advantages over the standard A-V shunt and the A-V fistula. Nephron. 1974;12(1):22–28. doi: 10.1159/000180253. [DOI] [PubMed] [Google Scholar]
  4. Callender C. O., Simmons R. L., Yunis E. J., Toledo-Pereyra L. H., DeShazo M. T., Najarian J. S. Anti-HL-A antibodies: Failure to correlate with renal allograft rejection. Surgery. 1974 Oct;76(4):573–580. [PubMed] [Google Scholar]
  5. Condie R. M., White J. G., Najarian J. S. Platelet activity of antilymphocyte serum (ALS) preparations. Transplant Proc. 1973 Mar;5(1):555–559. [PubMed] [Google Scholar]
  6. Halpern B., Cachera J. P., Lacombe M., Hathaway A., Crepin Y., Hung B. M., Lacassagne J. P., Leandri J., Laurent D., Dubost C. The efficiency of sheep antidog antilymphocyte serum (SADALS) in the prolongation of canine heart allografts. Transplant Proc. 1969 Mar;1(1):467–469. [PubMed] [Google Scholar]
  7. Immons R. L., Ozerkis A. J., Hoehn R. J. Antiserum to lymphocytes: interactions with chemical immunosuppressants. Science. 1968 Jun 7;160(3832):1127–1130. doi: 10.1126/science.160.3832.1127. [DOI] [PubMed] [Google Scholar]
  8. Inman F. P., Nisonoff A. Reversible dissociation of fragment Fc of rabbit gamma-G-immunoglobulin. J Biol Chem. 1966 Jan 25;241(2):322–329. [PubMed] [Google Scholar]
  9. Iwasaki Y., Porter K. A., Amend J. R., Marchioro T. L., Zühlke V., Starzl T. E. The preparation and testing of horse antidog and antihuman antilymphoid plasma or serum and its protein fractions. Surg Gynecol Obstet. 1967 Jan;124(1):1–24. [PMC free article] [PubMed] [Google Scholar]
  10. JEEJEEBHOY H. F. EFFECTS OF RABBIT ANTI-RAT-LYMPHOCYTE PLASMA ON IMMUNE RESPONSE OF RATS THYMECTOMISED IN ADULT LIFE. Lancet. 1965 Jul 17;2(7403):106–107. doi: 10.1016/s0140-6736(65)92222-1. [DOI] [PubMed] [Google Scholar]
  11. Jondal M., Holm G., Wigzell H. Surface markers on human T and B lymphocytes. I. A large population of lymphocytes forming nonimmune rosettes with sheep red blood cells. J Exp Med. 1972 Aug 1;136(2):207–215. doi: 10.1084/jem.136.2.207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Levey R. H., Medawar P. B. Nature and mode of action of antilymphocytic antiserum. Proc Natl Acad Sci U S A. 1966 Oct;56(4):1130–1137. doi: 10.1073/pnas.56.4.1130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Lopez C., Simmons R. L., Mauer S. M., Najarian J. S., Good R. A., Gentry S. Association of renal allograft rejection with virus infections. Am J Med. 1974 Mar;56(3):280–289. doi: 10.1016/0002-9343(74)90609-3. [DOI] [PubMed] [Google Scholar]
  14. Minowada J., Nonoyama M., Moore G. E., Rauch A. M., Pagano J. S. The presence of the Epstein-Barr viral genome in human lymphoblastoid B-cell lines and its absence in a myeloma cell line. Cancer Res. 1974 Aug;34(8):1898–1903. [PubMed] [Google Scholar]
  15. Mitchell R. M., Sheil A. G., Slafsky S. F., Murray J. E. The effect of heterologous immune serum on canine renal homografts. Transplantation. 1966 May;4(3):323–329. doi: 10.1097/00007890-196605000-00009. [DOI] [PubMed] [Google Scholar]
  16. Moberg A. W., Gewurz H., Jetzer T., Simmons R. L., Najarian J. S. Forced flow electrophoretic purification of anti-human antilymphoblast globulin. Surgery. 1970 Nov;68(5):862–869. [PubMed] [Google Scholar]
  17. Monaco A. P., Abbott W. M., Othersen H. B., Simmons R. L., Wood M. L., Flax M. H., Russell P. S. Antiserum to lymphocytes: prolonged survival of canine renal allografts. Science. 1966 Sep 9;153(3741):1264–1267. doi: 10.1126/science.153.3741.1264. [DOI] [PubMed] [Google Scholar]
  18. Monaco A. P., Codish S. D. Survey of the current status of the clinical uses of antilymphocyte serum. Surg Gynecol Obstet. 1976 Mar;142(3):417–426. [PubMed] [Google Scholar]
  19. Monaco A. P., Wood M. L., Russell P. S. Adult Thymectomy: Effect on Recovery from Immunologic Depression in Mice. Science. 1965 Jul 23;149(3682):432–435. doi: 10.1126/science.149.3682.432. [DOI] [PubMed] [Google Scholar]
  20. Monaco A. P., Wood M. L., Russell P. S. Some effects of purified heterologous antihuman lymphocyte serum in man. Transplantation. 1967 Jul;5(4 Suppl):1106–1114. doi: 10.1097/00007890-196707001-00046. [DOI] [PubMed] [Google Scholar]
  21. Nagaya H., Sieker H. O. Allograft survival: effect of antiserums to thymus glands and lymphocytes. Science. 1965 Nov 26;150(3700):1181–1182. doi: 10.1126/science.150.3700.1181. [DOI] [PubMed] [Google Scholar]
  22. Najarian J. S., Kjellstrand C. M., Simmons R. L., Buselmeier T. J., von Hartitzsch B., Goetz F. C. Renal transplantation for diabetic glomerulosclerosis. Ann Surg. 1973 Oct;178(4):477–484. doi: 10.1097/00000658-197310000-00010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Najarian J. S., Simmons R. L., Gewurz H., Moberg A., Merkel F., Moore G. E. Anti-serum to cultured human lymphoblasts: preparation, purification and immunosuppressive properties in man. Ann Surg. 1969 Oct;170(4):617–632. doi: 10.1097/00000658-196910000-00013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Najarian J. S., Simmons R. L. The clinical use of antilymphocyte globulin. N Engl J Med. 1971 Jul 15;285(3):158–166. doi: 10.1056/NEJM197107152850310. [DOI] [PubMed] [Google Scholar]
  25. Rabellino E., Colon S., Grey H. M., Unanue E. R. Immunoglobulins on the surface of lymphocytes. I. Distribution and quantitation. J Exp Med. 1971 Jan 1;133(1):156–167. doi: 10.1084/jem.133.1.156. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Reedman B. M., Klein G. Cellular localization of an Epstein-Barr virus (EBV)-associated complement-fixing antigen in producer and non-producer lymphoblastoid cell lines. Int J Cancer. 1973 May;11(3):499–520. doi: 10.1002/ijc.2910110302. [DOI] [PubMed] [Google Scholar]
  27. Sheil A. G., Kelly G. E., Mears D., May J., Johnson J. R., Ibels L. S., Stewart J. H. Antilymphocyte globulin in patients with renal allografts from cadaveric donors. Late results of a controlled trail. Lancet. 1973 Aug 4;2(7823):227–228. doi: 10.1016/s0140-6736(73)93132-2. [DOI] [PubMed] [Google Scholar]
  28. Simmons R. L., Kjellstrand C. M., Buselmeier T. J., Najarian J. S. Renal transplantation in high-risk patients. Arch Surg. 1971 Aug;103(2):290–298. doi: 10.1001/archsurg.1971.01350080206032. [DOI] [PubMed] [Google Scholar]
  29. Simmons R. L., Moberg A. W., Gewurz H., Soll R., Najarian J. S. Immunosuppression by antihuman lymphocyte globulin: correlation of human and animal assay systems with clinical results. Transplant Proc. 1971 Mar;3(1):745–748. [PubMed] [Google Scholar]
  30. Simmons R. L., Moberg A. W., Gewurz H., Soll R., Tallent M. B., Najarian J. S. Immunosuppressive assay of antilymphoblast globulin in man: effect of dose, histocompatibility, and serologic response to horse gamma globulin. Surgery. 1970 Jul;68(1):62–68. [PubMed] [Google Scholar]
  31. Simmons R. L., Thompson E. J., Kjellstrand C. M., Yunis E. J., Condie R. M., Mauer S. M., Buselmeier T. J., Najarian J. S. Parent-to-child and child-to-parent kidney transplants. Experience with 101 transplants at one centre. Lancet. 1976 Feb 14;1(7955):321–324. doi: 10.1016/s0140-6736(76)90082-9. [DOI] [PubMed] [Google Scholar]
  32. Starzl T. E., Brettschneider L., Penn I., Schmidt R. W., Bell P., Kashiwagi N., Townsend C. M., Putnam C. W. A trial with heterologous antilymphocyte globulin in man. Transplant Proc. 1969 Mar;1(1):448–454. [PMC free article] [PubMed] [Google Scholar]
  33. Starzl T. E., Marchioro T. L., Porter K. A., Iwasaki Y., Cerilli G. J. The use of heterologous antilymphoid agents in canine renal and liver homotransplantation and in human renal homotransplantation. Surg Gynecol Obstet. 1967 Feb;124(2):301–308. [PMC free article] [PubMed] [Google Scholar]
  34. Toledo-Pereyra L. H., Condie R. M., Malmberg R., Simmons R. L., Najarian J. S. A fibrinogen-free plasma perfusate for preservation of kidneys for one hundred and twenty hours. Surg Gynecol Obstet. 1974 Jun;138(6):901–905. [PubMed] [Google Scholar]
  35. Turcotte J. G., Feduska N. J., Haines R. F., Freier D. T., Gikas P. W., McDonald F. D., Johnson A. G., Morrell R. M., Thompson N. W. Antithymocyte globulin in renal transplant krecipients. A clinical trial. Arch Surg. 1973 Apr;106(4):484–488. doi: 10.1001/archsurg.1973.01350160102016. [DOI] [PubMed] [Google Scholar]
  36. WAKSMAN B. H., ARBOUYS S., ARNASON B. G. The use of specific "lymphocyte" antisera to inhibit hypersensitive reactions of the "delayed" type. J Exp Med. 1961 Dec 1;114:997–1022. doi: 10.1084/jem.114.6.997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. WOODRUFF M. F., ANDERSON N. F. THE EFFECT OF LYMPHOCYTE DEPLETION BY THORACIC DUCT FISTULA AND ADMINISTRATION OF ANTILYMPHOCYTIC SERUM ON THE SURVIVAL OF SKIN HOMOGRAFTS IN RATS. Ann N Y Acad Sci. 1964 Nov 30;120:119–128. doi: 10.1111/j.1749-6632.1964.tb34710.x. [DOI] [PubMed] [Google Scholar]
  38. Weil R., 3rd, Simmons R. L. Combined immunosuppression for canine renal allograft prolongation: antilymphocyte serum plus prednisolone or azathioprine. Ann Surg. 1968 Feb;167(2):239–245. doi: 10.1097/00000658-196802000-00013. [DOI] [PMC free article] [PubMed] [Google Scholar]

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