Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1985 Jun;75(6):1828–1834. doi: 10.1172/JCI111896

Deficiency of the autologous mixed lymphocyte reaction in patients with classic hemophilia treated with commercial factor VIII concentrate. Correlation with T cell subset distribution, antibodies to lymphadenopathy-associated or human T lymphotropic virus, and analysis of the cellular basis of the deficiency.

J S Smolen, P Bettelheim, U Köller, S McDougal, W Graninger, T A Luger, W Knapp, K Lechner
PMCID: PMC425538  PMID: 2989334

Abstract

14 patients with hemophilia were studied for the distribution of T cell subsets, the presence of antibody to lymphadenopathy-associated or human T lymphotropic virus type III (LAV/HTLV-III), and their responsiveness in autologous mixed lymphocyte reactions. In addition, mitogen and alloantigen responsiveness and Interleukin-2 production were investigated. Seven patients were found to have low Leu 3a/Leu 2a (T4/T8) ratios; eight patients had antibody to LAV/HTLV-III; and an additional patient had acquired immunodeficiency syndrome. Responsiveness to mitogens and alloantigens as well as Interleukin-2 production were comparable with those of healthy individuals. However, patients with low ratio, many of whom had antibodies to LAV/HTLV-III, had a highly deficient autologous mixed lymphocyte reaction. This reduced response of T cells to autologous non-T cells could not be corrected by elimination of Leu 2a/T8 cells, which indicated that there was a preferential loss of the Leu 3a cell subset(s) which responded to autologous non-T cells. Thus, these patients have a deficiency of intercellular communication within their immune system.

Full text

PDF
1828

Selected References

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

  1. Barré-Sinoussi F., Chermann J. C., Rey F., Nugeyre M. T., Chamaret S., Gruest J., Dauguet C., Axler-Blin C., Vézinet-Brun F., Rouzioux C. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science. 1983 May 20;220(4599):868–871. doi: 10.1126/science.6189183. [DOI] [PubMed] [Google Scholar]
  2. Centers for Disease Control (CDC) Pneumocystis carinii pneumonia among persons with hemophilia A. MMWR Morb Mortal Wkly Rep. 1982 Jul 16;31(27):365–367. [PubMed] [Google Scholar]
  3. Centers for Disease Control (CDC) Update on acquired immune deficiency syndrome (AIDS) among patients with hemophilia A. MMWR Morb Mortal Wkly Rep. 1982 Dec 10;31(48):644-6, 652. [PubMed] [Google Scholar]
  4. Curran J. W., Lawrence D. N., Jaffe H., Kaplan J. E., Zyla L. D., Chamberland M., Weinstein R., Lui K. J., Schonberger L. B., Spira T. J. Acquired immunodeficiency syndrome (AIDS) associated with transfusions. N Engl J Med. 1984 Jan 12;310(2):69–75. doi: 10.1056/NEJM198401123100201. [DOI] [PubMed] [Google Scholar]
  5. Davis K. C., Horsburgh C. R., Jr, Hasiba U., Schocket A. L., Kirkpatrick C. H. Acquired immunodeficiency syndrome in a patient with hemophilia. Ann Intern Med. 1983 Mar;98(3):284–286. doi: 10.7326/0003-4819-98-3-284. [DOI] [PubMed] [Google Scholar]
  6. Dos Reis G. A., Glimcher L. H., Shevach E. M. T cell clones and hybridomas as probes for the analysis of the syngeneic mixed leukocyte reaction. Behring Inst Mitt. 1983 May;(72):59–66. [PubMed] [Google Scholar]
  7. Elliott J. L., Hoppes W. L., Platt M. S., Thomas J. G., Patel I. P., Gansar A. The acquired immunodeficiency syndrome and Mycobacterium avium-intracellulare bacteremia in a patient with hemophilia. Ann Intern Med. 1983 Mar;98(3):290–293. doi: 10.7326/0003-4819-98-3-290. [DOI] [PubMed] [Google Scholar]
  8. Engleman E. G., Benike C. J., Hoppe R. T., Kaplan H. S., Berberich F. R. Autologous mixed lymphocyte reaction in patients with Hodgkin's disease. Evidence for a T cell defect. J Clin Invest. 1980 Jul;66(1):149–158. doi: 10.1172/JCI109828. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gallo R. C., Salahuddin S. Z., Popovic M., Shearer G. M., Kaplan M., Haynes B. F., Palker T. J., Redfield R., Oleske J., Safai B. Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS. Science. 1984 May 4;224(4648):500–503. doi: 10.1126/science.6200936. [DOI] [PubMed] [Google Scholar]
  10. Gatenby P. A., Kotzin B. L., Kansas G. S., Engleman E. G. Immunoglobulin secretion in the human autologous mixed leukocyte reaction. Definition of a suppressor-amplifier circuit using monoclonal antibodies. J Exp Med. 1982 Jul 1;156(1):55–67. doi: 10.1084/jem.156.1.55. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Glimcher L. H., Longo D. L., Green I., Schwartz R. H. Murine syngeneic mixed lymphocyte response. I. Target antigens are self Ia molecules. J Exp Med. 1981 Nov 1;154(5):1652–1670. doi: 10.1084/jem.154.5.1652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Goldsmith J. C., Moseley P. L., Monick M., Brady M., Hunninghake G. W. T-lymphocyte subpopulation abnormalities in apparently healthy patients with hemophilia. Ann Intern Med. 1983 Mar;98(3):294–296. doi: 10.7326/0003-4819-98-3-294. [DOI] [PubMed] [Google Scholar]
  13. Gupta S., Safai B. Deficient autologous mixed lymphocyte reaction in Kaposi's sarcoma associated with deficiency of Leu-3+ responder T cells. J Clin Invest. 1983 Feb;71(2):296–300. doi: 10.1172/JCI110769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hausman P. B., Raff H. V., Gilbert R. C., Picker L. J., Stobo J. D. T cells and macrophages involved in the autologous mixed lymphocyte reaction are required for the response to conventional antigen. J Immunol. 1980 Sep;125(3):1374–1379. [PubMed] [Google Scholar]
  15. Hausman P. B., Stobo J. D. Specificity and function of a human autologous reactive T cell. J Exp Med. 1979 Jun 1;149(6):1537–1542. doi: 10.1084/jem.149.6.1537. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Innes J. B., Kuntz M. M., Kim Y. T., Weksler M. E. Induction of suppressor activity in the autologous mixed lymphocyte reaction and in cultures with concanavalin A. J Clin Invest. 1979 Dec;64(6):1608–1613. doi: 10.1172/JCI109622. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. James S. P., Elson C. O., Waggoner J. G., Jones E. A., Strober W. Deficiency of the autologous mixed lymphocyte reaction in patients with primary biliary cirrhosis. J Clin Invest. 1980 Dec;66(6):1305–1310. doi: 10.1172/JCI109982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kalden J. R., Leitner O., Klöckel O., Kirchner H., Manger B., Koch B. The autologous mixed lymphocyte reaction in patients with rheumatoid arthritis. Behring Inst Mitt. 1983 May;(72):193–202. [PubMed] [Google Scholar]
  19. Klatzmann D., Barré-Sinoussi F., Nugeyre M. T., Danquet C., Vilmer E., Griscelli C., Brun-Veziret F., Rouzioux C., Gluckman J. C., Chermann J. C. Selective tropism of lymphadenopathy associated virus (LAV) for helper-inducer T lymphocytes. Science. 1984 Jul 6;225(4657):59–63. doi: 10.1126/science.6328660. [DOI] [PubMed] [Google Scholar]
  20. Kornfeld H., Vande Stouwe R. A., Lange M., Reddy M. M., Grieco M. H. T-lymphocyte subpopulations in homosexual men. N Engl J Med. 1982 Sep 16;307(12):729–731. doi: 10.1056/NEJM198209163071206. [DOI] [PubMed] [Google Scholar]
  21. Lane H. C., Masur H., Edgar L. C., Whalen G., Rook A. H., Fauci A. S. Abnormalities of B-cell activation and immunoregulation in patients with the acquired immunodeficiency syndrome. N Engl J Med. 1983 Aug 25;309(8):453–458. doi: 10.1056/NEJM198308253090803. [DOI] [PubMed] [Google Scholar]
  22. Lechner K., Niessner H., Bettelheim P., Deutsch E., Fasching I., Fuhrmann M., Hinterberger W., Korninger C., Neumann E., Liszka K. T-cell alterations in hemophiliacs treated with commercial clotting factor concentrates. Thromb Haemost. 1983 Aug 30;50(2):552–556. [PubMed] [Google Scholar]
  23. Ledbetter J. A., Evans R. L., Lipinski M., Cunningham-Rundles C., Good R. A., Herzenberg L. A. Evolutionary conservation of surface molecules that distinguish T lymphocyte helper/inducer and cytotoxic/suppressor subpopulations in mouse and man. J Exp Med. 1981 Feb 1;153(2):310–323. doi: 10.1084/jem.153.2.310. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Lederman M. M., Ratnoff O. D., Scillian J. J., Jones P. K., Schacter B. Impaired cell-mediated immunity in patients with classic hemophilia. N Engl J Med. 1983 Jan 13;308(2):79–83. doi: 10.1056/NEJM198301133080205. [DOI] [PubMed] [Google Scholar]
  25. Luban N. L., Kelleher J. F., Jr, Reaman G. H. Altered distribution of T-lymphocyte subpopulations in children and adolescents with haemophilia. Lancet. 1983 Mar 5;1(8323):503–505. doi: 10.1016/s0140-6736(83)92193-1. [DOI] [PubMed] [Google Scholar]
  26. Luger T. A., Smolen J. S., Chused T. M., Steinberg A. D., Oppenheim J. J. Human lymphocytes with either the OKT4 or OKT8 phenotype produce interleukin 2 in culture. J Clin Invest. 1982 Aug;70(2):470–473. doi: 10.1172/JCI110637. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Menitove J. E., Aster R. H., Casper J. T., Lauer S. J., Gottschall J. L., Williams J. E., Gill J. C., Wheeler D. V., Piaskowski V., Kirchner P. T-lymphocyte subpopulations in patients with classic hemophilia treated with cryoprecipitate and lyophilized concentrates. N Engl J Med. 1983 Jan 13;308(2):83–86. doi: 10.1056/NEJM198301133080206. [DOI] [PubMed] [Google Scholar]
  28. Miyasaka N., Sauvezie B., Pierce D. A., Daniels T. E., Talal N. Decreased autologous mixed lymphocyte reaction in Sjögren's syndrome. J Clin Invest. 1980 Nov;66(5):928–933. doi: 10.1172/JCI109960. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Opelz G., Kiuchi M., Takasugi M., Terasaki P. I. Autologous stimulation of human lymphocyte subpopulation. J Exp Med. 1975 Nov 1;142(5):1327–1333. doi: 10.1084/jem.142.5.1327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Poon M. C., Landay A., Prasthofer E. F., Stagno S. Acquired immunodeficiency syndrome with Pneumocystis carinii pneumonia and Mycobacterium avium-intracellulare infection in a previously healthy patient with classic hemophilia. Clinical, immunologic, and virologic findings. Ann Intern Med. 1983 Mar;98(3):287–290. doi: 10.7326/0003-4819-98-3-287. [DOI] [PubMed] [Google Scholar]
  31. Popovic M., Sarngadharan M. G., Read E., Gallo R. C. Detection, isolation, and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre-AIDS. Science. 1984 May 4;224(4648):497–500. doi: 10.1126/science.6200935. [DOI] [PubMed] [Google Scholar]
  32. Raff H. V., Picker L. J., Stobo J. D. Macrophage heterogeneity in man. A subpopulation of HLA-DR-bearing macrophages required for antigen-induced T cell activation also contains stimulators for autologous-reactive T cells. J Exp Med. 1980 Sep 1;152(3):581–593. doi: 10.1084/jem.152.3.581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Ragni M. V., Lewis J. H., Spero J. A., Bontempo F. A. Acquired-immunodeficiency-like syndrome in two haemophiliacs. Lancet. 1983 Jan 29;1(8318):213–214. doi: 10.1016/s0140-6736(83)92589-8. [DOI] [PubMed] [Google Scholar]
  34. Ramsey R. B., Palmer E. L., McDougal J. S., Kalyanaraman V. S., Jackson D. W., Chorba T. L., Holman R. C., Evatt B. L. Antibody to lymphadenopathy-associated virus in haemophiliacs with and without AIDS. Lancet. 1984 Aug 18;2(8399):397–398. doi: 10.1016/s0140-6736(84)90559-2. [DOI] [PubMed] [Google Scholar]
  35. Richardson B., Stobo J. D. Autologous reactive T cell clones and T-T hybrids. Behring Inst Mitt. 1983 May;(72):87–88. [PubMed] [Google Scholar]
  36. Romain P. L., Schlossman S. F., Reinherz E. L. Surface molecules involved in self-recognition and T cell activation in the autologous mixed lymphocyte reaction. J Immunol. 1984 Sep;133(3):1093–1100. [PubMed] [Google Scholar]
  37. Sakane T., Steinberg A. D., Green I. Failure of autologous mixed lymphocyte reactions between T and non-T cells in patients with systemic lupus erythematosus. Proc Natl Acad Sci U S A. 1978 Jul;75(7):3464–3468. doi: 10.1073/pnas.75.7.3464. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Salahuddin S. Z., Groopman J. E., Markham P. D., Sarngadharan M. G., Redfield R. R., McLane M. F., Essex M., Sliski A., Gallo R. C. HTLV-III in symptom-free seronegative persons. Lancet. 1984 Dec 22;2(8417-8418):1418–1420. doi: 10.1016/s0140-6736(84)91619-2. [DOI] [PubMed] [Google Scholar]
  39. Sarngadharan M. G., Popovic M., Bruch L., Schüpbach J., Gallo R. C. Antibodies reactive with human T-lymphotropic retroviruses (HTLV-III) in the serum of patients with AIDS. Science. 1984 May 4;224(4648):506–508. doi: 10.1126/science.6324345. [DOI] [PubMed] [Google Scholar]
  40. Schüpbach J., Popovic M., Gilden R. V., Gonda M. A., Sarngadharan M. G., Gallo R. C. Serological analysis of a subgroup of human T-lymphotropic retroviruses (HTLV-III) associated with AIDS. Science. 1984 May 4;224(4648):503–505. doi: 10.1126/science.6200937. [DOI] [PubMed] [Google Scholar]
  41. Smith J. B., Knowlton R. P., Koons L. S. Immunologic studies in chronic lymphocytic leukemia: defective stimulation of T-cell proliferation in autologous mixed lymphocyte culture. J Natl Cancer Inst. 1977 Mar;58(3):579–585. doi: 10.1093/jnci/58.3.579. [DOI] [PubMed] [Google Scholar]
  42. Smolen J. S., Chused T. M., Leiserson W. M., Reeves J. P., Alling D., Steinberg A. D. Heterogeneity of immunoregulatory T-cell subsets in systemic lupus erythematosus. Correlation with clinical features. Am J Med. 1982 May;72(5):783–790. doi: 10.1016/0002-9343(82)90544-7. [DOI] [PubMed] [Google Scholar]
  43. Smolen J. S., Chused T. M., Novotny E. A., Steinberg A. D. The human autologous mixed lymphocyte reaction. III. Immune circuits. J Immunol. 1982 Sep;129(3):1050–1053. [PubMed] [Google Scholar]
  44. Smolen J. S., Luger T. A., Chused T. M., Steinberg A. D. Responder cells in the human autologous mixed lymphocyte reaction. J Clin Invest. 1981 Dec;68(6):1601–1604. doi: 10.1172/JCI110416. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Smolen J. S., Sharrow S. O., Reeves J. P., Boegel W. A., Steinberg A. D. The human autologous mixed lymphocyte reaction. I. Suppression by macrophages and T cells. J Immunol. 1981 Nov;127(5):1987–1993. [PubMed] [Google Scholar]
  46. Smolen J. S., Sharrow S. O., Reeves J. P., Boegel W. A., Steinberg A. D. The human autologous mixed lymphocyte reaction. I. Suppression by macrophages and T cells. J Immunol. 1981 Nov;127(5):1987–1993. [PubMed] [Google Scholar]
  47. Smolen J. S., Siminovitch K., Luger T. A., Steinberg A. D. Responder cells in the human autologous mixed lymphocyte reaction (AMLR). Characterization and interactions in healthy individuals and patients with systemic lupus erythematosus. Behring Inst Mitt. 1983 May;(72):135–142. [PubMed] [Google Scholar]
  48. Tadokoro K., Stadler B. M., De Weck A. L. Factor-dependent in vitro growth of human normal bone marrow-derived basophil-like cells. J Exp Med. 1983 Sep 1;158(3):857–871. doi: 10.1084/jem.158.3.857. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Vande Stouwe R. A., Kunkel H. G., Halper J. P., Weksler M. E. Autologous mixed lymphocyte culture reactions and generation of cytotoxic T cells. J Exp Med. 1977 Dec 1;146(6):1809–1814. doi: 10.1084/jem.146.6.1809. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Vilmer E., Barre-Sinoussi F., Rouzioux C., Gazengel C., Brun F. V., Dauguet C., Fischer A., Manigne P., Chermann J. C., Griscelli C. Isolation of new lymphotropic retrovirus from two siblings with haemophilia B, one with AIDS. Lancet. 1984 Apr 7;1(8380):753–757. doi: 10.1016/s0140-6736(84)91275-3. [DOI] [PubMed] [Google Scholar]
  51. Wallace J. I., Coral F. S., Rimm I. R., Lane H., Levine H., Reinherz E. L., Schlossman S. F., Sonnabend J. T-cell ratios in homosexuals. Lancet. 1982 Apr 17;1(8277):908–908. doi: 10.1016/s0140-6736(82)92177-8. [DOI] [PubMed] [Google Scholar]
  52. Weksler M. E., Kozak R. Lymphocyte transformation induced by autologous cells. V. Generation of immunologic memory and specificity during the autologous mixed lymphocyte reaction. J Exp Med. 1977 Dec 1;146(6):1833–1838. doi: 10.1084/jem.146.6.1833. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Yamashita U., Shevach E. M. The syngeneic mixed leukocyte reaction: the genetic requirements for the recognition of self resemble the requirements for the recognition of antigen in association with self. J Immunol. 1980 Apr;124(4):1773–1778. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES