Advertisement

The Thymus: Its Influence on Recognition of “Self Major Histocompatibility Antigens” by T Cells and Consequences for Reconstitution of Immunodeficiency

  • Rolf M. Zinkernagel

Abstract

It has become clear that severe combined immunodeficiency (SCID) is a heterogeneous group of congential disorders and, similarly, that thymus hypoplasia or deficiency may have various aetiologies [1–4]. Thus, immunodeficiency can result if the thymus either fails to produce thymic hormone or fails to provide adequate epithelial cell-cell contact mechanisms to induce T cell differentiation. Stem cells may also be defective and cause immunodeficiency either because they are blocked in their normal differentiation programs or because they fail to enter the thymus or circulate properly through [5, 6]. Attempts at reconstituting immunodeficient patients by administering fetal thymus or stem cells have met with variable success. Immunocompetence may be restored to the degree that such patients responded to stimulation with PHA or rejected foreign skin grafts; unfortunately, in some cases they showed no increase in antibody production nor any lessening of their high susceptibility to infectious disease [1, 7–12]. In most of the clinical attempts at reconstitution, bone marrow transplants were HLA matched with the recipient, but not thymic or fetal liver cells [1]. The reasoning was that these fetal organs and cells were taken before immunocompetency was reached; therefore, a graft-versus-host disease was not possible [1–4]. Our hypothesis and experimental model in mice may offer an explanation for the variable therapeutic successes with fetal grafts and may reveal a basis for establishing improved rules for cellular engineering in reconstituting immunodeficient patients.

Keywords

Mixed Lymphocyte Reaction Severe Combine Immunodeficiency Severe Combine Immunodeficiency Disease Fetal Liver Cell Lymphocytic Choriomeningitis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Bortin, M. M., Rimm, A. A.: Severe combined immunodeficiency disease, characterization of the disease, and results of transplantation. J. Am. Med. Assoc. 238, 591–600 (1977)CrossRefGoogle Scholar
  2. 2.
    Githins, J. H.: Immunologic reconstitution with fetal tissue. N. Eng. J. Med. 294, 1116 (1976)CrossRefGoogle Scholar
  3. 3.
    Cooper, M. D.: Defective thymus development: A cause of combined immunodeficiency. N. Eng. J. Med. 293, 450 (1975)CrossRefGoogle Scholar
  4. 4.
    Pahwa, R., Pahwa, S., Good, R. A., Incefy, G. S., O’Reilly, R. J.: Rationale for combined use of fetal liver and thymus for immunological reconstruction in patients with variants of severe combined immunodeficiency. Proc. Natl. Acad. Sci. (USA) 74, 3002–3005 (1977)CrossRefGoogle Scholar
  5. 5.
    Le Douarin, N. M., Jotereau, F. V.: Tracing of cells of the avian thymus through embryonic life in interspecific chimeras. J. Exp. Med. 142, 17 (1975)PubMedCrossRefGoogle Scholar
  6. 6.
    Stutman, O., Good, R. A.: Traffic of hemopoietic cells to the thymus: Influence of histocompatibility differences. Exp. Hematol. 19, 12–15 (1969)Google Scholar
  7. 7.
    Githens, J. H., Fulginiti, V.A., Suvatte, V., Schroter, G., Hathaway, W. E., Pearlman, D. S., Kay, H. E. M., Terasaki, P. I., Hill, G. J., Kempe, C. H., Cox, S. T.: Grafting of fetal thymus and hematopoietic tissue in infants with immune deficiency syndromes. Transplantation 15, 427–434 (1973)PubMedCrossRefGoogle Scholar
  8. 8.
    August, C. S., Rosen, F. S., Filler, F. M., Janeway, C. A.: Implantation of a fetal thymus, restoring immunological competence in a patient with thymic aplasia (DiGeorge’s Syndrome). Lancet 2, 1210 (1968)PubMedCrossRefGoogle Scholar
  9. 9.
    Ammann, A J., Wara, D. W., Salmon, S., Perkins, H.: Thymus transplantation. Permanent reconstruction of cellular immunity in a patient with sex-linked combined immunodeficiency. N. Engl. J. Med. 289, 5–9 (1973)PubMedCrossRefGoogle Scholar
  10. 10.
    Buckley, R. H., Whisnant, J. K., Schiff, R. I., Gilbertsen, R. B., Huang, A. T., Platt, M. S.: Corrections of severe combined immunodeficiency by fetal liver cells. N. Engl. J. Med. 294, 1076 (1976)PubMedCrossRefGoogle Scholar
  11. 11.
    Keightley, R. G., Lawton, A. R., Cooper, M. D., Yunis, E. J.: Successful fetal liver transplantation in a child with severe combined immunodeficiency, Lancet 1975 II, 850CrossRefGoogle Scholar
  12. 12.
    Incefy, G. S., Dardenne, M., Pahwa, S., Grimes, E., Pahwa, R. N., Smithwick, E., O’Reilly, R., Good, R. A.: Thymic activity in severe combined immunodeficiency diseases. Proc. Natl. Acad. Sci. USA 74, 1250 (1977)PubMedCrossRefGoogle Scholar
  13. 13.
    Miller, J. F. A. P., Osoba, D.: Current concepts of the immunological function of the thymus. Phys. Rev. 47, 437 (1967)Google Scholar
  14. 14.
    Davies, A. J. S.: The thymus and the cellular basis of immunity. Transplant. Rev. 1, 43 (1969)PubMedGoogle Scholar
  15. 15.
    Good, R. A., Gabrielson, A. E.: The Thymus in Immunobiology. New York: Harper & Row 1964Google Scholar
  16. 16.
    Warner, N. L., Szenberg, A.: Effect of neonatal thymectomy on the immune response in the chicken. Nature 196, 784 (1962)PubMedCrossRefGoogle Scholar
  17. 17.
    Goldstein, A. L., Guha, A., Zatz, M. M., Hardy, M. A., White, A.: Purification and biological activity of thymosin, a hormone of the thymus gland. Proc. Natl. Acad. Sci. USA 69, 1800–1803 (1972)PubMedCrossRefGoogle Scholar
  18. 18.
    Bach, J.-F., Dardenne, M., Goldstein, A. L., Guha, A., White, A.: Apperance of T-cell markers in bone marrow rosette-forming cells after incubation with thymosin, a thymic hormone. Proc. Natl. Acad. Sci. USA 68, 2734–2738 (1971)PubMedCrossRefGoogle Scholar
  19. 19.
    Thymus Factors in Imunity, H. Friedman, ed. Ann. N. Y. Acad. Sci. 249, 1–547 (1975)Google Scholar
  20. 20.
    Dausset, J., Svejgard, A.: HLA and Disease. Copenhagen: Munksgaard 1977Google Scholar
  21. 21.
    Mitchison, N. A.: Passive transfer of transplantation immunity. Proc. Roy. Soc. Lond. Ser. B. 142,72 (1954)CrossRefGoogle Scholar
  22. 22.
    Thomas, L.: In: Cellular and humoral aspects of the hypersensitive states, H. S. Lawrence, ed. p 529 New York: Hoeber 1959Google Scholar
  23. 23.
    Lawrence, H. S.: Homograft sensitivity. Physiol. Rev. 39, 811, 1959PubMedGoogle Scholar
  24. 24.
    Kindred, B., Schreffler, D. C.: H-2 dependence of co-operation between T and B cells in vivo. J. Immunol. 109, 940 ( 1972PubMedGoogle Scholar
  25. 25.
    Katz, D. H., Hamoaka, T., Benacerraf, B.: Cell interactions between histoincompatible T and B lymphocytes. I1. Failure of physiologic cooperative interactions between T and B lymphocytes from allogeneic donor strains in humoral response to hapten-protein conjugates. J. Exp. Med. 137, 1405 (1973)PubMedCrossRefGoogle Scholar
  26. 26.
    Rosenthal, A. S., Shevach, E. M.: Function of macrophages in antigen recognition by guinea pig T lymphocytes. I. Requirement for histocompatible macrophages and lymphocytes. J. Exp. Med. 138, 1194 (1973)Google Scholar
  27. 27.
    Zinkernagel, R. M., Doherty, P. C.: Activity of sensitized thymus derived lymphocytes in lymphocytic choriomeningitis reflects immunological surveillance against altered self components. Nature 251, 547 (1974)PubMedCrossRefGoogle Scholar
  28. 28.
    Shearer, G. M.: Cell-mediated cytotoxicity to trinitrophenyl-modified syngenic lymphocytes. Eur. J. Immunol. 4, 257 (1974)CrossRefGoogle Scholar
  29. 29.
    Bevan, M. J.: The major histocompatibility complex determines susceptibility to cytotoxic T cells directed against minor histocompatibility antigens. J. Exp. Med. 142, 1349 (1975)PubMedCrossRefGoogle Scholar
  30. 30.
    Gordon, R. D., Simpson, E., Samelson, L. E.: In vitro cell-mediated immune responses to the male specific (H-Y) antigen in mice. J. Exp. Med. 142, 1108–1120 (1975)Google Scholar
  31. 3l.
    Zinkernagel, R. M., Althage, A., Jensen, F. C.: Cell-mediated immune response to lymphocytic choriomeningitis and vaccinia virus in rats. J. Immunol. 119, 1242 (1977)PubMedGoogle Scholar
  32. 32.
    Goulmy, E., Termijtelen, A., Bradley, B. A., Van Rood, J. J.: Y-antigen killing by T cells of women is restricted by HLA. Nature 266, 544 (1976)CrossRefGoogle Scholar
  33. 33.
    McMichael, A. J., Ting, A., Zweerink, H. J., Askonas, B. A.: HLA restriction of cell-mediated lysis of influenza virus-infected human cells. Nature 270, 524–526 (1977)PubMedCrossRefGoogle Scholar
  34. 34.
    Bergholtz, B. O., Thorsby, E.: Macrophage-dependent response of immune human T lymphocytes to PPD in vitro. Influence of HLA-D histocompatibility. Scand. J. Immunol. 6, 779 (1977)PubMedCrossRefGoogle Scholar
  35. 35.
    Dickmeiss, E., Soeberg, B., Svejgard, A.: Human cell-mediated cytotoxicity against modified target cells is restricted by HLA. Nature 270, 526–528 (1977)PubMedCrossRefGoogle Scholar
  36. 36.
    Toivanen, P., Toivanen, A., Vainio, O.: Complete restoration of bursadependent immune system after transplantation of semiallogenic stem cells into immunodeficient chicks. J. Exp. Med. 139, 1344 (1974)PubMedCrossRefGoogle Scholar
  37. 37.
    Wainberg, M. A., Markson, Y., Weiss, D. W., Donjanski, F.: Cellular immunity against Rous sarcoma of chickens. Preferential reactivity against autochthonous target cells as determined by lymphocyte adherence and cytotoxicity tests in vitro. Proc. Natl. Acad. Sci. USA 71, 3565 (1974)PubMedCrossRefGoogle Scholar
  38. 38.
    Munro, A., Bright, S.: Products of the major histocompatibility complex and their relationship to the immune response. 264, 145–152 (1976)Google Scholar
  39. 39.
    Paul, W. E., Benacerraf, B.: Functional specificity of thymus-dependent lymphocytes. Science 195, 1293 (1977)PubMedCrossRefGoogle Scholar
  40. 40.
    Klein, J.: The biology of the mouse histocompatibility-2 complex. New York: Springer 1975Google Scholar
  41. 41.
    McDevitt, H. O., Bodmer, W. F.: HL-A immune response genes, and disease. Lancet 1974 I, 1269–1275CrossRefGoogle Scholar
  42. 42.
    Transplant. Rev. 29, 1–310 (1976)Google Scholar
  43. 43.
    Origins of lymphocyte diversity. Cold Spr. Harb. Symp. Quant. Biol. 41, 505–626 (1976)Google Scholar
  44. 44.
    Katz, D. H., Benacerraf, B.: Genetic control of lymphocyte interactions and differentation. In: The Role of Products of the Histocompatibility Gene Complex in Immune Responses, p. 355. New York: Academic Press 1976Google Scholar
  45. 45.
    Bevan, M. J.: In a radiation chimera host H-2 antigens determine the immune responsiveness of donor cytotoxic cells. Nature 269, 417 (1977)PubMedCrossRefGoogle Scholar
  46. 46.
    Zinkernagel, R. M., Callahan, G. N., Klein, J., Dennert, G.: Cytotoxic T cells learn specificity for self H-2 during differentation in the thymus. Nature 271, 251 (1978)PubMedCrossRefGoogle Scholar
  47. 47.
    Zinkernagel, R. M., Callahan,, G. N., Althage, A., Cooper, S., Klein, P. A., Klein, J.: On the thymus in the differentation of “H-2 self-recognition” by T cells: Evidence for dual recognition? J. Exp. Med. 147, 882 (1978)Google Scholar
  48. 48.
    Zinkernagel, R. M., Callahan, G. N., Althage, A., Cooper, S., Streilein, J. W., Klein, J.: The lymphoreticular system in triggering virus-plus-self-specific cytotoxic T cells: Evidence for T help. J. Exp. Med. 147, 897 (1978)CrossRefGoogle Scholar
  49. 49.
    Burnet, F. M.: The clonal selection theory of acquired immunity. Cambridge: University Press 1959Google Scholar
  50. 50.
    Jerne, N. K.: The somatic generation of immune recognition. Eur. J. Immunol. 1, 1 (1971)PubMedCrossRefGoogle Scholar
  51. 51.
    von Boehmer, H., Haas, W.: Cytotoxic T lymphocytes recognize allogeneic tolerated TNP-conjugated cell. Nature 261, 139 (1976)CrossRefGoogle Scholar
  52. 52.
    Pfizenmaier, K., Starzinski-Powitz, A., Rodt, H., Rollinghoff, M., Wagner, H.: Virus and TNPhapten specific T cell mediated cytotoxicity against H-2 incompatible target cells. J. Exp. Med. 143, 999 (1976)PubMedCrossRefGoogle Scholar
  53. 53.
    Zinkernagel, R. M.: H-2 restriction of virus-specific cytotoxicity across the H-2 barrier separate effector T cell specificities are associated with self-H-2 and with the tolerated allogeneic H-2 in chimeras. J. Exp. Med. 144, 933 (1976)PubMedCrossRefGoogle Scholar
  54. 54.
    Gengozian, N., Rabette, B., Congdon, C. C.: Abnormal immune mechanism in allogeneic radiation chimeras. Science 149, 645–647 (1965)PubMedCrossRefGoogle Scholar
  55. 55.
    Dauphinee, M. J., Nordin, A. A.: Studies of the immunological capacity of germ-free mouse radiation chimeras. IV. Cell-mediated immunity. Cell. Immunol. 14, 394 (1974)PubMedCrossRefGoogle Scholar
  56. 56.
    Urso, P., Gengozian, N.: Variation in T and B cell deficiency in different mouse allogeneic radiation chimeras. J. Immunol. 113, 1170–1779 (1974)Google Scholar
  57. 57.
    Kindred, B., Loor, F.: Activity of host-derived T cells which differentiate in nude mice grafted with co-isogenic or allogenic thymuses. J. Exp. Med. 139, 1215–1227 (1974)PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1979

Authors and Affiliations

  • Rolf M. Zinkernagel
    • 1
  1. 1.Department of Cellular and Developmental ImmunologyScripps Clinic and Research FoundationLa JollaUSA

Personalised recommendations