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. 1983 Feb 1;157(2):755–771. doi: 10.1084/jem.157.2.755

Allosuppressor and allohelper T cells in acute and chronic graft-vs.- host disease. II. F1 recipients carrying mutations at H-2K and/or I-A

PMCID: PMC2186941  PMID: 6218218

Abstract

By induction of a graft-vs.-host reaction (GVHR) in nonirradiated H-2- different F1 mice, one can induce stimulatory pathological symptoms, such as lymphadenopathy and hypergammaglobulinemia, combined with the production of autoantibodies characteristic of systemic lupus erythematosus (SLE). Alternatively, the GVHR can lead to the suppressive pathological symptoms, such as pancytopenia and hypogammaglobulinemia, characteristic of acute GVH disease (GVHD). Whether stimulatory or suppressive symptoms are induced by a GVHR depends, in our view (2-4), on the functional subset of donor T cells activated in the F1 host. The purpose of the present study was to investigate whether class I and/or class II H-2 alloantigens can selectively trigger, out of a pool of unselected donor T cells, those subpopulations of T cells responsible for the stimulatory and suppressive GVH symptoms, respectively. For the induction of the GVHR, 10(8) lymphoid cells from C57BL/6 (B6) donors were injected into three kinds of F1 hybrid mice, which had been bred from H-2 mutant strains on a B6 background. Whereas the I-A-disparate (B6 X bm12)F1 recipients exclusively developed stimulatory GVH symptoms, including SLE-like autoantibodies and immune complex glomerulonephritis, the K locus- disparate (B6 X bm1)F1 recipients showed neither clearly stimulatory nor clearly suppressive GVH symptoms. In marked contrast, the (bm1 X bm12)F1 recipients, which differ from the B6 donor strain by mutations at both K and I-A locus, initially developed stimulatory GVH symptoms, but rapidly thereafter showed the suppressive pathological symptoms of acute GVHD and died. Moreover, spleen cells obtained from (B6 X bm12)F1 mice injected with B6 donor cells helped the primary anti-sheep erythrocyte (SRBC) response of normal (B6 X bm12)F1 spleen cells in vitro, whereas spleen cells (bm1 X bm12)F1 mice injected with B6 donor cells strongly suppressed the primary anti-SRBC response of normal (bm1 X bm12)F1 spleen cells. Spleen cells from the K locus-disparate (B6 X bm1)F1 recipients also suppressed the primary anti-SRBC of normal (B6 X bm1)F1 spleen cells; this suppression, however, was weak when compared with the suppression induced by spleen cells from GVH (bm1 X bm12)F1 mice. Taken together, these findings indicate that a small class II (I- A) antigenic difference suffices to trigger the alloreactive donor T helper cells causing SLE-like GVHD. In contrast, both class I (H-2K) and class II (I-A) differences are required to trigger the subsets of donor T cells responsible for acute GVHD. It appears that alloreactive donor T helper cells induce the alloreactive T suppressor cells, which then act as the suppressor effector cells causing the pancytopenia of acute GVHD. These findings may help to understand the variability of GVH-like diseases caused by a given etiologic agent, their cellular pathogenesis, and association with certain HLA loci.

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Selected References

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

  1. Bergholtz B. O., Thorsby E. HLA-D restriction of the macrophage-dependent response of immune human T lymphocytes to PPD in vitro: inhibition by anti-HLA-DR antisera. Scand J Immunol. 1978;8(1):63–73. doi: 10.1111/j.1365-3083.1978.tb00496.x. [DOI] [PubMed] [Google Scholar]
  2. Cantor H., Asofsky R. Synergy among lymphoid cells mediating the graft-versus-host response. 3. Evidence for interaction between two types of thymus-derived cells. J Exp Med. 1972 Apr 1;135(4):764–779. doi: 10.1084/jem.135.4.764. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cantor H., Boyse E. A. Regulation of cellular and humoral immune responses by T-cell subclasses. Cold Spring Harb Symp Quant Biol. 1977;41(Pt 1):23–32. doi: 10.1101/sqb.1977.041.01.006. [DOI] [PubMed] [Google Scholar]
  4. Cantor H., Gershon R. K. Immunological circuits: cellular composition. Fed Proc. 1979 Jun;38(7):2058–2064. [PubMed] [Google Scholar]
  5. Daguillard F., Garneau R., Deschenes L., Chouinard C., Fudenberg H. H., Schanfield M. Hyperactive production of antibody of a boy with thymic dysplasia undergoing graft versus host reaction. Clin Immunol Immunopathol. 1973 Nov;2(1):52–61. doi: 10.1016/0090-1229(73)90035-4. [DOI] [PubMed] [Google Scholar]
  6. Elkins W. L. Cellular immunology and the pathogenesis of graft versus host reactions. Prog Allergy. 1971;15:78–187. [PubMed] [Google Scholar]
  7. Gleichmann E., Van Elven E. H., Van der Veen J. P. A systemic lupus erythematosus (SLE)-like disease in mice induced by abnormal T-B cell cooperation. Preferential formation of autoantibodies characteristic of SLE. Eur J Immunol. 1982 Feb;12(2):152–159. doi: 10.1002/eji.1830120210. [DOI] [PubMed] [Google Scholar]
  8. Gleichmann H., Gleichmann E., André-Schwartz J., Schwartz R. S. Chronic allogeneic disease. 3. Genetic requirements for the induction of glomerulonephritis. J Exp Med. 1972 Mar 1;135(3):516–532. doi: 10.1084/jem.135.3.516. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gleichmann H. Studies on the mechanism of drug sensitization: T-cell-dependent popliteal lymph node reaction to diphenylhydantoin. Clin Immunol Immunopathol. 1981 Feb;18(2):203–211. doi: 10.1016/0090-1229(81)90026-x. [DOI] [PubMed] [Google Scholar]
  10. Klein J., Chiang C. L. Ability of H-2 regions to induce graft-vs-host disease. J Immunol. 1976 Sep;117(3):736–740. [PubMed] [Google Scholar]
  11. Klein J. Relative importance of H-2 regions in the development of graft-versus-host reactions. Transplant Proc. 1976 Sep;8(3):335–338. [PubMed] [Google Scholar]
  12. Korngold R., Sprent J. Lethal graft-versus-host disease after bone marrow transplantation across minor histocompatibility barriers in mice. Prevention by removing mature T cells from marrow. J Exp Med. 1978 Dec 1;148(6):1687–1698. doi: 10.1084/jem.148.6.1687. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Livnat S., Klein J. Graft versus host reaction in strains of mice identical for H-2K and H-2D antigens. Nat New Biol. 1973 May 9;243(123):42–44. [PubMed] [Google Scholar]
  14. McKean D. J., Melvold R. W., David C. Tryptic peptide comparison of Ia antigen alpha and beta polypeptides from the I-A mutant B6.C-H-2bm12 and its congenic parental strain B6. Immunogenetics. 1981;14(1-2):41–51. doi: 10.1007/BF00344298. [DOI] [PubMed] [Google Scholar]
  15. McKenzie I. F., Morgan G. M., Sandrin M. S., Michaelides M. M., Melvold R. W., Kohn H. I. B6.C-H-2bm12. A new H-2 mutation in the I region in the mouse. J Exp Med. 1979 Dec 1;150(6):1323–1338. doi: 10.1084/jem.150.6.1323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Nisizawa T., Ewenstein B. M., Uehara H., McGovern D., Nathenson S. G. Biochemical studies on the H-2K antigens of the MHC mutant bml. Immunogenetics. 1981;12(1-2):33–44. doi: 10.1007/BF01561649. [DOI] [PubMed] [Google Scholar]
  17. Oppltová L., Démant P. Genetic determinants for the graft-vs.-host reaction in the H-2 complex. Transplant Proc. 1973 Dec;5(4):1367–1371. [PubMed] [Google Scholar]
  18. Pickel K., Hoffmann M. K. Suppressor T cells arising in mice undergoing a graft-vs-host response. J Immunol. 1977 Feb;118(2):653–656. [PubMed] [Google Scholar]
  19. Pickel K., Hoffmann M. K. The Ly phenotype of suppressor T cells arising in mice subjected to a graft-versus-host reaction. J Exp Med. 1977 May 1;145(5):1169–1175. doi: 10.1084/jem.145.5.1169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Rolink A. G., Radaszkiewicz T., Pals S. T., van der Meer W. G., Gleichmann E. Allosuppressor and allohelper T cells in acute and chronic graft-vs-host disease. I. Alloreactive suppressor cells rather than killer T cells appear to be the decisive effector cells in lethal graft-vs.-host disease. J Exp Med. 1982 May 1;155(5):1501–1522. doi: 10.1084/jem.155.5.1501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Shakir R. A., Behan P. O., Dick H., Lambie D. G. Metabolism of immunoglobulin A, lymphocyte function, and histocompatibility antigens in patients on anticonvulsants. J Neurol Neurosurg Psychiatry. 1978 Apr;41(4):307–311. doi: 10.1136/jnnp.41.4.307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Shand F. L. Ly and Ia phenotype of suppressor T cells induced by graft-vs.-host reaction. Eur J Immunol. 1977 Oct;7(10):746–748. doi: 10.1002/eji.1830071019. [DOI] [PubMed] [Google Scholar]
  23. Shulman H. M., Sullivan K. M., Weiden P. L., McDonald G. B., Striker G. E., Sale G. E., Hackman R., Tsoi M. S., Storb R., Thomas E. D. Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. Am J Med. 1980 Aug;69(2):204–217. doi: 10.1016/0002-9343(80)90380-0. [DOI] [PubMed] [Google Scholar]
  24. Simon M. M., Eichmann K. T cell subsets participating in the generation of cytotoxic T cells. Springer Semin Immunopathol. 1980 May;3(1):39–62. doi: 10.1007/BF00199925. [DOI] [PubMed] [Google Scholar]
  25. Swain S. L., Bakke A., English M., Dutton R. W. Ly phenotypes and MHC recognition: the allohelper that recognizes K or D is a mature Ly123 cell. J Immunol. 1979 Dec;123(6):2716–2724. [PubMed] [Google Scholar]
  26. Swain S. L., Dutton R. W. Negative allogeneic effects in vitro. I. Allogeneic T cells markedly suppress the secondary antibody-forming cell response. J Immunol. 1977 Jun;118(6):2262–2268. [PubMed] [Google Scholar]
  27. Swain S. L., Panfili P. R., Dutton R. W., Lefkovits I. Frequency of allogeneic helper T cells responding to whole H-2 differences and to an H-2K difference alone. J Immunol. 1979 Sep;123(3):1062–1067. [PubMed] [Google Scholar]
  28. Van Elven E. H., Rolink A. G., Veen F. V., Gleichmann E. Capacity of genetically different T lymphocytes to induce lethal graft-versus-host disease correlates with their capacity to generate suppression but not with their capacity to generate anti-F1 killer cells. A non-H-2 locus determines the inability to induce lethal graft-versus-host disease. J Exp Med. 1981 Jun 1;153(6):1474–1488. doi: 10.1084/jem.153.6.1474. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Van Oudenaren A., Hooijkaas H., Benner R. Improvement of the protein A plaque assay for immunoglobulin secreting cells by using immunoglobulin-depleted guinea pig serum as a source of complement. J Immunol Methods. 1981;43(2):219–224. doi: 10.1016/0022-1759(81)90026-0. [DOI] [PubMed] [Google Scholar]
  30. Widmer M. B., Alter B. J., Bach F. H., Bach M. L. Lymphocyte reactivity to serologically undetected components of the major histocompatibility complex. Nat New Biol. 1973 Apr 25;242(121):239–241. doi: 10.1038/newbio242239a0. [DOI] [PubMed] [Google Scholar]
  31. de Waal L. P., Melief C. J., Melvold R. W. Cytotoxic T lymphocytes generated across and I-Ab mutant difference are directed against a molecule bearing Ia antigens. Eur J Immunol. 1981 Mar;11(3):258–265. doi: 10.1002/eji.1830110317. [DOI] [PubMed] [Google Scholar]
  32. van Bekkum D. W., Roodenburg J., Heidt P. J., van der Waaij D. Mitigation of secondary disease of allogeneic mouse radiation chimeras by modification of the intestinal microflora. J Natl Cancer Inst. 1974 Feb;52(2):401–404. doi: 10.1093/jnci/52.2.401. [DOI] [PubMed] [Google Scholar]
  33. van Rappard-van der Veen F. M., Rolink A. G., Gleichmann E. Diseases caused by reactions of T lymphocytes towards incompatible structures of the major histocompatibility complex. VI. Autoantibodies characteristic of systemic lupus erythematosus induced by abnormal T-B cell cooperation across I-E. J Exp Med. 1982 May 1;155(5):1555–1560. doi: 10.1084/jem.155.5.1555. [DOI] [PMC free article] [PubMed] [Google Scholar]

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