Immunological rationale for induction therapy in patients with donor-specific memory T cells

  • Sylvie Fournel
  • Nathalie Bonnefoy-Bérard
  • Romain Paillot
  • Olga Assossou
  • Eric Robinet
  • Carole Ferraro
  • David Fevre
  • Laurent Genestier
  • Aicha Demidem
  • Jean-Pierre Revillard
Part of the Transplantation and Clinical Immunology book series (TRAC, volume 29)


The phenomenon of’ second set’ or ‘accelerated’ rejection which characterizes the rapid destruction of a second tissue or organ transplant from the same donor into the same recipient was first described by Medawar and coworkers. Those observations made in untreated recipients were considered as a major evidence for the immunological mechanisms of allograft rejection since such capacity to reject transplants of donor strain origin in an accelerated mode could be transferred to naive recipients by T cells from the presensitized hosts. Cross-reactive grafts from donors sharing MHC class I and/or class II alleles with the sensitizing donor were also rejected in an accelerated fashion, suggesting that accelerated rejection was mediated by sensitized CD4 + and/or CD8 + donor specific alloreactive T cells. The capacity to mount an anamnestic rejection could persist several weeks or months after completion of the first graft rejection, suggesting that memory T cells had been produced following the first transplant. However the mechanisms of memory induction and the phenotypic and functional differences between memory and effector T cells remain controversial. The allograft response entails the clonal expansion of donor MHC class II and MHC class I specific CD4 + and CD8 + T cells, associated with several phenotypic changes, including increased surface expression of CD2 and CD58 (LFA-3), increased affinity of the integrin CD11a/CD18 (LFA-1), de novo expression of the integrin α4β1 (CD29/49d, VLA-4), changes in expression of CD62L and CD44 and decrease of the CD45RA isoform with a compensatory increase of the shorter CD45RO isoform.


Clonal Expansion Membranous Nephropathy Clonal Deletion Mixed Leukocyte Reaction Clonal Anergy 
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.


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  1. 1.
    Etablissement Français des Greffes. Annual report from the Conseil Medical et Scientifique, 1996.Google Scholar
  2. 2.
    Traeger J, Touraine JL, Malik MC, Revillard JP, Laville M. Antilymphocyte globulin and thoracic duct drainage in renal transplantation. Kidney Int. 1983; 23(Suppl. 14); S74–S81.Google Scholar
  3. 3.
    Touraine JL, Traeger J, Bétuel H et al Antilymphocyte globulin in renal transplantation. Transplant Clin. Immunol. 1983; 15: 41–47.Google Scholar
  4. 4.
    Revillard JP, Laville M, Vincent C. Serum C-reactive protein assay in renal transplantation. In: Allen R, Bienvenu J, Laurent P, Suskind R (eds.), Marker Proteins in Inflammation. Walter de Gruyter, Berlin, 1982, pp. 509–510.Google Scholar
  5. 5.
    Constant S, Zain M, Pasqualini T, Ranney P, Bottomly K. Are primed CD4 + T lymphocytes different from unprimed cells? Eur. J. Immunol. 1994; 24: 1073–1079.PubMedCrossRefGoogle Scholar
  6. 6.
    Luqman M, Bottomly K. Activation requirements for CD4 + T cells differing in CD45R expression. J. Immunol. 1992; 149: 2300–2306.PubMedGoogle Scholar
  7. 7.
    Johnson JG, Jenkins MK. Monocytes provide a novel costimulatory signal to T cells that is not mediated by the CD28/B7 interaction. J. Immunol. 1994; 152: 429–437.PubMedGoogle Scholar
  8. 8.
    Van de Velde I, Lorré K, Bakkus M, Thielemans K, Ceuppens L, de Boer M. CD45RO + memory T cells but not CD45RA + naive T cells can be efficiently activated by remote co-stimulation with B7. Int. Immunol. 1993; 5: 1483–1487.PubMedCrossRefGoogle Scholar
  9. 9.
    Anasetti C, Tan P, Hansen JA, Martin PJ. Induction of specific nonresponsiveness in unprimed human T cells by anti-CD3 antibody and alloantigen. J. Exp. Med. 1990; 172: 1691–1700.PubMedCrossRefGoogle Scholar
  10. 10.
    Tan P, Anasetti C, Hansen JA, Melrose J, Brunvand M, Bradshaw J, Ledbetter JA, Linsley PS. Induction of alloantigen-specific hyporesponsiveness in human T lymphocytes by blocking interaction of CD28 with its ligand B7/BB1. J. Exp. Med. 1993; 177: 165–173.PubMedCrossRefGoogle Scholar
  11. 11.
    Vincent C, Fournel S, Wijdenes J, Revillard JP. Specific hyporesponsiveness of alloreactive peripheral T cells induced by CD4 antibodies. Eur. J. Immunol. 1995; 25: 816–822.PubMedCrossRefGoogle Scholar
  12. 12.
    Fournel S, Vincent C, Assossou O et al. CD4 mAbs prevent progression of alloactivated CD4 + T cells into the S phase of the cell cycle without interfering with early activation signals. Transplantation 1996; 62: 1136–1143.PubMedCrossRefGoogle Scholar
  13. 13.
    Robinet E, Fournel S, Fatmi A, Revillard JP. IL-2-resistant hyporesponsiveness induced by CD4 mAbs in OKT3-activated human T cells is reversed by CD45RA triggering. Cell Immunol. 1996; 167: 1–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Gupta M, Satyaraj E, Durkik JM, Rath S, Bal V. Differential regulation of T cell activation for primary versus secondary proliferative responses. J. Immunol. 1997; 158: 4113–4121.PubMedGoogle Scholar
  15. 15.
    Lynch DH, Ramsdell F, Alderson MR. Fas and Fas-L in the homeostatic regulation of immune responses. Immunol. Today 1995; 16: 569–574.PubMedCrossRefGoogle Scholar
  16. 16.
    Trauth BC, Klas C, Peters AMJ, Matzku S, Möller P, Falk W, Debatin KM, Krammer PH. Monoclonal antibody-mediated tumor regression by induction of apoptosis. Science 1989; 245: 301–305.PubMedCrossRefGoogle Scholar
  17. 17.
    Itoh N., Yonehara S, Ishii A et al. The polypeptide encoded by cDNA for human cell surface antigen Fas can mediate apoptosis. Cell 1991; 66: 233–243.PubMedCrossRefGoogle Scholar
  18. 18.
    Smith CA, Farrah T, Goodwin RG. The TNF receptor superfamily of cellular and viral proteins: activation, costimulation and death. Cell 1994; 76: 959–962.PubMedCrossRefGoogle Scholar
  19. 19.
    Armitage RJ. Tumor necrosis factor receptor superfamily members and their ligands. Curr. Opin. Immunol. 1994; 6: 407–413.PubMedCrossRefGoogle Scholar
  20. 20.
    Suda T, Takahashi T, Golstein P, Nagata S. Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell 1993; 75: 1169–1178.PubMedCrossRefGoogle Scholar
  21. 21.
    Suda T, Nagata S. Purification and characterization of the Fas-ligand that induces apoptosis. J. Exp. Med. 1994; 179: 873.PubMedCrossRefGoogle Scholar
  22. 22.
    Suda T, Okazaki T, Naito Y et al. Expression of the Fas ligand in cells of T cell lineage. J. Immunol. 1995; 154: 3806–3813.PubMedGoogle Scholar
  23. 23.
    Kayagaki N, Kawasaki A, Ebata T et al. Metalloproteinase-mediated reiease of human Fas ligand. J. Exp. Med. 1995; 182: 1777–1783.PubMedCrossRefGoogle Scholar
  24. 24.
    Mariani SM, Matiba B, Baümler C, Krammer PH. Regulation of cell surface APO-1/Fas (CD95) ligand expression by metalloproteases. Eur. J. Immunol. 1995; 25: 2303–2304.PubMedCrossRefGoogle Scholar
  25. 25.
    Watanabe-Fukanaga RC, Brannan I, Coneland NG et al. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 1992; 356: 314–317.CrossRefGoogle Scholar
  26. 26.
    Ramsdell, F, Seaman MS, Miller RE, Tough TW, Alderson MR, Lynch DH. gld/gld mice are unable to express a functional ligand for Fas. Eur. J. Immunol. 1994; 4: 928–933.CrossRefGoogle Scholar
  27. 27.
    Takahashi T, Tanaka M, Brannan CI et al. Generalized lymphoproliferation disease in mice, caused by a point mutation in the Fas ligand. Cell 1994; 76: 969–976.PubMedCrossRefGoogle Scholar
  28. 28.
    Rieux-Laucat F, Le Deist F, Hivroz C et ai. Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science 1995; 268: 1347–1349.PubMedCrossRefGoogle Scholar
  29. 29.
    Fisher GH, Rosenberg FJ, Straus SE et al. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell 1995; 81: 935–946.PubMedCrossRefGoogle Scholar
  30. 30.
    MacDonald HR, Baschieri S, Lees RK. Clonal expansion precedes anergy and death of Vβ8 + peripheral T cells responding to staphylococcal enterotoxin B in vivo. Eur. J. Immunol. 1991; 21: 1963–1966.PubMedCrossRefGoogle Scholar
  31. 31.
    Lenardo MJ. Interleukin-2 programs mouse αβ T lymphocytes for apoptosis. Nature 1991; 353: 858–861.PubMedCrossRefGoogle Scholar
  32. 32.
    Klas C, Debatin KM, Jonker RR, Krammer PH. Activation interferes with the Apo-1 pathway in mature human T cells. Int. Immunol. 1993; 5: 625–630.PubMedCrossRefGoogle Scholar
  33. 33.
    Fournel S, Genestier L, Robinet E, Flacher M, Revillard JP. Human T cells require IL-2 but not G1/S transition to acquire susceptibility to Fas-mediated apoptosis. J. Immunol. 1996; 157: 4309–4315.PubMedGoogle Scholar
  34. 34.
    Wang R, Rogers AM, Rush BJ, Russel JH. Induction of sensitivity to activation-induced death in primary CD4 + cell: a role for interleukin-2 in the negative regulation of response by mature CD4 + cells. Eur. J. Immunol. 1996; 26: 2263–2270.PubMedCrossRefGoogle Scholar
  35. 35.
    Kneitz B, Herrmann T, Yonera S, Schimpl A. Normal clonal expansion but impaired Fasmediated cell death and anergy induction in interleukin-2-deficient mice. Eur. J. Immunol. 1995; 25: 2572–2577.PubMedCrossRefGoogle Scholar
  36. 36.
    Kündig, TM, Schorle H, Bachmann MF et al. Immune responses in interleukin-2-deficient mice. Science 1993; 262: 1059–1061.PubMedCrossRefGoogle Scholar
  37. 37.
    Willerford DM, Chen J, Ferry JA et al. Interleukin-2 receptor a chain regulates the size and content of the peripheral lymphoid. Immunity 1995; 3: 521–530.PubMedCrossRefGoogle Scholar
  38. 38.
    Suzuki H, Kündig TM, Furlonger C et al. Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor β. Nature 1995; 268: 1472–1476.Google Scholar
  39. 39.
    Anel A, Buferne M, Boyer C, Schmitt-Verhulst A-M, Golstein P. T cell receptor-induced Fas ligand expression in cytotoxic T lymphocyte clones is blocked by protein tyrosine kinase inhibitors and cyclosporin A. Eur. J. Immunol. 1994; 24: 2469–2476.PubMedCrossRefGoogle Scholar
  40. 40.
    Sambhara SR, Miller RG. Programmed cell death of T cells signaled by the T cell receptor and the α3 domain of class I CMH. Science 1991; 252: 1424–1427.PubMedCrossRefGoogle Scholar
  41. 41.
    Genestier L, Paillot R, Bonnefoy-Berard N, Waldmann H, Revillard JP. T cell sensitivity to HLA class I-mediated apoptosis is dependent on IL-2 and IL-4. Eur. J. Immunol. 1997; 27: 495–499.PubMedCrossRefGoogle Scholar
  42. 42.
    Genestier L, Paillot R, Bonnefoy-Berard N et al. Fas independent apoptosis of activated T cells induced by antibodies to the HLA class I α1 domain. Blood 1997; 90 (in press, Nov. issue).Google Scholar
  43. 43.
    Genestier L, Meffre G, Garrone P et al. Antibodies to HLA class I α1 domain trigger apoptosis of CD40-activated human B lymphocytes. Blood 1997; 90: 726–735.PubMedGoogle Scholar
  44. 44.
    Mollereau B, Deckert M, Déas O et al. CD2-induced apoptosis in activated human peripheral T cells: A Fas-independent pathway that requires early protein tyrosine phosphorylation. J. Immunol. 1996; 151: 3184–3190.Google Scholar
  45. 45.
    Gonzalez-Garcia A, Borlando L, Leonardo E, Mérida I, Martinez A, Carrera AC. Lck is necessary and sufficient for Fas-ligand expression and apoptotic cell death in mature cycling T cells. J. Immunol. 1997; 158: 4104–4112.PubMedGoogle Scholar
  46. 46.
    Gribben JG, Freeman GJ, Boussiotis VA et al. CTLA-4 mediates antigen-specific apoptosis of human T cells. Proc. Natl. Acad. Sci. USA 1995; 92: 811–815.PubMedCrossRefGoogle Scholar
  47. 47.
    Lee SY, Park CG, Choi Y. T cell receptor-dependent cell death of T cell hybridomas mediated by the CD30 cytoplasmic domain in association with Tumor Necrosis Factor receptor-associated factors. J. Exp. Med. 1996; 183: 669–674.PubMedCrossRefGoogle Scholar
  48. 48.
    Klaus SJ, Sidorenko SP, Clark EA. CD45 ligation induces programmed cell death in T and B lymphocytes. J. Immunol. 1996; 156: 2743–2753.PubMedGoogle Scholar
  49. 49.
    Brown TJ, Shuford WW, Wang W-C et al. Characterization of a CD43/leukosialin-mediated pathway for inducing apoptosis in human T-lymphoblastoid cells. J. Biol. Chem. 1996; 271: 27686–27695.PubMedCrossRefGoogle Scholar
  50. 50.
    Hess S, Engelmann H. A novel function of CD40: induction of cell death in transformed cells. J. Exp. Med. 1996; 183: 159–167.PubMedCrossRefGoogle Scholar
  51. 51.
    Cronstein BN, Eberle MA, Gruber HE, Levin RI. Methotrexate inhibits neutrophil function by stimulating adenosine release from connective tissue cells. Proc. Natl. Acad. Sci. USA 1991; 88: 2441–2445.PubMedCrossRefGoogle Scholar
  52. 52.
    Friesen C, Herr I, Krammer P, Debatin K-M. Involvement of the CD95 (APO-1/Fas) receptor/ligand system in drug-induced apoptosis in leukemia cells. Nature Med. 1996; 2: 574–577.PubMedCrossRefGoogle Scholar
  53. 53.
    Müller M, Strand S, Hug H et al. Drug-induced apoptosis in hepatoma cells is mediated by the CD95 (APO-1/Fas) receptor/ligand system and involves activation of wild-type p53. J. Clin. Invest. 1997; 99: 403–413.PubMedCrossRefGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1997

Authors and Affiliations

  • Sylvie Fournel
  • Nathalie Bonnefoy-Bérard
  • Romain Paillot
  • Olga Assossou
  • Eric Robinet
  • Carole Ferraro
  • David Fevre
  • Laurent Genestier
  • Aicha Demidem
  • Jean-Pierre Revillard

There are no affiliations available

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