Immunologic Research

, Volume 38, Issue 1–3, pp 201–209 | Cite as

Immunological lessons learnt from patients transplanted with fully mismatched stem cells

  • Jean-Louis Touraine
  • Hélène Plotnicky
  • Maria-Grazia Roncarolo
  • Rosa Bacchetta
  • Lucette Gebuhrer


Fully HLA-mismatched stem cells from human fetal livers were transplanted into 17 infants and two fetuses to treat severe combined immunodeficiency disease in 1976–2000. Donor cell engraftment and immunological reconstitution were obtained in 14/19 patients, three of whom have been extensively and repeatedly studied immunologically during prolonged follow-up. T-cells were derived totally from donor cells; B-cells and antigen-presenting cells (APC) remained mainly of host origin. Due to class I and II mismatches between T-cells and all other cells (APC, B-cells, virus-infected target cells), limitations in the defense against infections in vivo and in T-cell functions in vitro (helper and cytotoxic activities) were predicted; however, these did not occur. Anti-tetanus toxoid responses (including specific antibody production) developed despite HLA disparities between T-cells and B-cells or APC in the chimeric children. Similarly, cytotoxic T-cells (of donor HLA phenotype) recognized host Epstein-Barr virus-infected target cells. Recognition of antigenic peptide by T-cells under these conditions involved presentation by host allogeneic HLA molecules and not by self HLA antigens. Tolerance to donor antigens was acquired by clonal deletion; tolerance to host antigens existed despite the presence of many host-reactive T-cells and involved clonal anergy.


Stem cells Transplantation Human chimeras T-cell differentiation T-cell recognition Tolerance 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Touraine JL. Bone-marrow and fetal-liver transplantation in immunodeficiencies and inborn errors of metabolism: Lack of significant restriction of T-cell function in long-term chimeras despite HLA-mismatch. Immunol Rev 1983;71:103–21.PubMedCrossRefGoogle Scholar
  2. 2.
    Zinkernagel RM, Callahan GN, Althage A, Cooper S, Klein PA, Klein J. On the thymus in the differentiation of “H-2 self-recognition” by T-cells: Evidence for dual recognition? J Exp Med 1978;147(3):882–96.PubMedCrossRefGoogle Scholar
  3. 3.
    Zinkernagel RM, Callahan GN, Althage A, Cooper S, Streilein JW, Klein J. The lymphoreticular system in triggering virus plus self-specific cytotoxic T-cells: Evidence for T help. J Exp Med 1978;147(3):897–911.PubMedCrossRefGoogle Scholar
  4. 4.
    Touraine JL, Raudrant D, Golfier F, Rebaud A, Sembeil R, Roncarolo MG et al. Reappraisal of in utero stem cell transplantation based on long-term results. Fetal Diagn Ther 2004;19 (4):305–12.PubMedCrossRefGoogle Scholar
  5. 5.
    Roncarolo MG, Yssel H, Touraine JL, Bétuel H, de Vries JE, Spits H. Autoreactive T-cell clones specific for class I and class II HLA antigens isolated from a human chimera. J Exp Med 1988;167(5):1523–34.PubMedCrossRefGoogle Scholar
  6. 6.
    Plotnicky H, Touraine JL. Cytotoxic T-cells from a human chimera induce regression of Epstein-Barr virus-infected allogeneic host cells. Int Immunol 1993;5(11):1413–20.PubMedCrossRefGoogle Scholar
  7. 7.
    Roncarolo MG, Yssel H, Touraine JL, Bacchetta R, Gebuhrer L, de Vries JE et al. Antigen recognition by MHC-incompatible cells of a human mismatched chimera. J Exp Med 1988;168(12):2139–52.PubMedCrossRefGoogle Scholar
  8. 8.
    Roncarolo MG, Touraine JL, Banchereau J. Cooperation between major histocompatibility complex mismatched mononuclear cells from a human chimera in the production of antigen-specific antibody. J␣Clin Invest 1986;77(3):673–80.PubMedGoogle Scholar
  9. 9.
    Plotnicky H, Touraine JL. Recognition of Epstein-Barr virus (EBV)-infected cells by T-cell colonies from a human chimera: Restriction by allogeneic determinants. Clin Exp Immunol 1993;94(3):494–99.PubMedGoogle Scholar
  10. 10.
    Betuel H Gebuhrer L, Lambert J, Freidel AC, Farre A. A possible new HLA-DR allele. Hum Immunol 1983;8(3):227–37.CrossRefGoogle Scholar
  11. 11.
    Bacchetta R, Vandekerckhove BAE, Touraine JL, Bigler M, Martino S, Gebuhrer L et al. Chimerism and tolerance to host and donor in severe combined immunodeficiencies transplanted with fetal liver stem cells. J Clin Invest 1993;91(3):1067–78.PubMedCrossRefGoogle Scholar
  12. 12.
    Spits H, Touraine JL, Yssel H, de Vries JE, Roncarolo MG. Presence of host-reactive and MHC-restricted T-cells in a transplanted severe combined immunodeficient (SCID) patient suggests positive selection and absence of clonal deletion. Immunol Rev 1990;116:101–116.PubMedCrossRefGoogle Scholar
  13. 13.
    Touraine JL, Roncarolo MG, Plotnicky H, Bacchetta R, Spits H. T lymphocytes from human chimeras do recognize antigen in the context of allogeneic determinants of the major histocompatibility complex. Immunol Lett 1994;39(1):9–12.CrossRefGoogle Scholar
  14. 14.
    Touraine JL, Roncarolo MG, Raudrant D, Bacchetta R, Golfier F, Sembeil R et al. Induction of transplantation tolerance in humans using fetal cell transplants. Transplant Proc 2005;37(1):65–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Doherty PC, Biddison WE, Bennink JR, Knowles BB. Cytotoxic T-cell responses in mice infected with influenza and vaccinia viruses vary in magnitude with H-2 genotype. J Exp Med 1978;148(2):534–43.PubMedCrossRefGoogle Scholar
  16. 16.
    Doherty PC, Korngold R, Schwartz DH, Bennink JR. Development and loss of virus-specific thymic competence in bone marrow radiation chimeras and normal mice. Immunol Rev 1981;58:37–72.PubMedCrossRefGoogle Scholar
  17. 17.
    Touraine JL. Perinatal fetal-cell and gene therapy. Int J Immunopharmacol 2000;2(12):1033–40.CrossRefGoogle Scholar
  18. 18.
    Vandekerckhove BAE, Namikawa R, Bacchetta R, Roncarolo MG. Human hematopoietic cells and thymic epithelial cells induce tolerance via different mechanisms in the SCID-hu mice mouse thymus. J␣Exp Med 1992;175(4):1033.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  • Jean-Louis Touraine
    • 1
    • 4
  • Hélène Plotnicky
    • 1
  • Maria-Grazia Roncarolo
    • 1
    • 2
  • Rosa Bacchetta
    • 1
    • 2
  • Lucette Gebuhrer
    • 1
    • 3
  1. 1.Department of Transplantation and Clinical ImmunologyClaude Bernard University and Edouard Herriot HospitalLyonFrance
  2. 2.TIGETMilanItaly
  3. 3.Blood Transfusion ServiceLyonFrance
  4. 4.Pav. P, Hôpital Ed. HerriotLyon Cedex 3France

Personalised recommendations