Immunological lessons learnt from patients transplanted with fully mismatched stem cells
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Immunological lessons learnt from patients transplanted with fully mismatched stem cells Jean-Louis Touraine Æ He´le`ne Plotnicky Æ Maria-Grazia Roncarolo Æ Rosa Bacchetta Æ Lucette Gebuhrer
Published online: 1 June 2007 Ó Humana Press Inc. 2007
Abstract 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. Keywords Stem cells Transplantation Human chimeras T-cell differentiation T-cell recognition Tolerance
J.-L. Touraine H. Plotnicky M.-G. Roncarolo R. Bacchetta L. Gebuhrer Department of Transplantation and Clinical Immunology, Claude Bernard University and Edouard Herriot Hospital, Lyon, France M.-G. Roncarolo R. Bacchetta TIGET, Milan, Italy L. Gebuhrer Blood Transfusion Service, Lyon, France J.-L. Touraine (&) Pav. P, Hoˆpital Ed. Herriot, 69437 Lyon Cedex 3, France e-mail: [email protected]
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Immunol Res (2007) 38:201–209
Introduction Infants who have severe combined immunodeficiency disease (SCID) can be fully cured with a bone marrow transplant (BMT) from an HLA-identical sibling donor [1]. Immunological reconstitution develops readily in these patients who acquire defense mechanisms against micro-organisms rapidly and can then enjoy a normal life. Unfortunately many patients lack an HLA genotypically identical donor for a BMT. Three varieties of cell transplants can be proposed as alternatives: an HLA phenotypically identical BMT; a haplo-identical BMT from the father or the mother; or a fully mismatched fetal liver cell transplant (FLT). The latter mode of treatment was applied to 17 infants and two human fetuses (in utero) who had SCID. Advantage was taken of the immunological immaturity of both the host (because of immunodeficiency) and the donor (cells collected from fet
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