Immunological lessons learnt from patients transplanted with fully mismatched stem cells.
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.
Touraine
Jean-Louis
JL
Department of Transplantation and Clinical Immunology, Claude Bernard University and Edouard Herriot Hospital, Lyon, France. jean-louis.touraine@chu-lyon.fr
Plotnicky
Hélène
H
Roncarolo
Maria-Grazia
MG
Bacchetta
Rosa
R
Gebuhrer
Lucette
L
D017635:Clonal Anergy; D003602:Cytotoxicity, Immunologic; D005260:Female; D006680:HLA Antigens / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000276:immunology*; D006650:Histocompatibility Testing; D006801:Humans; D007223:Infant; D019520:Living Donors; D008297:Male; D016511:Severe Combined Immunodeficiency / Q000601:surgery*; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D023001:Transplantation Tolerance; D016896:Treatment Outcome
D006680:HLA Antigens