A SCID patient reconstituted with HLA-incompatible fetal stem cells as a model for studying transplantation tolerance.
We studied a severe combined immunodeficiency (SCID) patient who received transplantations with completely HLA-mismatched fetal liver and thymus from two different donors. The patient is now 14 years old, healthy and shows normal immunoresponses to recall antigens. His T cells are of donor origin, whereas the monocytes, B cells, and natural killer (NK) cells are of the recipient. The successful immunological reconstitution raised questions as to how T and B cells could collaborate across an HLA barrier and how tolerance was achieved. We have shown that tetanus toxin-specific T cell clones isolated from this patient recognized this antigen in the context of host and not of donor HLA-DR, indicating that those cells were educated in the host environment, presumably the thymus. Despite this, an unexpectedly high frequency of host-reactive clones was found that could recognize MHC antigens of the host. It was particularly striking that CD8+ CTL clones were obtained that recognized class I MHC antigens on the host cells. Nevertheless, the patient did not show any sign of acute or chronic graft-versus-host disease (GVHD). These data indicated that no or only incomplete clonal deletion had taken place in this patient and suggest the presence of a peripheral suppressor mechanism. Thus far, we have no indication for the existence of suppressor T cells. Inasmuch as it was found that host-reactive T cells fail to produce IL-4, which is exceptional for CD4+ T cells, we are exploring the possibility that abnormal cytokine production patterns of host-reactive T cells are associated with suppression of these cells in vivo.
Roncarolo
M G
MG
DNAX Research Institute, Human Immunology Department, Palo Alto, CA 94304-1104.
Bacchetta
R
R
Bigler
M
M
Touraine
J L
JL
de Vries
J E
JE
Spits
H
H
D001402:B-Lymphocytes / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D016332:Fetal Tissue Transplantation / Q000276:immunology*; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation; D006650:Histocompatibility Testing; D006801:Humans; D007108:Immune Tolerance; D007223:Infant; D016031:Liver Transplantation / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D016511:Severe Combined Immunodeficiency / Q000276:immunology / Q000601:surgery*; D013601:T-Lymphocytes / Q000276:immunology; D013950:Thymus Gland / Q000196:embryology / Q000276:immunology / Q000637:transplantation