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DYSFUNCTIONAL CYTOKINE PRODUCTION BY HOST-REACTIVE T-CELL - CLONES ISOLATED FROM A CHIMERIC SEVERE COMBINED IMMUNODEFICIENCY PATIENT TRANSPLANTED WITH HAPLOIDENTICAL BONE-MARROW
DYSFUNCTIONAL CYTOKINE PRODUCTION BY HOST-REACTIVE T-CELL - CLONES ISOLATED FROM A CHIMERIC SEVERE COMBINED IMMUNODEFICIENCY PATIENT TRANSPLANTED WITH HAPLOIDENTICAL BONE-MARROW BLOOD Bacchetta, R., Parkman, R., McMahon, M., Weinberg, K., Bigler, M., deVries, J. E., Roncarolo, M. G. 1995; 85 (7): 1944-1953Abstract
We have investigated the mechanism of tolerance in a patient with severe combined immunodeficiency (SCID) transplanted with HLA-haploidentical, T cell-depleted bone marrow cells obtained from the mother. At 4 years after transplantation, T cells, natural killer (NK) cells, and a small percentage (2%) of B cells were found to be of donor origin, whereas monocytes and the majority of B cells remained of host origin. In primary mixed lymphocyte cultures (MLC), the engrafted T cells of the donor did not proliferate in response to the host cells, whereas untransplanted donor T cells showed good proliferative responses. However, CD4+ and CD8+ T-cell clones of donor origin with specificity for class II and class I HLA determinants of the host were isolated. CD8+, host-reactive T-cell clones displayed normal cytotoxic activity after stimulation with the host cells, but proliferative responses of CD4+, host-reactive T-cell clones were considerably reduced. In addition, both CD8+ and CD4+, host-reactive T-cell clones produced very low to undetectable levels of interleukin-2 (IL-2), IL-4, IL-5, IL-10, interferon-gamma, and granulocyte-macrophage colony-stimulating factor after specific antigenic activation, which may be responsible for their nonresponsive state in vivo. Expression of the CD3 zeta subunit of the T-cell receptor (TcR) was normal, and after stimulation via CD3, Raf-1 and p42 mitogen activated protein (MAP) kinase were phosphorylated, indicating that this part of the signaling pathway after triggering of the TcR/CD3 complex is present. These results, together with our previous observation that dysfunctional, host-reactive T-cell clones can be isolated in SCID patients transplanted with fetal liver stem cells, demonstrate that lack of clonal deletion of host-reactive T cells is a general phenomenon after HLA-mismatched stem cell transplantation.
View details for Web of Science ID A1995QP61300033
View details for PubMedID 7703497