Dysfunctional cytokine production by host-reactive T-cell clones isolated from a chimeric severe combined immunodeficiency patient transplanted with haploidentical bone marrow.

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.

[1]  R. de Waal Malefyt,et al.  High levels of interleukin 10 production in vivo are associated with tolerance in SCID patients transplanted with HLA mismatched hematopoietic stem cells , 1994, The Journal of experimental medicine.

[2]  P. Lansdorp,et al.  Ontogeny-related changes in proliferative potential of human hematopoietic cells , 1993, The Journal of experimental medicine.

[3]  K. Brorson,et al.  Molecular Regulation of the IL‐2 Gene: Rheostatic Control of the Immune System , 1993, Immunological reviews.

[4]  M. Dallman,et al.  Cytokines and Peripheral Tolerance to Alloantigen , 1993, Immunological reviews.

[5]  J. D. de Vries,et al.  Chimerism and tolerance to host and donor in severe combined immunodeficiencies transplanted with fetal liver stem cells. , 1993, The Journal of clinical investigation.

[6]  R. de Waal Malefyt,et al.  IL-10 is produced by subsets of human CD4+ T cell clones and peripheral blood T cells. , 1992, Journal of immunology.

[7]  F. Ramsdell,et al.  Maintenance of in Vivo Tolerance by Persistence of Antigen , 1992, Science.

[8]  J. Abrams,et al.  Strategies of Anti‐Cytokine Monoclonal Antibody Development: Immunoassay of IL‐10 and IL‐5 in Clinical Samples , 1992, Immunological reviews.

[9]  M. Cobb,et al.  Extracellular signal-regulated kinases in T cells. Anti-CD3 and 4 beta-phorbol 12-myristate 13-acetate-induced phosphorylation and activation. , 1992, Journal of immunology.

[10]  J. Allison,et al.  CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones , 1992, Nature.

[11]  M. Pallavicini,et al.  Engraftment and long-term expression of human fetal hemopoietic stem cells in sheep following transplantation in utero. , 1992, The Journal of clinical investigation.

[12]  M. Amiot,et al.  Sequence requirements for induction of cytolysis by the T cell antigen Fc receptor ζ chain , 1992, Cell.

[13]  W. Friedrich,et al.  Self‐nonself discrimination and repertoire selection of human T cells differentiated in an HLA‐semiallogeneic environment following bone marrow transplantation for severe combined immunodeficiency , 1991, European journal of immunology.

[14]  J. D. de Vries,et al.  Comparison of lymphokine secretion and responsiveness of human T cell clones isolated in IL-4 and in IL-2. , 1991, Cellular immunology.

[15]  J. Shabanowitz,et al.  Identification of the regulatory phosphorylation sites in pp42/mitogen‐activated protein kinase (MAP kinase). , 1991, The EMBO journal.

[16]  M. Dallman,et al.  Peripheral tolerance to alloantigen results from altered regulation of the interleukin 2 pathway , 1991, The Journal of experimental medicine.

[17]  P. Warne,et al.  Stimulation of p21ras upon T-cell activation , 1990, Nature.

[18]  R. Schwartz,et al.  A cell culture model for T lymphocyte clonal anergy. , 1990, Science.

[19]  J. Sprent,et al.  T cell reactivity to MHC molecules: immunity versus tolerance. , 1990, Science.

[20]  F. Ramsdell,et al.  Clonal deletion versus clonal anergy: the role of the thymus in inducing self tolerance. , 1990, Science.

[21]  J. Abrams,et al.  Host-reactive CD4+ and CD8+ T cell clones isolated from a human chimera produce IL-5, IL-2, IFN-gamma and granulocyte/macrophage-colony-stimulating factor but not IL-4. , 1990, Journal of immunology.

[22]  P. Anderson,et al.  Monoclonal antibodies reactive with the T cell receptor zeta chain: production and characterization using a new method. , 1989, Journal of immunology.

[23]  J. Strominger.  Developmental biology of T cell receptors. , 1989, Science.

[24]  B. Dupont,et al.  Tolerance of engrafted donor T cells following bone marrow transplantation for severe combined immunodeficiency. , 1988, Clinical immunology and immunopathology.

[25]  J. Abrams,et al.  Simultaneous production of IL-2, IL-4, and IFN-gamma by activated human CD4+ and CD8+ T cell clones. , 1988, Journal of immunology.

[26]  J. D. de Vries,et al.  Autoreactive T cell clones specific for class I and class II HLA antigens isolated from a human chimera , 1988, The Journal of experimental medicine.

[27]  K. Arai,et al.  Recombinant interleukin 4 promotes the growth of human T cells. , 1987, Journal of immunology.

[28]  R. Buckley,et al.  Modified responses to recipient and donor B cells by genetically donor T cells from human haploidentical bone marrow chimeras. , 1987, Journal of immunology.

[29]  W. V. van Blitterswijk,et al.  Serum-free medium for generation and propagation of functional human cytotoxic and helper T cell clones. , 1984, Journal of immunological methods.

[30]  J. D. de Vries,et al.  Human T4+ and T8+ cytotoxic T lymphocyte clones directed at products of different class II major histocompatibility complex loci. , 1983, Journal of immunology.

[31]  R. Perlmutter,et al.  Regulation of lymphocyte function by protein phosphorylation. , 1993, Annual review of immunology.

[32]  M. Davis,et al.  Molecular components of T-cell recognition. , 1992, Annual review of immunology.

[33]  A. Weiss,et al.  Regulation of protein tyrosine kinase activation by the T-cell antigen receptor zeta chain. , 1992, Cold Spring Harbor symposia on quantitative biology.

[34]  A. Weiss.  Molecular and genetic insights into T cell antigen receptor structure and function. , 1991, Annual review of genetics.

[35]  N. Flomenberg,et al.  Cytotoxic and proliferative T-cell clones with antidonor reactivity from a patient transplanted for severe combined immunodeficiency disease. , 1990, Human Immunology.

[36]  T. Small,et al.  The use of HLA-non-identical T-cell-depleted marrow transplants for correction of severe combined immunodeficiency disease. , 1989, Immunodeficiency reviews.

[37]  R. Schwartz,et al.  Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy. , 1989, Annual review of immunology.

[38]  C. Griscelli,et al.  Self‐tolerance to host and donor following HLA‐mismatched bone marrow transplantation , 1986, European journal of immunology.