1,721,003 research outputs found
Thirty international cases of Bare Lymphocyte Syndrome: biological significance of HLA antigens
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Interleukin-4 suppresses immunoglobulin production by peripheral blood lymphocytes of patients with common variable immunodeficiency (CVI) induced by supernatants of T cell clones.
No full textSupernatants of both CD4+ and CD8+ alloreactive T cell clones induced IgM, IgG and IgA synthesis by peripheral blood lymphocytes (PBL) of healthy donors in vitro. These supernatants were also tested on their capacity to induce immunoglobulin production by PBL of four patients with CVI and one patient with CVI and thymoma. A low degree of IgM, IgG and IgA production was induced in one patient with CVI. In the patient with CVI and thymoma, induction of IgG and IgA synthesis was in the normal range, whereas IgM production was reduced. In the three other patients only a low production of IgM was induced. Interestingly, pre-incubation of the PBL for 24 h with interleukin-4 (IL-4) suppressed immunoglobulin production both by PBL of the patients with CVI and healthy donors. The strongest inhibitory effects were observed on IgA synthesis. These data indicate that B cells of three patients with CVI can not be induced to switch to IgG or IgA producing cells in vitro. In contrast, B cells of the patient with CVI and thymoma were able to respond to the relevant B cell growth and differentiation factors present in the T cell clone supernatants, suggesting that the T cells of this patient may fail to produce these factors. However, the proliferative responses of the T cells to phytohaemagglutinin (PHA), concanavalin A (Con A) and pokeweed mitogen (PWM), were normal in all five patients tested. In addition, the interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) production by PBL of the five patients was also in the normal range. Although only a small number of patients was tested, these results support the view that defects in both regulatory T cell functions and/or intrinsic B cell defects may contribute to the pathogenesis of CVI
A SCID PATIENT RECONSTITUTED WITH HLA-INCOMPATIBLE FETAL STEM-CELLS AS A MODEL FOR STUDYING TRANSPLANTATION TOLERANCE
No full textWe 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
Immunological lessons learnt from patients transplanted with fully mismatched stem cells
No full textFully 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 11 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
“Increased percentage of activated Ia+ T lymphocytes in peripheral blood of neonates following exchange blood transfusion”.
No full textThe expression of Ia-like antigens in peripheral blood T lymphocytes from newborns receiving postnatal total blood exchange was analyzed. A significantly increased percentage of Ia-positive T lymphocytes (Ia+ T cells) was observed 2 days after postnatal transfusion with total blood in comparison to data observed on Days 0, 5, and 15. Ia+ T cells were also significantly higher than in normal control newborns tested in the same period. When newborns received the blood exchange with irradiated total blood or with leukocyte-depleted blood, no increase in Ia+ T cells was observed and the percentage of these cells remained in the normal range (1-7%) on all the days tested (0, 2, 5, 15 days). For easy identification of the origin of Ia+ T cells, sex-incompatible blood was used for exchange, and a karyotype analysis was carried out for the detection of the Y chromosome on Ia+ T cells separated from peripheral blood on Day 2 and then cultured with interleukin 2 (IL-2) for 48 hr. It was thus established that Ia+ T cells were not of donor origin. Simultaneously with the expression of Ia-like antigens, host T cells also carried the interleukin-2 receptor (TAC). An allogeneic response, comparable to a host-versus-graft reaction, was probably responsible for the activation of T cells 2 days after total blood exchange in newborns
CHIMERISM AND TOLERANCE TO HOST AND DONOR IN SEVERE COMBINED IMMUNODEFICIENCIES TRANSPLANTED WITH FETAL LIVER STEM-CELLS
No full textWe have studied the peripheral T cell repertoire of two patients with severe combined immunodeficiency who were successfully treated with human histocompatibility leukocyte antigen (HLA)-mismatched fetal liver stem cell transplantation. The patients presented a split chimerism. T cells were of donor origin, whereas the B cells/monocytes were of the host phenotype. Interestingly, the natural killer (NK) cells in one patient were donor derived and in the other patient of host origin. The NK cells were functional but did not have antihost or donor reactivity. Despite the HLA mismatch between donor and host cells, complete tolerance was achieved in vivo, and a specific unresponsiveness of peripheral blood mononuclear cells from both patients toward the host cells was demonstrated in vitro. Nevertheless, we could isolate T cell receptor (TCR)alphabeta, CD4+ or CD8+, T cell clones specifically reacting with HLA class I and II molecules of the host. The CD4+ host-reactive T cell clones from both patients produced interleukins 2 and 5, interferon-gamma, granulocyte / macrophage colony-stimulating factor but are specifically defective in interleukin 4 production. The frequencies of CD8+ host-reactive T cells were high, and were in the same range as those observed for CD8+ alloreactive T cells. In contrast, no donor-reactive CD8+ T cells or host or donor-reactive TCRgammadelta+ T cells were detected. These data indicate that, after fetal stem cell transplantation, donor-reactive, but not host-reactive cells, are deleted from the T cell repertoire. Therefore, a peripheral mechanism of suppression or clonal anergy, rather than clonal deletion, is involved in maintaining in vivo tolerance toward the host
Tolerance to alloantigens and recognition for "allo + X" induced in humans by fetal stem cell transplantation
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