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Query: UMLS:C0085110 (SCID)
 11,041 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Dysfunctional cytokine production by host-reactive T-cell clones isolated from a chimeric severe combined immunodeficiency patient transplanted with haploidentical bone marrow. 770 97

Tumor cells transduced with cytokine genes provide a model to study host-effector mechanisms involved in tumor rejection. Local IL-2 production within a tumor site mimics a specific helper-T-cell response, bypassing an immunization phase. Growth of mouse B16F10 melanomas transduced with interleukin-2 (IL-2) in syngeneic hosts were significantly delayed. IL-2-producing B16F10 cells were super-transduced with interferon-gamma to up-regulate expression of major-histocompatibility-complex (MHC) antigens. Expression of class-I- or class-II-MHC molecules did not augment tumor rejection of IL-2-secreting tumor cells. Rejection of IL-2-transduced B16F10 cells in syngeneic mice was unaffected by depletion of CD8+ T-cell and NK1.1+ natural-killer (NK) cell populations. Tumor rejection occurred in SCID mice even after depletion of NK1.1+ cells, confirming that T cells and NK cells were not required for tumor rejection. Histologic examination of sites of tumor rejection showed inflammation, characterized by infiltrates of macrophages, occasional neutrophils, and areas of necrosis. When mice were treated systemically with macrophage-colony-stimulating factor to expand monocyte pools, tumor rejection was significantly augmented further. This study shows that in situ IL-2 production can result in tumor rejection mediated by inflammatory events, possibly involving macrophages, and mimicking a delayed-type hypersensitivity (DTH) response even in the absence of T cells and NK cells. Furthermore, tumor rejection can be enhanced by systemic administration of a cytokine to expand potential inflammatory cell populations.
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PMID:Rejection of mouse melanoma elicited by local secretion of interleukin-2: implicating macrophages without T cells or natural killer cells in tumor rejection. 770 56

Interleukin-2 (IL-2) has various trophic and neuromodulatory actions in the mammalian central nervous system (CNS). The interleukin-2 receptor alpha (IL-2R alpha) is an accessory subunit of the IL-2 receptor heterotrimer complex which is essential for 'high' affinity IL-2 binding. Although an IL-2R alpha (or IL-2R alpha-like) epitope has been localized in brain by immunohistocytochemistry, it was unknown whether the IL-2R alpha subunit expressed in brain was derived from the same or a different gene than the lymphocyte IL-2R alpha. Therefore, in the present study, the cDNA comprising the full length coding region was cloned and sequenced from saline-perfused forebrain. The brain IL-2R alpha cDNA was found to be 100% homologous with the corresponding lymphocyte IL-2R alpha cDNA sequence. IL-2R alpha mRNA was expressed at very low levels in saline-perfused forebrain of non-challenged BALB/c mice as well as in saline-perfused forebrain from severe combined immunodeficiency (SCID) mice. The present data, demonstrating IL-2R alpha gene expression in both well-perfused normal and SCID mouse forebrain from which no CD3 gamma gene expression was detected by PCR, provides evidence that the IL-2R alpha clones isolated are from resident brain cells and not from blood lymphocytes (e.g. T lymphocytes). Thus, these findings demonstrate that the protein coding sequence of the mouse brain IL-2R alpha is derived from the same gene coding sequence as the lymphocyte IL-2R alpha, and indicate that previously reported differences in the size of their respective mRNA transcripts appear to be due to differences in untranslated regions.
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PMID:Molecular cloning of the coding sequence of an interleukin-2 receptor alpha subunit cDNA in murine brain. 779 14

The interleukin-2 (IL-2) receptor gamma-chain is a common component of several members of the cytokine receptor superfamily including those for IL-2, IL-4, IL-7, IL-9, IL-15, and possibly IL-13, and has recently been renamed the common gamma-chain (gamma c-chain). Transfection experiments have shown that the gamma c-chain participates in signal transduction by IL-2, IL-4 and IL-7, but a functional role for the gamma c-chain in biological responses by normal T cells and B cells to these cytokines has not been established. In this study, we have used X-linked severe combined immunodeficiency (X-SCID) as a naturally occurring gamma c-chain gene disruption model to examine the role of the gamma c-chain in human B-cell responses to IL-2, IL-4, IL-13, and IL-15. Our experiments show that B cells from two X-SCID patients with characterized gamma c-chain gene mutations do not respond to IL-2 or IL-15, but respond as well or better than normal B cells to both IL-4 and IL-13 in assays for B-cell activation, proliferation, and IgE secretion. This finding raises important questions about the function of the gamma c-chain in receptors for IL-4 and IL-13, and the nature of the immune defect in X-SCID.
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PMID:Function of the interleukin-2 (IL-2) receptor gamma-chain in biologic responses of X-linked severe combined immunodeficient B cells to IL-2, IL-4, IL-13, and IL-15. 780 8

The administration of low doses of recombinant interleukin-2 (rIL-2) in vivo to patients with malignant neoplasms has been demonstrated to selectively increase the number of circulating natural killer (NK) cells in these patients. Recent evidence from SCID mouse models suggests that IgG subclass levels can be influenced by the presence and activity of NK cells. Therefore, we sought to examine the effect of rIL-2 infusions on human serum IgG subclass concentrations. We determined serum IgG subclass concentrations in 27 cancer patients receiving low-dose rIL-2 by daily continuous intravenous infusion. Eleven of these patients had active, metastatic, nonhematologic tumors; 16 patients had received IL-2 when they were in a minimal residual disease state after autologous or allogeneic bone marrow transplantation. Samples obtained before beginning IL-2 therapy and 8 to 10 weeks into therapy were tested. Treatment with IL-2 resulted in an increase in the percentage of CD56+ NK cells from 18% to 54% (P = .0001). A significant decrease in geometric mean IgG2 concentration from 2,017 micrograms/mL to 1,655 micrograms/mL was noted over this time interval (P = .03). Furthermore, the geometric mean IgG2 concentration after treatment was significantly lower than that of healthy controls (P = .026). In contrast, no significant changes in serum IgG1, IgG3, or IgG4 were noted during r-IL2 infusions. Our data suggest that rIL-2 treatment selectively decreases serum IgG2 concentrations. We speculate that increased NK cells mediate downregulation of human serum IgG2.
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PMID:Recombinant interleukin-2 infusions and decreased IgG2 subclass concentrations. 855 12

Gene defects causing three X-linked human immunodeficiencies, agammaglobulinemia (XLA), hyper-IgM syndrome (HIGM), and X-linked severe combined immunodeficiency (SCID), have been identified. These represent the first human disease phenotypes associated with three gene families already recognized to be important in lymphocyte development and signaling: XLA is caused by mutations of a B-cell specific intracellular tyrosine kinase; HIGM by mutations in the tumor necrosis factor-related CD40 ligand, through which T cells deliver helper signals by direct contact with B-cell CD40; and SCID by mutations in the gamma chain of the lymphocyte receptor for interleukin-2. The great variety of patient mutations in all three genes represent both a challenge for genetic diagnosis and a resource for dissecting molecular domains and physiologic functions of the gene products.
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PMID:Molecular basis for three X-linked immune disorders. 784 38

Recent experiments have shown that gamma interferon (IFN-gamma), either administered or induced in vivo, e.g., by certain bacteria, is a key mediator in inducing hypersensitivity to bacterial lipopolysaccharides. The source of endogenous IFN-gamma in this context (natural killer versus TH1 cells) has not been investigated yet. In order to investigate the role of antigen-specific, IFN-gamma-producing TH1 cells in murine Pseudomonas aeruginosa infection, a murine TH1 cell line was propagated in vitro by using recombinant P. aeruginosa outer membrane protein I. Adoptive transfer experiments were performed by intravenous injection of various amounts of TH1 cells into P. aeruginosa-challenged SCID mice. Adoptive transfer of 5 x 10(6) T cells into SCID mice followed by an intraperitoneal challenge with 1.4 x 10(6) CFU of live P. aeruginosa resulted in the rapid death of the animals within 12 h postchallenge, whereas transfer of lower T-cell doses and saline as a control did not cause any detrimental effects. After challenge with 2.8 x 10(6) CFU of P. aeruginosa, similar results were obtained 18 h postchallenge; however, at the end of the 72-h observation period, no significant differences in survival rates were obtained between the groups treated with different amounts of T cells. The rapid death of mice treated with 5 x 10(6) T cells was reflected by 860-fold-elevated levels of tumor necrosis factor alpha (TNF-alpha) present in serum 2 h postchallenge, whereas no significant differences in TNF-alpha serum levels were detectable in mice treated with lower doses of T cells or with saline. Pretreatment of T-cell-reconstituted SCID mice with neutralizing anti-IFN-gamma monoclonal antibodies completely protected mice from bacterial challenge and reduced TNF-alpha levels in serum. We conclude that under the experimental conditions described here, IFN-gamma- and interleukin-2-producing TH1 cells represent an important trigger mechanism inducing TNF-alpha-mediated hypersensitivity to bacterial endotoxin.
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PMID:TH1 cells trigger tumor necrosis factor alpha-mediated hypersensitivity to Pseudomonas aeruginosa after adoptive transfer into SCID mice. 786 34

Diabetes was dramatically accelerated in non-obese diabetic (NOD) transgenic mice that expressed interleukin-2 (IL-2) in their beta cells. A single cross to C57BL/6 completely prevented this effect and a further backcross to the NOD genetic background showed that at least two diabetes susceptibility loci (Idd1s and Idd3/10s) were required for the diabetes acceleration T cells activated to islet antigens were not circulating in the mice. The accelerating effect of IL-2 was present; but decreased, in NOD mice that lacked CD8+ T cells as well as in NOD SCID mice. The implications are that in the NOD genetic background, the production of cytokines, such as IL-2, by islet-specific CD4+ T cells can lead to beta cell damage and diabetes and that CD8+ T cells may have a role in accelerating diabetes onset.
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PMID:Genetic requirements for acceleration of diabetes in non-obese diabetic mice expressing interleukin-2 in islet beta-cells. 792 81

We report the development of miliary tuberculosis in a 7-year-old boy with severe combined immunodeficiency (SCID), whose immune system had been only partially reconstituted by haploidentical bone marrow transplantation. Although alpha beta and gamma delta T cells were of donor origin, alpha beta T cells in this patient showed defective interleukin-2 (IL-2) production, impaired IL-2 responsiveness and decreased cytolytic activity. However, gamma delta T cells could exhibit enough cytolytic activity after incubation with IL-2. Despite the presence of disseminated infection, C-reactive protein (CRP) remained negative. IL-2 therapy aggravated the disseminated tuberculosis though gamma delta T cells were supposed to be activated, and concurrently CRP became positive. These findings suggest that gamma delta T cells have no more than limited immunological roles in mycobacterium tuberculosis infection.
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PMID:Pulmonary miliary tuberculosis and T-cell abnormalities in a severe combined immunodeficient patient reconstituted with haploidentical bone marrow transplantation. 808 24

We have previously described a type of selective T cell deficiency (STD) characterized by persistent infections reminiscent of severe combined immunodeficiency. We show here that STD patients carry a mutation of zap-70, resulting in loss of the activity of this kinase. The thymi of zap-70-/- patients show the presence of CD4+CD8+ cells in the cortex; however, only CD4, not CD8, single-positive cells are present in the medulla. Peripheral CD4+ T cells from the zap-70-/- patients exhibit markedly reduced tyrosine phosphorylation, fail to produce interleukin-2, and do not proliferate in response to T cell receptor stimulation by mitogens or antigens. Thus, Zap-70 kinase appears to be indispensable for the development of CD8 single-positive T cells as well as for signal transduction and function of single-positive CD4 T cells.
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PMID:Defective T cell receptor signaling and CD8+ thymic selection in humans lacking zap-70 kinase. 812 27


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