Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085110 (SCID)
 11,041 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The IL2RG gene encoding the gamma chain of the lymphocyte receptor for IL-2 lies in human Xq13.1 and is mutated in males with X-linked severe combined immunodeficiency (SCID). In a large Canadian pedigree genetic linkage studies demonstrated that the proband's grandmother was the source of an X-linked SCID mutation. However, her T cells did not show the expected skewed X chromosome inactivation pattern of female carriers of SCID, despite her having one affected son and two carrier daughters with skewed X inactivation. Single strand conformation polymorphism analysis of IL2RG in the affected proband was abnormal in exon 5; sequencing revealed a nine nucleotide in-frame duplication insertion. The three duplicated amino acids included the first tryptophan of the "WSXWS" motif found in all members of the cytokine receptor gene superfamily. Mutation detection in the pedigree confirmed that the founder grandmother's somatic cells had only normal IL2RG, and further showed that the SCID-associated X chromosome haplotype was inherited by three daughters, one with a wild type IL2RG gene and two others with the insertional mutation. Female germ line mosaicism is unusual, but its presence in this X-linked SCID family emphasizes the limitations of genetic diagnosis by linkage as compared with direct mutation analysis.
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PMID:Female germ line mosaicism as the origin of a unique IL-2 receptor gamma-chain mutation causing X-linked severe combined immunodeficiency. 786 Jul 24

Interleukin-12 (IL-12) is important in the regulation of resistance to Toxoplasma gondii in mice with severe combined immunodeficiency (SCID). The protective ability of IL-12 in SCID mice appears to be through its activity on natural killer (NK) cells to induce production of interferon-gamma (IFN-gamma). In this study we assessed the role of IL-12 in the acute stage of toxoplasmosis in immunocompetent mice. Administration of IL-12 to BALB/c mice infected with the virulent C56 strain of T. gondii remarkably delayed time to death. The protective activity of IL-12 was abrogated by administration of monoclonal antibodies to IFN-gamma or tumour necrosis factor-alpha (TNF-alpha), and by depletion of NK cells using an antisera against asialoGM1. Whereas BALB/c mice infected with the ME49 strain of T. gondii survived infection, administration of anti-IL-12 to infected mice resulted in 100% mortality accompanied by decreased serum levels of IFN-gamma. Furthermore, this treatment significantly reversed the suppression of spleen cell proliferation to concanavalin A (Con A), which is associated with the acute stage of infection, and resulted in decreased ex vivo production of IFN-gamma, IL-2, IL-4 and IL-10 in response to Con A. Our results indicate an important role for IL-12 in mediating resistance to T. gondii during acute infection in immunocompetent mice, that NK cells are required for this protective activity, and that IL-12 is involved in the immunosuppression which accompanies this infection.
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PMID:Studies on the role of interleukin-12 in acute murine toxoplasmosis. 789 Mar

Mice lacking functional T and B lymphocytes offer an in vivo animal model for the study of human immune functions. We have attempted to optimize the reconstitution of severe combined immunodeficiency (SCID) mice with human peripheral blood lymphocytes (PBL) using radiation, anti-asialo GM1 antibody or cyclophosphamide (Cy) treatment of the mice and in vitro stimulation of human PBL with interleukin (IL)-2 prior to their transfer to the mice. Total human IgG and tetanus-toxoid (TT)-specific human IgG responses of the mice were used as parameters of successful reconstitution. Treatment of the mice with anti-asialo GM1 antibody significantly enhanced total human IgG levels, but not TT-specific antibody responses, whereas irradiation or Cy treatment of the mice had no effect on human antibody production. In vitro treatment of human PBL with IL-2 prior to engraftment significantly decreased total human IgG responses of human PBL-grafted SCID mice. The immune responses of individual mice within a group were highly variable, which constitutes a major disadvantage of this model.
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PMID:Limitations of the severe combined immunodeficiency (SCID) mouse model for study of human B-cell responses. 789 26

Transplantation of HLA mismatched hematopoietic stem cells in patients with severe combined immunodeficiency (SCID) can result in a selective engraftment of T cells of donor origin with complete immunologic reconstitution and in vivo tolerance. The latter may occur in the absence of clonal deletion of donor T lymphocytes able to recognize the host HLA antigens. The activity of these host-reactive T cells is suppressed in vivo, since no graft-vs. -host disease is observed in these human chimeras. Here it is shown that the CD4+ host-reactive T cell clones isolated from a SCID patient transplanted with fetal liver stem cells produce unusually high quantities of interleukin 10 (IL-10) and very low amounts of IL-2 after antigen-specific stimulation in vitro. The specific proliferative responses of the host-reactive T cell clones were considerably enhanced in the presence of neutralizing concentrations of an anti-IL-10 monoclonal antibody, suggesting that high levels of endogenous IL-10 suppress the activity of these cells. These in vitro data correlate with observations made in vivo. Semi-quantitative polymerase chain reaction analysis carried out on freshly isolated peripheral blood mononuclear cells (PBMC) of the patient indicated that the levels of IL-10 messenger RNA (mRNA) expression were strongly enhanced, whereas IL-2 mRNA expression was much lower than that in PBMC of healthy donors. In vivo IL-10 mRNA expression was not only high in the T cells, but also in the non-T cell fraction, indicating that host cells also contributed to the high levels of IL-10 in vivo. Patient-derived monocytes were found to be major IL-10 producers. Although no circulating IL-10 could be detected, freshly isolated monocytes of the patient showed a reduced expression of class II HLA antigens. However, their capacity to stimulate T cells of normal donors in primary mixed lymphocyte cultures was within the normal range. Interestingly, similar high in vivo IL-10 mRNA expressions in the T and non-T cell compartment were also observed in three SCID patients transplanted with fetal liver stem cells and in four SCID patients transplanted with T cell-depleted haploidentical bone marrow stem cells. Taken together, these data indicate that high endogenous IL-10 production is a general phenomenon in SCID patients in whom allogenic stem cell transplantation results in immunologic reconstitution and induction of tolerance. Both donor T cells and host accessory cells contribute to these high levels of IL-10, which would suppress the activity of host-reactive T cell in vivo.
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PMID:High levels of interleukin 10 production in vivo are associated with tolerance in SCID patients transplanted with HLA mismatched hematopoietic stem cells. 790 18

Protective immunity against Toxoplasma gondii is mediated by the host cellular immune response. Interleukin-12 (IL-12), a recently described cytokine that stimulates NK cells to produce gamma interferon (IFN-gamma), is able to enhance host protection against this parasite in SCID mice. Administration of IL-12 to A/J mice significantly increased survival over that of control mice when IL-12 was delivered early in the course of acute infection. If it was administered at day 3 or thereafter, there was no observed difference in mortality between treated and control mice. Antibody depletion of IL-12 increased susceptibility to infection, as measured by mortality, only when the IL-12 was administered before day 3 postinfection. Mice treated with IL-12 at day 0 postinfection exhibited a significant rise above the control in both IL-2 and IFN-gamma production. Once infection has been established in the host (3 days), administration of exogenous IL-12 is unable to alter parasite-induced downregulation of IFN-gamma production. Thus, IL-12 appears to play an important, but transitory, role in protection against acute infection with T. gondii in the normal murine host.
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PMID:Interleukin-12 enhances murine survival against acute toxoplasmosis. 790 36

X chromosome-linked severe combined immunodeficiency disease (SCIDX1) is characterized by the absence of T-cell and natural killer cell development and results from molecular mutations of the interleukin 2 receptor (IL-2R) gamma chain. The IL-2R gamma chain is a common component of the IL-2, IL-4, and IL-7 receptor systems, which may explain the severe immunophenotype in SCIDX1. We have previously described an atypical SCIDX1 syndrome demonstrating poorly functioning peripheral T cells, which we hypothesized to represent a variant allele at the SCIDX1 locus. We now demonstrate that a splice site mutation in the IL-2R gamma gene is responsible for this atypical SCIDX1. Aberrant RNA splicing resulted in the generation of two IL-2R gamma transcripts: an abundant, nonfunctional isoform containing a small intronic insertion and a second functional isoform with a single amino acid substitution present in limited amounts. Radiolabeled IL-2 binding studies revealed a 5-fold decreased level of expression of functional high-affinity IL-2Rs, which correlated with the quantity of full-length IL-2R gamma transcripts. Further analysis of the T-cell antigen receptor beta-chain repertoire of the patient's T cells demonstrated oligoclonality in multiple V beta families, thus strongly suggesting that the defect in the IL-2R gamma chain generated a limited number of peripheral T-cell clones. This atypical SCIDX1 patient demonstrates that certain IL-2R gamma chain abnormalities can also result in partial immunodeficiency phenotypes, potentially through differential effects on the IL-2, IL-4, or IL-7 receptor systems.
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PMID:Defective human interleukin 2 receptor gamma chain in an atypical X chromosome-linked severe combined immunodeficiency with peripheral T cells. 793 90

A genetically engineered fusion protein consisting of a human/mouse chimeric anti-ganglioside GD2 antibody (ch14.18) and recombinant human interleukin 2 (rhIL-2) was tested for its ability to target rhIL-2 to tumor sites and stimulate immune effector cells sufficiently to achieve effective tumor cell lysis in vivo. The ch14.18-IL-2 fusion protein proved more effective than equivalent doses of rhIL-2 in suppressing dissemination and growth of human neuroblastoma in an experimental hepatic metastases model of scid (severe combined immunodeficiency) mice reconstituted with human lymphokine-activated killer cells. The ch14.18-IL-2 fusion protein was also more proficient than equivalent doses of rhIL-2 in prolonging the life-span of these animals. This recombinant antibody-cytokine fusion protein may prove useful for future treatment of GD2-expressing human tumors in an adjuvant setting.
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PMID:A recombinant antibody-interleukin 2 fusion protein suppresses growth of hepatic human neuroblastoma metastases in severe combined immunodeficiency mice. 793 18

A patient with severe combined immunodeficiency was transplanted with T cell depleted haploidentical bone marrow from his father and was later given a thymic graft from an unrelated donor. alpha/beta and gamma/delta T cells of bone marrow donor origin appeared only after the thymus transplantation procedure. Among the peripheral blood lymphocytes (PBL), gamma/delta T cells comprised 10-20% and most of them were delta TCS1+. The alpha/beta T cells were single positive cells, either CD4+ or CD8+. Expression of CD5, CD7 and CD8 alpha,beta molecules on alpha/beta T cells was reduced. Functional studies showed that gamma/delta T cells proliferated slightly in response to anti-CD3 stimulation, and proliferated well with exogenous IL-2 stimulation, while alpha/beta T cells did not proliferate following mitogenic stimulation even in the presence of IL-2. gamma/delta T cells but not alpha/beta T cells exhibited some LAK activity after culturing with IL-2. Since alpha/beta T cells expressed IL-2R alpha and beta chains after mitogenic stimulation and bound IL-2, the deficit(s) in these cells was considered to occur after IL-2 binding to the IL-2R. These results indicate thymic dependency of both types of T cells and that two types of T cells differed in the acquisition of IL-2 responsiveness during development.
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PMID:Differences of LAK-activity and IL-2 responsiveness between alpha/beta and gamma/delta T cells which developed after thymus transplantation. 794 3

Intraperitoneal injection of lymphoid cells from EBV+ donors into SCID mice might provide a useful tool for studying the pathways of B-cell lymphomagenesis in man. Since previous studies showed that donor T cells greatly favor B-cell proliferation and tumor generation in this model, we addressed the host and donor factors involved in limiting or promoting lymphoma development. The number of EBV-infected B-cell precursors was crucial, since purified B lymphocytes, which alone were unable to generate tumors, underwent expansion and established tumor masses when the animals were inoculated with an EBV-containing supernatant. Host factors were critical in limiting tumor development; in vivo NK-cell removal allowed purified B cells to expand and proceed to tumors in the absence of T lymphocytes, whereas potentiation of mouse NK-cell activity prevented tumor generation in PBMC- and LCL-injected animals. The T-cell-derived factors that favor lymphomagenesis could not be identified; IL-2, IL-4, IL-6, and soluble CD23 were not able to promote B-cell expansion, and treatment of PBMC-injected mice with the relevant anti-cytokine anti-sera did not counteract lymphoma development. These experiments also showed that IL-6 plays a minor role, if any, in B-cell lymphoproliferation in this model. Our data indicate that reconstitution of SCID mice with PBMC from EBV+ donors may constitute a useful model for determining the events involved in lymphomagenesis in humans, provided that strict control of all the experimental variables is guaranteed.
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PMID:Lymphoproliferative disease in human peripheral-blood-mononuclear-cell- injected scid mice. II. Role of host and donor factors in tumor generation. 796 Feb 41

Tetanus toxoid-specific T cells have been generated from human splenic lymphocytes by an initial 6-day stimulation period with antigen, followed by a proliferation period with recombinant IL-2 and human feeder cells. Proliferating T cells were subsequently cloned by limiting dilution. A human T-cell clone that was functionally characterized showed: (i) a specific proliferative response to tetanus toxoid in the presence of autologous Epstein-Barr virus (EBV)-transformed lymphoblastoid cells; (ii) a phenotype characteristic for the helper/inducer CD4+/CD8-/CD450R0+ T cells, and (iii) a lymphokine profile, as determined by mRNA analysis, representative of Th0-like human CD4+ T helper cells. This tetanus toxoid-specific T-cell clone which showed antigen-dependent helper activity for antibody production by autologous B cells in vitro could also provide T-cell help to antigen-specific human B cells transplanted into severe combined immunodeficiency (scid/beige) mice.
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PMID:Human Th0-type T helper-cell clone supports antigen-specific immunoglobulin production in scid/beige-hu mice. 797 59


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