Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P14784 (IL-2 receptor)
 3,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 4-y-old female with severe combined immunodeficiency disease had normal numbers of T cells in her circulation and normal T-cell subsets. However, her T cells proliferated poorly to mitogens and did not proliferate to antigens or to anti-CD3 MAb. IL-2 receptor expression was normal, but IL-2 synthesis was undetectable. The addition of recombinant IL-2 to a mitogen-stimulated culture resulted in normalization of the proliferative response. Northern blot analysis of total RNA derived from the patient's T cells revealed a weak or absent expression of mRNA coding for IL-2, IL-3, IL-4, and IL-5. In contrast, there were normal amounts of mRNA coding for granulocyte-macrophage colony-stimulating factor. Tumor necrosis factor and IL-6 production were also normal. Nuclear run-on transcriptional assays revealed markedly decreased levels of newly initiated nuclear transcripts coding for IL-2, IL-3, IL-4, and IL-5 and normal levels of granulocyte-macrophage colony-stimulating factor transcripts in the patient relative to control lymphocytes. Gel retardation assays suggest that the NFAT-1 nuclear transcription complex is abnormal in this patient. These results indicate that the patient suffers from a defect that affects the transcription of multiple T-cell lymphokines and suggest that abnormalities affecting the production of T-cell lymphokines may underlie some of the primary immunodeficiency diseases.
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PMID:Severe combined immunodeficiency with selective T-cell cytokine genes. 843 71

Guanine ribonucleosides which have been substituted at the N7 and/or C8 positions have been shown previously to activate natural killer (NK) cells and to act as sparing agents for interleukin-2 (IL-2) in the in vitro generation of lymphokine activated killer (LAK) cells. In this paper we examined a disubstituted guanosine, 7-allyl-8-oxoguanosine (loxoribine), for the ability to activate NK cells and to interact with IL-2 in the generation of LAK cells in vivo. Following iv administration, loxoribine enhanced murine splenic NK activity in a dose-related fashion, with optimal responses occurring at 3 mg/mouse. Enhanced lysis of YAC-1 cells was seen within 6 hr of injection and NK activity remained elevated for over 96 hr. Mature B and T cells were not required for NK activation since SCID mice responded to loxoribine within the same dose range as did the normal, immunocompetent mice. Both effector and precursor cells were eliminated by the administration of anti-asialo GM1 antibodies and NK activation was totally blocked in mice injected with anti-NK 1.1 antibodies. To test whether loxoribine would act as a sparing agent for IL-2 stimulated LAK activation, mice were injected with 2 mg loxoribine followed by twice daily administration of 10,000 units IL-2. In assays performed 48, 72, and 96 hr after injection of loxoribine, the cytolytic activity with the combination therapy exceeded the activity expected from the algebraic sum of the responses to the individual agents. Single injections of 2 mg loxoribine and 25,000 units IL-2 also stimulated NK/LAK activity, but the greatest enhancement was seen when loxoribine was administered 24 hr before the IL-2. Analysis of mRNA transcripts for the alpha chain of the IL-2 receptor indicated that gene transcription was enhanced within hours of loxoribine administration.
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PMID:In vivo activation of natural killer cells and priming of IL-2 responsive cytolytic cells by loxoribine (7-allyl-8-oxoguanosine). 845 74

X-SCID, the most common form of human SCID, is due to mutations in the common gamma chain gene (gamma-c) that encodes an essential component of the cytokine receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, and IL-15. Activation of the Janus family tyrosine kinases Jak1 and Jak3 is necessary for appropriate signalling through the IL-2 receptor (IL-2R). Neither Jak1 nor Jak3 was phosphorylated after IL-2 stimulation of an Epstein-Barr virus-transformed cell line (LCL) from an X-SCID patient with a gamma-c null mutation. However, we now show that appropriate IL-2R function can be restored in an X-SCID LCL by transduction of a wild-type gamma-c gene. A retroviral vector, G1gamma-cSvNa, was constructed and produced in the PG13 packaging line. Transduced X-SCID LCL expressed the G1gamma-cSvNa transcript. IL-2 stimulation of the transduced cell line resulted in appropriate tyrosine phosphorylation of both Jak1 and Jak3. Thus, retroviral-mediated transduction of normal gamma-c can reconstitute downstream signalling through the IL-2R in X-SCID cell lines, suggesting that gene therapy may be a treatment for this disease.
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PMID:Correction of interleukin-2 receptor function in X-SCID lymphoblastoid cells by retrovirally mediated transfer of the gamma-c gene. 860 23

SCID X1 is characterized by faulty T-cell and natural killer cell differentiation caused by mutation of the gamma-c chain gene encoding a number of multiple cytokine receptors (interleukin-2 [IL-2], IL-4, IL-7, IL-9, and IL-15 receptors). To assess the feasibility of inducing long-term expression and function of the gamma-c chain, Epstein-Barr virus (EBV)-transformed B-cell lines from two patients with SCID X1 were transduced with a Moloney-derived retroviral vector containing the gamma-c chain cDNA. The viral LTR was used as the promoter. Immediately after two cycles of coculture with the psi-crip clone producing the MFG(B2)-gamma-c cDNA vector, gamma-c expression, assessed by detection of the mRNA and membrane protein expression, was found in 15% to 20% of cells. The degree of membrane expression was similar to that in control EBV-B cells. Expression increased steadily over 6 months, becoming detectable in 100% of cells, and remained stable thereafter for a total of 9 months, reflecting positive selection of transduced cells. A study of provirus integration sites showed multiple integration. The expressed gamma-c was functional, because it restored high-affinity IL-2 receptor binding, IL-2 endocytosis, and IL-2-triggered phosphorylation of JAK-3 tyrosine kinase. Similar results were obtained with the two B-cell lines. These results show that efficient gamma-c gene transfer into B-cells lacking functional gamma-c is feasible and results in strong and stable expression of a functional gamma-c chain, apparently conferring a selective growth advantage in culture. Further in vitro studies of gamma-c gene transfer into gamma-c- hematopoietic progenitors are being conducted to assess the feasibility of correcting lymphocyte differentiation defects.
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PMID:gamma-c gene transfer into SCID X1 patients' B-cell lines restores normal high-affinity interleukin-2 receptor expression and function. 860 24

We previously examined the Ig heavy (H) chain gene of pretransplant patients with X-linked SCID (XSCID), having defects in the gene of the IL-2 receptor (R) gamma chain. In the present study, we analyzed two post-transplant XSCID patients, in whom T cell-depleted haploidentical BMT resulted in lymphoid split chimeras, i.e., donor functional T cells coexisting with recipient B cells. Although the recipient B cells produced IgM, no isohemagglutinin or Ag-specific Ab was detected. To investigate the cause of failure to produce Ab in the patients, we sequenced the complementarity determining region 3 (CDR3) and adjacent region of Ig H chain gene, which govern Ab specificity. Among the 64 post-transplant CDR3 junctional sequences, combinatorial and junctional diversity were normal compared with those in age-matched controls. All of the post-transplant joining regions except one clone were equal to germline and the frequency of somatic mutation was significantly lower than that in age-matched controls. The results indicated that T cell reconstitution by BMT does not restore diversification of the Ig gene in the IL-2R gamma chain-deficient B cells, which might be associated with the defect in the Ag-specific Ab production.
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PMID:T cell reconstitution by haploidentical BMT does not restore the diversification of the Ig heavy chain gene in patients with X-linked SCID. 875 Feb 73

Metastasis is a critical problem in the treatment of human lung cancer. Thus, a suitable animal model of metastasis of human lung cancer is required for in vivo biological and preclinical studies. In this study, we tried to establish a suitable model for this, using SCID mice. Neither human SCLC H69/VP cells (5 x 10(6)) nor squamous-cell carcinoma RERF-LC-AI cells (1 x 10(6)), injected through a tail vein, formed metastases in untreated SCID mice. Pre-treatment of SCID mice with anti-asialo GM1 serum resulted in only a few metastases of H69/VP cells, but pre-treatment with anti-mouse IL-2 receptor beta chain Ab (TM-beta 1) resulted in numerous lymph-node metastases 56 days after tumor inoculation. H69/VP-M cells, an in vivo-selected variant line, formed significant numbers of lymph-node metastases even in SCID mice pre-treated with anti-asialo GM1 serum. SCID mice depleted of NK cells by treatment with TM-beta 1 showed different patterns of metastasis when inoculated intravenously with the 2 different human lung cancer cell lines (H69/VP and RERF-LC-AI cells): H69/VP cells formed metastases mainly in systemic lymph nodes and the liver, whereas RERF-LC-AI cells formed metastases mainly in the liver and kidneys, with only a few in lymph nodes. A histopathological study showed that the metastatic colonies consisted of cancer cells. The numbers of metastatic colonies formed by the 2 cell lines increased with the number of cells inoculated. TM-beta 1 treatment of SCID mice efficiently removed NK cells from peripheral blood for at least 6 weeks, whereas, after treatment of the mice with anti-asialo GM1 serum, NK cells were recovered within 9 days. These findings suggest that NK-cell-depleted SCID mice may be useful as a model in biological and pre-clinical studies on metastasis of human lung cancer.
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PMID:Novel metastasis model of human lung cancer in SCID mice depleted of NK cells. 876 May 90

To analyze the early development of T cell precursors in the absence of TCR gene rearrangement, recombinase-activating gene-deficient (RAG-2 -/-) thymocytes were compared with thymocytes from SCID mice on the C.B-17 (BALB) and B6 genetic backgrounds. RAG-2 -/- thymocytes accumulate as quiescent cells with a heat-stable Ag (HSA)-positive CD25+ CD44- c-kit(low) phenotype, resembling normal cells just before selection for functional TCR beta-chain expression. CD44 and c-kit progressively down-regulate in the HSA+ subset, providing a background-independent and TCR-independent developmental clock. On this basis, compared with RAG-2 -/- thymocytes, SCID thymocytes 1) arrest at more heterogeneous, and generally earlier, stages; 2) accumulate to lower overall cell numbers; and 3) maintain higher populations of cycling and activated G1 cells, showing both increased responsiveness and increased cell death. B6-SCID thymocytes appear to die particularly early. Low levels of Fas were observed on "advanced" HSA+ SCID thymocytes but not on any RAG-2 -/- thymocytes, suggesting a potential difference in activation state or mechanism of death. In both RAG-2 -/- and SCID thymocytes, there are also two discrete subsets of HSA(low) CD25- CD44+ c-kit+ cells: a Sca-1+ CD44++ CD122- NK1.1- putative progenitor subset and an NK-like Sca-1- CD44+(+) CD122+ NK1.1+ subset. The absolute cell numbers in these HSA(low) subsets and the extent of NK cell differentiation, measured by perforin expression, are nearly constant in all the mutant strains analyzed, in contrast to the HSA+ CD25+ population, which was expanded in the RAG-2 -/-. Thus, the SCID thymocytes appear to undergo a normal generation but a premature death as compared with the RAG-2 -/- thymocytes.
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PMID:Different developmental arrest points in RAG-2 -/- and SCID thymocytes on two genetic backgrounds: developmental choices and cell death mechanisms before TCR gene rearrangement. 912 63

JAK3 is a protein tyrosine kinase that specifically associates with the common gamma chain (gammac), a shared subunit of receptors for interleukin (IL) 2, 4, 7, 9, and 15. Patients deficient in either JAK3 or gammac presented with virtually identical forms of severe combined immunodeficiency (SCID), underscoring the importance of the JAK3-gammac interaction. Despite the key roles of JAK3 and gammac in lymphocytic development and function, the molecular basis of this interaction remains poorly understood. In this study, we have characterized the regions of JAK3 involved in gammac association. By developing a number of chimeric JAK3-JAK2 constructs, we show that the binding specificity to gammac can be conferred to JAK2 by transferring the N-terminal domains of JAK3. Moreover, those JAK3-JAK2 chimeras capable of binding gammac were also capable of reconstituting IL-2 signaling as measured by inducible phosphorylation of the chimeric JAK3-JAK2 protein, JAK1, the IL-2 receptor beta chain, and signal transducer and activator of transcription 5A. Subsequent deletion analyses of JAK3 have identified the N-terminal JH7-6 domains as a minimal region sufficient for gammac association. Furthermore, expression of the mutant containing only the JH7-6 domains effectively competed with full-length JAK3 for binding to gammac. We conclude that the JH7-6 domains of JAK3 are necessary and sufficient for gammac association. These studies offer clues toward a broader understanding of JAK-mediated cytokine signaling and may provide a target for the development of novel therapeutic modalities in immunologically mediated diseases.
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PMID:The amino terminus of JAK3 is necessary and sufficient for binding to the common gamma chain and confers the ability to transmit interleukin 2-mediated signals. 919 65

One of the most common human immunodeficiencies is an X-linked condition arising from mutations of the gamma subunit of the interleukin-2 receptor (IL-2Rgamma). The IL-2Rgamma protein is one chain of the heterotrimeric (alpha, beta, gamma) IL-2 receptor, but also participates in the formation of the IL-4, 7, 9, and 15 receptor complexes. The diagnosis of X-linked SCID is usually relatively simple due to the distinctive immunological presentation; IL-2Rgamma-deficient patients typically lacking mature T lymphocytes (T-B+). However, it is becoming clear that this merely represents one extreme of a potential range of clinical presentations. We describe here a novel mutation of the human IL-2Rgamma chain (R222C) resulting in an unusual immunological phenotype. Although clinically immunodeficient, this patient has normal numbers of peripheral T and B cells, responds normally to mitogenic stimuli, and unusually, has a normal thymus gland. This IL-2Rgamma mutation is distinctive in that the protein is sufficiently stable to be expressed at the cell surface. While the T cell receptor repertoire appears complete, suggesting normal T cell differentiation occurs, patient T cells demonstrate a reduced ability to bind IL-2 and this appears sufficient to cause a deficiency in their ability to participate in antigenic responses. Early clinical recognition of this phenotype is critical as a delay in diagnosis may result in a fatal infection.
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PMID:An interleukin-2 receptor gamma chain mutation with normal thymus morphology. 939 50

Malignant pleural effusion (PE) is a frequent problem in lung cancer. In this study, we established a model of malignant PE of human adenocarcinoma cells, PC-14, in SCID mice. Intravenously injected PC-14 cells formed colonies in the lungs as early as week 4 after tumor inoculation, and produced bloody PE in all recipient SCID mice by week 8. Pretreatment of SCID mice with anti-mouse IL-2 receptor beta chain antibody (TM-beta 1) to deplete natural killer (NK) cells markedly promoted the production of bloody PE and metastases to multiple organs, such as the lungs, liver, kidneys, and lymph nodes 4 weeks after tumor inoculation. Histological studies indicated that PC-14 cells formed colonies in the lungs, and then invaded the pleura and spread to the pleural cavity. To establish cell lines with a high potential to produce PE, we harvested PE, expanded the tumor cells in vitro, and injected them into SCID mice again. By four in vivo selection cycles in this way we obtained PC-14-PM4 cells, which produce lung metastases and PE earlier than PC-14 cells. The survival of SCID mice inoculated with PC-14-PM4 cells was significantly shorter than that of mice inoculated with PC-14 cells. The expressions of adhesion molecules, such as CD44, CD49d, ICAM-1, and MHC class I, on PC-14-PM4 cells tended to increase compared with PC-14 cells. These changes of adhesion molecules seem to be one of possible mechanisms involved in higher metastatic potential of PC-14-PM4 cells. PE models with PC-14 and PC-14-PM4 cells should be useful for biological and preclinical studies on malignant PE produced by human lung cancer.
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PMID:Model of malignant pleural effusion of human lung adenocarcinoma in SCID mice. 956 4


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