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)

Mutations affecting the expression of the Janus family kinase JAK3 were recently shown to be responsible for autosomal recessive severe combined immunodeficiency (SCID). JAK3-deficient patients present with a clinical phenotype virtually indistinguishable from boys affected by X-linked SCID, a disease caused by genetic defects of the common gamma chain (gamma c) that is a shared component of the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15. The specific interaction of JAK3 and gamma c represents the biochemical basis for the similarities between these two immunodeficiencies. Both forms of SCID are characterized by recurrent, severe infections leading to death in infancy unless successfully treated by allogeneic bone marrow transplantation. Because of the potentially lethal complications associated with allogeneic bone marrow transplantation and the frequent lack of suitable marrow donors, the development of alternative forms of therapy is highly desirable. To this end, we investigated a retroviral-mediated gene correction approach for JAK3-deficiency. A vector carrying a copy of JAK3 cDNA was constructed and used to transduce B cell lines derived from patients with JAK3-deficient SCID. We demonstrate restoration of JAK3 expression and phosphorylation upon IL-2 and IL-4 stimulation. Furthermore, patients' cells transduced with JAK3 acquired the ability to proliferate normally in response to IL-2. These data indicate that the biological defects of JAK3-deficient cells can be efficiently corrected in vitro by retroviral-mediated gene transfer, thus providing the basis for future investigation of gene therapy as treatment for JAK3-deficient SCID.
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PMID:In vitro correction of JAK3-deficient severe combined immunodeficiency by retroviral-mediated gene transduction. 867 91

Chronic lymphocytic leukemia (CLL) is a heterogeneous disease of the elderly which can present in one of three stages; benign, intermediate or advanced. The molecular events governing the progression of CLL are poorly understood. In order to develop model systems for predicting the aggressiveness of leukemic clones in CLL, in vivo transplantation of SCID mice with CLL cells, and the in vitro growth of CLL cells on mouse and human stromal layers, were investigated. Bone marrow or peripheral blood cells from 40 patients at different stages of CLL were transplanted into 172 immune-deficient SCID mice. Thirty-five percent of SCID mice injected with CLL cells were positive for the presence of human DNA by Southern blot or PCR analysis. The most frequently involved sites were the spleen, lung, kidney and bone marrow, at levels corresponding from 0.1 to 10 percent human DNA. Thrice-weekly intraperitoneal injections of IL-2, alone or in combination with IL-7, did not increase the level of human cell engraftment. SCID mice developed endogenous thymic lymphomas at an incidence of 10-33 percent, a rate that was not increased by CLL cell transplantation. In vitro, CLL cells were able to proliferate for 9 weeks on human stromal layers supplemented with CM (conditioned media from a culture of the human bladder carcinoma cell line 5637), but failed to thrive on the murine stromal cell line MTE cultured either in CM or autologous serum. FACS analysis revealed that 81 percent of proliferating cells on human stromal layers carried the CD5 cell surface marker, identifying them as CLL cells. Previously EBV-negative CLL cells became EBV-positive after 9 to 12 weeks in culture. The results of this study provide a firm foundation for the development of in vivo and in vitro model systems for the study of human CLL.
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PMID:Engraftment of human chronic lymphocytic leukemia cells in SCID mice: in vivo and in vitro studies. 870 47

Expression of the co-stimulatory molecule B7-1 (CD80) on pancreatic beta cells can overcome peripheral T cell tolerance in transgenic models of autoimmune disease. This study aimed to determine if aberrant B7-1 or B7-2 (CD86) expression on pancreatic beta cells is involved in the pathogenesis of autoimmune diabetes in non-obese diabetic (NOD) mice. Immunohistochemical analysis of NOD pancreas sections revealed no evidence of B7-1 or B7-2 expression on pancreatic beta cells at any stage prior to the onset of either spontaneously arising or cyclophosphamide-accelerated diabetes. Likewise, the NOD-derived NIT-1 beta cell line did not express surface B7 or B7-1 mRNA either constitutively or following exposure to IFN-gamma and TNF-alpha, two cytokines known to be present in the insulitis lesion of NOD mice, or cAMP which can induce B7-1 expression on B cells. Both B7-1 and B7-2 were, however, highly expressed on the majority of islet-infiltrating inflammatory cells in NOD mice between days 7 and 12 after the administration of cyclophosphamide which results in accelerated beta cell destruction. Likewise B7-1 and B7-2 were extensively expressed on islet-infiltrating cells present at the time of diabetes onset in NOD SCID mice with adoptively transferred diabetes. By immunohistochemistry and flow cytometry, it was determined that the phenotype of B7+ cells in the pancreas of NOD mice 9 days after cyclophosphamide included a mixture of macrophages and both CD4+ and CD8+ T cells. B7-2 was also expressed on islet-infiltrating cells in the spontaneously occurring diabetes of female NOD mice, but the levels of B7-1 expression were low in comparison with the accelerated models of diabetes. RIP-IL-2 transgenic mice, which have extensive islet infiltration but no autoimmune beta cell destruction, also had virtually no B7-1 expression and a minority of B7-2-expressing inflammatory cells. Thus, the activation of beta cell-specific T cells in NOD mice does not appear to be a result of aberrant expression of B7 on the beta cells. Expression of B7-1 and B7-2 on islet-infiltrating cells is, however, associated with autoimmune beta cell destruction, suggesting a role for the B7-CD28 interaction in this process.
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PMID:Pancreatic expression of B7 co-stimulatory molecules in the non-obese diabetic mouse. 874 58

It has been hypothesized that TH1 cells mediate the archetypical cell-mediated immune response of acute allograft rejection, whereas TH2 cells promote allograft acceptance. To test this, we transfused SCID cardiac allograft recipients with polarized TH1-like or TH2-like graft-reactive T cells, and monitored graft function and graft-reactive immune responses in the graft recipients. Polarized THl-like cells, which were generated in vitro by stimulating syngeneic splenocytes with donor alloantigens in the presence of anti-IL-4 mAb, produced IFNg but not IL-4 when restimulated with donor alloantigen. Polarized TH2-like populations, which are generated in vitro by stimulating syngeneic splenocytes with donor alloantigens in the presence of IL-4, produced IL-4 but not IFNg when restimulated with donor alloantigen. Interestingly, bioassays of culture SN from restimulated TH1 but not TH2 cells revealed IL-2 production, although LDA analyses revealed that the TH1 and TH2 cells had identical frequencies of IL-2-producing cells. Transfusion of THl-like cells into SCID cardiac allograft recipients resulted in acute rejection within 7-10 days that was characterized by cellular infiltration, myocyte necrosis, and edema. Graft-infiltrating cells (GIC) recovered from TH1-transfused animals contained large numbers of graft-reactive IL-2-producing cells (68-269/10(6) GIC), but no LDA-detectable IL-4-producing cells. These data support the hypothesis that donor-reactive TH1 cells can promote acute allograft rejection. In contrast to the hypothesis, transfusion of the polarized TH2-like population into SCID cardiac allograft recipients also resulted in histologically similar acute rejection within 7-10 days. Infiltrating cells recovered from TH1-transfused allografts contained large numbers of graft-reactive (109-1458/10(6) GIC), LDA-detectable, IL-4-producing cells--indicating that the TH2 cells had arrived at the graft-but promoted acute allograft rejection rather than allograft acceptance.
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PMID:Transfusion of polarized TH2-like cell populations into SCID mouse cardiac allograft recipients results in acute allograft rejection. 875 21

Regulatory and protective functions have been attributed to murine natural killer (NK) cells in a number of infectious diseases including listeriosis. We have developed an in vitro model to study parameters underlying the activation of naive NK cells using heat-killed Listeria monocytogenes (HKL) as stimulator. Independent from expression of the cell surface marker NK1.1, NK cells lysed YAC-1 cells after in vitro stimulation with HKL or HKL + Interleukin (IL)-2, but not medium or IL-2 alone. In contrast, NK cells from severely immunocompromised SCID or RAG-1-/-mutant mice failed to respond to HKL alone, but required exogenous IL-2. Using single-gene-disruption mutant mice, we show that NK-cell activation can be supported by either T-cell receptor (TCR) alpha beta cells, TCR- gamma delta cells. MHC class I or MHC class II gene products. We conclude from these data that recognition of listerial components alone is insufficient for activation of naive NK cells, and that additional costimulatory signals are necessary. These can be provided by various lymphoid cells and appear to be cytokines.
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PMID:Activation of natural killer cells by heat-killed Listeria monocytogenes requires additional signals from lymphoid cells. 879 63

The state of activation of the immune system may be an important factor which renders a host more receptive to human immunodeficiency virus (HIV) and more vulnerable to its effects. To explore this issue with a practical in vivo model, we developed a modified protocol of HIV infection in hu-PBL-SCID mice. First, we assessed the time course of activation of human peripheral blood lymphocytes (hu-PBL) in the peritoneal cavity of SCID mice. At 2 to 24 h after the intraperitoneal injection into SCID mice, there was a clear-cut increase in the percentage of hu-PBL expressing early activation markers (CD69), concomitant with the release of soluble intercellular adhesion molecule-1 (sICAM-1) and the soluble interleukin-2 receptor (sIL-2R) and with the accumulation of mRNAs for a number of human cytokines. At 2 weeks, virtually all of the hu-PBL expressed the memory phenotype (CD45RO) and HLA-DR antigens as well. Cells collected from the SCID mouse peritoneum at 2 and 24 h after transplantation were fully susceptible to in vitro infection with HIV type 1 (HIV-1) in the absence of either IL-2 or mitogens. The injection of HIV into hu-PBL-SCID mice at 2 h after reconstitution resulted in a generalized and productive HIV infection of the xenochimeras. This early HIV-1 infection resulted in a dramatic depletion of human CD4+ cells and in decreased levels of sICAM-1 (in the peritoneal lavage fluid) as well as of sIL-2R and immunoglobulins M and A (in the serum). Enzyme-linked immunosorbent assay and/or reverse transcriptase PCR analysis showed higher levels of IL-4, IL-5, and IL-10 in the HIV-infected animals than in control hu-PBL-SCID mice, while gamma interferon levels in the two groups were comparable. When we compared the current model of HIV-1 infection at 2 weeks after the intraperitoneal injection of the hu-PBL in the SCID mice with the model described here, we found that the majority of immune dysfunctions induced in the 2-h infection of the xenochimeras are not inducible in the 2-week infection. This supports the concept that the state of activation of human cells at the moment of the in vivo infection with HIV-1 is a crucial factor in determining the immune derangement observed in AIDS patients. These results show that some immunological dysfunctions induced by HIV infection in AIDS patients can be mimicked in this xenochimeric model. Thus, the hu-PBL-SCID mouse model may be useful in exploring, in vivo, the relevance of hu-PBL activation and differentiation in HIV-1 infection and for testing therapeutic intervention directed towards either the virus or the immune system.
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PMID:T-cell dysfunctions in hu-PBL-SCID mice infected with human immunodeficiency virus (HIV) shortly after reconstitution: in vivo effects of HIV on highly activated human immune cells. 889 19

We reported that LEC rats are genetically deficient in the development of thymic CD4+8- cells and that this defect is caused by bone marrow (BM)-derived stem cells. To determine which BM-derived cells are responsible for the arrest of T-cell development in LEC rats, fetal thymuses of LEC rats, or LEA rats which bear the same major histocompatibility complex (MHC) as LEC rats but are immunologically normal, were engrafted under the kidney capsule of severe combined immunodeficiency (SCID) mice (LEC-TG and LEA-TG mice, respectively). We than examined the differentiation of T cells and their immunological functions in the SCID mice. A large number of rat-derived CD4+ T cells appeared in the peripheral blood, lymph nodes (LN) and spleens in LEC-TG mice. Furthermore, the peripheral LN cells in LEC-TG mice appeared to be functional. These cells produced IL-2 upon Con A stimulation, whereas LN cells from LEC rats produced no IL-2 in the same conditions. Thymopoiesis was observed at 3 weeks in LEC-TG as well as LEA-TG mice. The distribution of thymocyte subsets with respect to CD4 and CD8 expression in LEC-TG mice closely resembled that of LEA rat thymus and that in LEA-TG mice, suggesting that normal T-cell differentiation occurred in LEC-TG mice. The results indicated that BM-derived progenitor T cells of LEC rats could differentiate to functional CD4+ T cells.
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PMID:Development of functional rat-derived T cells in SCID mice engrafted with the fetal thymus of LEC rats which are defective in CD4+ T cells. 890 11

The mechanism of leukemogenesis or neoplastic cell growth in adult T cell leukemia (ATL) still remains unclear, although Tax of human T cell leukemia/lymphoma virus type I (HTLV-I), the etiologic virus, has been reported to affect the expression of various cellular genes which encode molecules involved in cell growth or cell death. We have studied the cell growth of HTLV-I-infected human T cells in severe combined immunodeficiency (SCID) mice and found that fresh leukemic cells or cell lines derived from leukemic cell clones but not HTLV-I-infected cell lines of nonleukemic cell origin showed tumorigenicity, and neither HTLV-I nor IL-2 expression was needed for cell growth in vivo, indicating that accumulating changes in addition to the initial events induced by HTLV-I infection were required for the development of ATL. The interaction between ATL cells and vascular endothelial cells appears to be one of the important factors which determine the pattern of organ infiltration by leukemic cells. E-selectin and its ligand are one of the major cell adhesion pathways between ATL cells and human umbilical vein endothelial cells (HUVEC). Another pathway that had not been identified was studied using newly developed monoclonal antibodies capable of blocking cell adhesion. The molecules which directly mediate adhesion between ATL cells and HUVEC were determined to be OX40 and gp34, a member of the tumor necrosis factor receptor (TNF-R) family and TNF family, respectively. The OX40/gp34 system may play a key role in the trafficking and homing of not only ATL cells but also activated normal T cells.
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PMID:ATL and HTLV-I: in vivo cell growth of ATL cells. 894 74

Several disease mechanisms have been studied in the model of GCA. GCA patients exhibit a genetic susceptibility which has been mapped to the HLA-DRB1 gene. Polymorphic amino acid residues localized at the floor of the antigen binding site are highly selected in GCA patients suggesting a role for antigen binding and presentation in the disease. This and other genetic risk factors might actually be a surrogate for the distinct geographic distribution of the disease with a marked preference for Northern Europe. Studies on functional aspects of T cells accumulating in the vasculitic foci have demonstrated a strong bias for Th1 helper T cells which locally release IL-2 and IFN-gamma. IFN-gamma appears to be a key cytokine in this vasculitis. IFN-gamma producing T cells represent a minority of the tissue infiltrating cell population suggesting that very few cells have disease relevance and the majority of T cells is recruited as bystanders. IFN-gamma secreting CD4 T cells preferentially localize to the adventitial-medial junction and are thus placed distant from the center of pathology, the intima and internal media. TCRs expressed by T cells accumulated in the affected tissue are not randomly distributed but are biased toward selected specificities. These selected T cells undergo proliferation in the tissue and can be isolated from nonadjacent and independent sites of the vasculitis. This distribution pattern indicates a common driving factor, suspected to be a tissue residing antigen [8]. Further support for an antigen driving this pathological T cell response comes from the finding that temporal artery specimens engrafted into SCID mice continue to show the typical disease process indicating that all components relevant for the disease are contained in the temporal artery wall. So far no shared TCR utilized by different patients has been identified, raising the question whether distinct antigens can elicit GCA as a common pathway of reactivity. Besides its role in investigating pathomechanisms the SCID mouse model of GCA provides the unique opportunity to study the therapeutic effects of established and novel treatments. It can be expected that some of the pathogenic rules established for GCA can be applied to other vasculitic syndromes.
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PMID:The pathogenic role of T lymphocytes in vasculitis. 894 85

Genetic evidence suggests that mutations in the gamma(c) receptor subunit cause X-linked severe combined immunodeficiency (X-SCID). The gamma(c) subunit can be employed in receptor complexes for IL-2, -4, -7, -9, and -15, and the multiple signaling defects that would result from a defective gamma(c) chain in these receptors are proposed to cause the severe phenotype of X-SCID patients. Interestingly, gene disruption of either IL-7 or the IL-7 receptor (IL-7R) alpha subunit in mice leads to immunological defects that are similar to human X-SCID. These observations suggest the functional importance of gamma(c) in the IL-7R complex. In the present study, structure/function analyses of the IL-7R complex using a chimeric receptor system demonstrated that gamma(c) is indeed critical for IL-7R function. Nonetheless, only a limited portion of the cytoplasmic domain of gamma(c) is necessary for IL-7R signal transduction. Furthermore, replacement of the gamma(c) cytoplasmic domain by a severely truncated erythropoeitin receptor does not affect measured IL-7R signaling events. These findings support a model in which gamma(c) serves primarily to activate signal transduction by the IL-7R complex, while IL-7R alpha determines specific signaling events through its association with cytoplasmic signaling molecules. Finally, these studies are consistent with the hypothesis that the molecular pathogenesis of X-SCID is due primarily to gamma(c)-mediated defects in the IL-7/IL-7R system.
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PMID:Shared gamma(c) subunit within the human interleukin-7 receptor complex. A molecular basis for the pathogenesis of X-linked severe combined immunodeficiency. 900 84


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