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

Severe combined immunodeficiency (SCID) due to deficiency of the purine metabolic enzyme adenosine deaminase (ADA) is a fatal childhood immunodeficiency disease. Immune reconstitution by transplantation with HLA-identical bone marrow is the treatment of choice. For patients not candidates for bone marrow transplantation, we propose to attempt immune reconstitution by using infusions of autologous T lymphocytes expanded in tissue culture and genetically corrected by insertion of a normal ADA gene using retroviral-mediated gene transfer. The vector is LASN, in which the human ADA gene is promoted by the LTR while the NeoR gene is driven by the SV40 early gene promoter. The packaging line is PA317. The protocol is designed to have two parts. In Part 1, autologous gene-corrected T lymphocytes would be infused repeatedly in low numbers in order to build an immune repertoire of T cells and also to obtain information as to how long gene corrected T cells survive in vivo. In Part 2A, the gene-corrected T cells would be selected in G418 and/or 2'deoxyadenosine and reinfused into the patient at monthly intervals for approximately 6 months. The goals would be essentially the same as in Part 1. In Part 2B, the number of gene-corrected T cells would be escalated in half-log increments to the predicted therapeutic level (probably around 1 x 10(9)/kg). 1-3 x 10(9)/kg gene-corrected cells would be infused several times and the patients would be monitored in order to determine if significant clinical improvement has occurred.
 ...
PMID:The ADA human gene therapy clinical protocol. 208 Nov 98

In ataxia-telangiectasia, B-cell and T-cell deficiencies are thought to be due to a defect of rearrangements of immunoglobulin and T-cell receptor genes. T cells recognize antigens through two types of CD3-associated receptors: alpha/beta chains on mature cells and gamma/delta chains mostly on immature cells. We studied 10 patients with ataxia-telangiectasia and found that most had a relative increase of circulating T cells bearing gamma/delta receptors rather than alpha/beta receptors, as compared with normal subjects (P less than 0.001). Patients with other immune deficits, including eight with common variable immunodeficiency, one with Wiskott-Aldrich syndrome, two with hyperimmunoglobulinemia E syndrome, and one with severe combined immunodeficiency, had normal ratios of gamma/delta-bearing to alpha/beta-bearing cells. A marked predominance of gamma/delta-bearing T cells was found in a patient with a primary T-cell defect. The relative increase in gamma/delta-bearing T cells in the patients with ataxia-telangiectasia was largely accounted for by cells that reacted with the monoclonal antibody BB3, an apparently distinct subset of T cells that selectively express the C gamma 1 gene product of the T-cell receptor. Although they had normal ratios of gamma/delta-bearing to alpha/beta-bearing T cells, the patients with common variable immunodeficiency had a significant increase (P = 0.01) in the number of T cells expressing C gamma 2 that reacted with the monoclonal antibody delta-TCS-1. We conclude that the increased ratio of gamma/delta-bearing to alpha/beta-bearing T cells in ataxia-telangiectasia may reflect both a recombinational defect that interferes with T-cell and B-cell gene rearrangements and an inability to repair damage to the DNA.
 ...
PMID:Relative increase of T cells expressing the gamma/delta rather than the alpha/beta receptor in ataxia-telangiectasia. 221

The T-cell receptor (TCR) for antigen is a complex consisting of at least seven polypeptides chains. Two chains form the clonotypic heterodimer, which determines antigen-specificity. The other five constitute the monomorphic CD3 components, which are thought to be involved in signal transduction. We have reported a familial defect in the surface expression of the TCR/CD3 complex on otherwise phenotypically normal T lymphocytes. As a consequence of the surface defect, an impaired T-lymphocyte activation through the TCR and CD3 complex by both antigens and mitogens is observed in this type of immunodeficiency (ID) for which we propose the name TCR ID. In contrast, normal proliferative responses were recorded to TCR-independent activation or proliferation signals (i.e: anti-CD2, phorbol esters and IL-2). We believe that other ID with similar clinical and immunological characteristics, described before the general availability of monoclonal antibodies, may have also been TCR ID. Severe and mild clinical phenotypes of the disease exist which correlate with differences in the levels of TCR surface expression and of T-cell function in vitro. The biochemical basis of the defect in one of the cases thus far studied is an impaired association of CD3-zeta chain with the other chains of the complex. This defect prevented the maturation and transport of the incomplete complex to the cell surface. Due to the multi-subunit nature of the TCR/CD3 complex it is possible that other biochemical defects in TCR assembly may also give rise to TCR ID. The description of mild as well as a severe phenotype in TCR ID points to a threshold effect of TCR/CD3 expression necessary for normal T cell function in vivo since mild TCR ID is clinically asymptomatic. In contrast, severe TCR ID behaves as a clinical SCID, with clear autoimmune features and profound lymphoid tissue depletion. TCR ID and other naturally occurring SCID variants may shed light on fundamental questions of the development, function and biochemistry of the in vivo immune system. Their study and characterization also opens the door to somatic gene therapy in this kind of disorder, which is an obvious goal in ID research.
 ...
PMID:Congenital T-cell receptor immunodeficiencies in man. 214

The pathogenic profiles of two heterologous animal rotaviruses, rhesus rotavirus strain MMU 18006 and bovine rotavirus strain WC3, were evaluated in mice with severe combined immunodeficiency (SCID mice) and normal BALB/c mice. Control animals were inoculated with homologous murine strain EDIM 5099 or a tissue culture-adapted murine rotavirus. Heterologous infection with rhesus rotavirus resulted in hepatitis in 84% of SCID and 21% of BALB/c mice, with mortality rates of 27 and 0%, respectively. Surviving SCID animals developed chronic liver disease, while symptoms in BALB/c mice resolved in 2 to 4 weeks after onset. Histopathologic examination revealed a diffuse hepatitis with focal areas of parenchymal necrosis. Rotavirus was detected in liver tissue from 100% of 29 SCID and 85% (11 of 13) BALB/c animals tested by cell culture infectivity, immunofluorescence, or electron microscopy. No extramucosal spread of virus or hepatitis was observed after infection with heterologous bovine strain WC3 or homologous murine rotaviruses. This finding of a novel rotavirus-induced disease manifestation suggests altered tissue tropism in a heterologous host for a group of viruses previously shown to replicate exclusively in the gut mucosa. The implications of our observations suggest that in human vaccine trials utilizing heterologous rotavirus strains, special attention should be paid to children with immunodeficiency disorders, and screening for hepatic function should be included in vaccine protocols.
 ...
PMID:Extramucosal spread and development of hepatitis in immunodeficient and normal mice infected with rhesus rotavirus. 215 22

T- and B-lymphocyte populations in peripheral lymphoid tissues occur in distinct compartments (e.g., the periarteriolar lymphocyte sheath of the splenic white pulp is a T-cell area). The authors report on two patients with severe combined immunodeficiency (SCID) and one patient with immunodeficiency after anti-T-cell treatment for rejection of a heart transplant, in which the area surrounding the central arteriole in spleen white pulp was well-populated despite T-cell deficiency (documented by, for example, severe depletion of lymph node paracortex). Immunologic phenotyping showed the B-lymphoid lineage of lymphocytes at this location. The framework in the periarteriolar area consisted of follicular dendritic cells, which are typical framework components of B-cell areas. We conclude that assessment of only conventional histopathology of the spleen in these patients leads to erroneous conclusions about the type of immunodeficiency and that immunologic phenotyping is required to document the exact nature of the deficiency.
 ...
PMID:The periarteriolar lymphocyte sheath in immunodeficiency T- or B-lymphocyte area? 220 64

Hereditary multiple atresias involving the gastrointestinal tract from pylorus to rectum are the most unusual form of intestinal atresia; the type of inheritance was suggested to be autosomal recessive. The inheritance of the severe combined immunodeficiency syndrome can be autosomal recessive or X-linked. We report on 3 sibs with multiple-level intestinal atresias. One sib had severe combined immunodeficiency syndrome and clinical histories of the other 2 sibs strongly suggested a congenital immunodeficiency syndrome. The parents of those children were healthy and nonconsanguineous. To our knowledge, this is the first report of the association of multiple gastrointestinal atresias and immunodeficiency which appears to have an autosomal recessive pattern of transmission. Our family report suggests that, in the presence of multiple gastrointestinal atresias, attention should be given to possible associated immunological disorders.
 ...
PMID:Severe combined immunodeficiency syndrome associated with autosomal recessive familial multiple gastrointestinal atresias: study of a family. 224 32

The SCID-hu mouse, engrafted with human hematolymphoid organs, is permissive for infection with the human immunodeficiency virus (HIV). This mouse model was used to test compounds for antiviral efficacy. Two weeks after infection with HIV, 100 percent (40/40) of SCID-hu mice were positive for HIV by the polymerase chain reaction. When first treated with 3'-azido-3'-deoxythymidine (AZT), none (0/17) were HIV-positive by this assay. However, AZT-treated SCID-hu mice did have a few infected cells; after AZT treatment was stopped, viral spread was detected by polymerase chain reaction in such mice. Thus, the SCID-hu mouse provides a means to directly compare new antiviral compounds with AZT and to further improve antiviral efficacy.
 ...
PMID:Suppression of HIV infection in AZT-treated SCID-hu mice. 230 Aug 16

The opportunistic pathogen Pneumocystis carinii (Pc) poses a major clinical health problem in individuals with immune deficiency, including those patients with human immunodeficiency (HIV)-associated acquired immune deficiency disease (AIDS). Heretofore, in vivo investigations of the biology of Pc and pathogenesis of pneumocystosis have generally employed steroid-induced immune suppression with antibiotic prophylaxis and protein deprivation. This approach has many drawbacks, chief among them being the widespread, multiple interacting effects caused by the inducing agents. Athymic (nude) mice and rats have been used, but are less than ideal, as the immune defect primarily affects T lymphocytes. This article describes the natural history, pathobiology, and environmental effects on Pc pneumonitis in nonaxenically housed mice homozygous for the autosomal recessive mutation 'severe combined immunodeficiency' (scid), which almost totally lack both cell-mediated and antibody-mediated immune functions. The predictability, unequivocal expression, high morbidity, and well-defined genetic basis make scid/scid mutant mice the model of choice for in vivo studies of spontaneous pneumocystosis.
 ...
PMID:Spontaneous Pneumocystis carinii pneumonia in immunodeficient mutant scid mice. Natural history and pathobiology. 234 68

Thymulin, a peptide secreted by human thymic epithelial cells, circulates in peripheral blood. Levels of plasma thymulin (FTS-Zn) activity were analyzed in 21 patients with lethal combined immunodeficiency disorders who were treated with transplantation of HLA-haplotype-mismatched parental bone marrow depleted of T cells by differential agglutination with soybean agglutinin and E-rosetting (SBA-E-BMT). Among these 21 infants, 15 were patients with severe combined immunodeficiency (SCID) and 6 had combined immunodeficiency (CID) with Omenn's syndrome or CID with T cell predominance (CIDTP). In contrast to normal infants who possess high levels of plasma thymulin activity, 20 of the 21 patients demonstrated undetectable or low plasma thymulin levels for their age at admission prior to transplantation. Following SBA-E-BMT, however, thymulin became detectable in the plasma of 17 of 18 evaluable patients and reached normal or near-normal levels between 21 and 125 days posttransplant. In patients in whom the timing of engraftment could be established by emergence of donor lymphocytes, thymulin appeared in the plasma at approximately the same time as lymphoid chimerism was detected, and in all patients who were engrafted and immunologically reconstituted, the increment in thymulin levels preceded development of immune functions. These studies support the concept that normal marrow-derived cells in the graft can provide a stimulus necessary for induction of thymic epithelial secretory function in patients with thymic dysplasia. Further, immunologic reconstitution in these patients was not seen following SBA-E-BMT unless and until recovery of thymus function had been observed.
 ...
PMID:Evidence that appearance of thymulin in plasma follows lymphoid chimerism and precedes development of immunity in patients with lethal combined immunodeficiency transplanted with T cell-depleted haploidentical marrow. 236 51

We developed a monoclonal antibody (mAb) (9D7) against a synthetic peptide (P13K) selected from the deduced amino acid sequence of the constant region of the gamma chain of the murine T-cell antigen receptor (TCR) (amino acids 118-130). Using this mAb, we identified a putative second TCR expressed on peripheral blood lymphocytes from a patient with severe combined immunodeficiency (SCID) that were propagated in culture with recombinant interleukin 2 (rIL-2) and Con A. This mAb immunoprecipitated two polypeptide chains of 40 and 58 kDa under nonreducing conditions and of 40 and 56 kDa under reducing conditions from 125I-labeled denatured lysates of T3+ WT31- lymphocytes expanded in culture from a SCID patient. These polypeptide chains were not disulfide linked and were not present on human peripheral blood lymphocytes from normal donors cultured for 5 days with phytohemagglutinin or for 2 weeks with rIL-2 and polyclonal activators or on cells of the Jurkat lymphoblastoid human T-cell line. Chemical crosslinking of 125I-labeled cells followed by immunoprecipitation with anti-Leu-4 mAb under nonreducing or reducing conditions revealed that the 40- and 56-kDa polypeptide chains were associated with the T3 differentiation antigen. These results were confirmed by sequential immunoprecipitation with anti-Leu-4 mAb followed by 9D7 anti-P13K mAb. The 9D7 anti-P13K mAb immunoprecipitated two polypeptide chains of 43 and 64 kDa from denatured lysates of lymphocytes from a patient with severe common variable immunodeficiency (CVI) that were expanded in culture with rIL-2 and Con A. Thus, this second TCR may be composed of two polypeptide chains (gamma gamma'), both of which appear to be the product of the gamma-chain gene. These experiments were done with polyclonal cell populations. Cloned T3+ WT31- cell populations are required to determine whether this TCR contains two gamma polypeptide chains. In contrast, only one polypeptide chain of 56 kDa was immunoprecipitated by the 9D7 anti-P13K mAb from peripheral blood lymphocytes from a patient with mild CVI expanded in culture with rIL-2 and polyclonal activators. Using the same 9D7 anti-P13K mAb and immunoblotting analysis, we identified a 35 kDa gamma-chain polypeptide under reducing conditions expressed on purified L3T4- Lyt2- BALB/c mouse thymocytes. This gamma-chain TCR is disulfide linked and has a molecular mass of 80 kDa under nonreducing conditions.
 ...
PMID:Identification of a second T-cell antigen receptor in human and mouse by an anti-peptide gamma-chain-specific monoclonal antibody. 243 95


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>