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Severe Combined Immunodeficiency (severe + combined_immunodeficiency)
Selected AbstractsExtensive Tinea in a Patient With Severe Combined ImmunodeficiencyPEDIATRIC DERMATOLOGY, Issue 2 2009RAFAEL JIMÉNEZ-PUYA M.D. Although the X-linked recessive form is most common (60,70%), there are autosomal recessive forms (20%) and spontaneous mutations. While SCID may present with many nosocomial infections, dermatophyte infections are not common. We reported a case of SCID which was associated with a widespread skin infection with Trichophyton mentagrophytes. [source] Severe combined immunodeficiencies (SCID)CLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 2 2000A. Fischer First page of article [source] Gene therapy of severe combined immunodeficienciesIMMUNOLOGICAL REVIEWS, Issue 1 2000Alain Fischer First page of article [source] Transient recovery of endogenous immune function following haploidentical peripheral stem cell transplantation in a patient with severe combined immunodeficiency without evidence of engraftmentACTA PAEDIATRICA, Issue 2 2000J Levy No abstract is available for this article. [source] Adoptive transfer of an anti-MART-127,35 -specific CD8+ T,cell clone leads to immunoselection of human melanoma antigen-loss variants in SCID miceEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 2 2003Francesco Lozupone Abstract The identification of appropriate mouse models could be useful in carefully evaluating the actual role of the in vivo development of antigen-loss variants during antigen-specific vaccine therapy of human tumors. In this study we investigated the level of efficacy of a MART-1/Melan-A-specific CD8+ T,cell clone against its autologous melanoma in a severe combined immunodeficiency (SCID) mouse model, in which the tumor cells expressed in vivo heterogeneous and suboptimal levels of MART-1. The subcutaneous co-injection of the MART-1/Melan-A-reactive T,cell clone A42 with MART-1/Melan-A+ autologous human melanoma cells into SCID mice caused a total inhibition of tumor growth. However, the systemic treatment with A42 clone lymphocytes resulted inonly 50,60% inhibition of tumor growth, although the T,cell clone targeted the tumors and the MART-1+ cells virtually disappeared from the tumors. This study suggests that an immunotherapybased on the expansion of an antigen-specific T,cell clone generated in vitro is highly efficient in abolishing tumor growth when the target antigen is fully expressed, but leads to in vivoimmunoselection of antigen-loss variants in the presence of suboptimal levels of antigen expression. Furthermore, this work shows that human tumors/SCID mouse models may be useful in evaluating thein vivo efficacy of adoptive immunotherapies. [source] Functional epitope of common , chain for interleukin-4 bindingFEBS JOURNAL, Issue 5 2002Jin-Li Zhang Interleukin 4 (IL-4) can act on target cells through an IL-4 receptor complex consisting of the IL-4 receptor , chain and the common , chain (,c). An IL-4 epitope for ,c binding has previously been identified. In this study, the ,c residues involved in IL-4 binding were defined by alanine-scanning mutational analysis. The epitope comprises ,c residues I100, L102, and Y103 on loop EF1 together with L208 on loop FG2 as the major binding determinants. These predominantly hydrophobic determinants interact with the hydrophobic IL-4 epitope composed of residues I11, N15, and Y124. Double-mutant cycle analysis revealed co-operative interaction between ,c and IL-4 side chains. Several ,c residues involved in IL-4 binding have been previously shown to be mutated in X-linked severe combined immunodeficiency. The importance of these binding residues for ,c function is discussed. These results provide a basis for elucidating the molecular recognition mechanism in the IL-4 receptor system and a paradigm for other ,c -dependent cytokine receptor systems. [source] Mutations in severe combined immune deficiency (SCID) due to JAK3 deficiencyHUMAN MUTATION, Issue 4 2001Luigi D. Notarangelo Abstract During the last 10 years, an increasing number of genes have been identified whose abnormalities account for primary immunodeficiencies, with defects in development and/or function of the immune system. Among them is the JAK3 -gene, encoding for a tyrosine kinase that is functionally coupled to cytokine receptors which share the common gamma chain. Defects of this gene cause an autosomal recessive form of severe combined immunodeficiency with almost absent T-cells and functionally defective B-cells (T,B+ SCID). Herewith, we present molecular information on the first 27 unique mutations identified in the JAK3 gene, including clinical data on all of the 23 affected patients reported so far. A variety of mutations scattered throughout all seven functional domains of the protein, and with different functional effects, have been identified. Availability of a molecular screening test, based on amplification of genomic DNA, facilitates the diagnostic approach, and has permitted recognition that JAK3 deficiency may also be associated with atypical clinical and immunological features. Development of a structural model of the JAK3 kinase domain has allowed characterization of the functional effects of the various mutations. Most importantly, molecular analysis at the JAK3 locus results in improved genetic counseling, allows early prenatal diagnosis, and prompts appropriate treatment (currently based on hematopoietic stem cell transplantation) in affected families. Hum Mutat 18:255,263, 2001. © 2001 Wiley-Liss, Inc. [source] Characterization of T-regulatory cells, induced by immature dendritic cells, which inhibit enteroantigen-reactive colitis-inducing T-cell responses in vitro and in vivoIMMUNOLOGY, Issue 4 2004Monika Gad Summary Regulatory T (Treg) cells, derived from co-cultures of unfractionated CD4+ T cells and immature dendritic cells (DC), suppress enteroantigen-induced proliferation of CD4+ CD25, T cells. The DC-induced Treg cells are a mixture of CD25+ (10,20%) and CD25, (80,90%) T cells. However, all the suppressor activity in vitro and in vivo resides in the CD25+ T-cell subset. The CD25+ DC-induced Treg cells can inhibit enteroantigen-induced proliferation in vitro through a transwell membrane, and their function does not appear to depend on previous activation. DC-induced CD25+ Treg cells display a naïve phenotype, expressing high levels of CD45RB and l -selectin (CD62L). In addition, the DC-induced Treg cells mediate a stronger suppressive activity than prototype CD25+ regulatory T cells. The DC-induced Treg cells, and hereof purified CD25+ and CD25, T-cell fractions, were co-injected into severe combined immunodeficiency (SCID) mice with colitis-inducing CD4+ CD25, T cells. Both unfractionated CD4+ and purified CD25+ Treg cells fully protected the recipients against the development of colitis. In contrast, co-transfer of fractionated CD25, T cells offered no protection against disease development. Enterobacterial antigen-exposed CD4+ T cells of the protected mice secreted higher levels of interleukin-10 and lower levels of interferon-, than the unprotected mice. The present data demonstrate DC-induced CD4+ CD25+ Treg cells, which phenotypically and functionally differ from the generally accepted prototype of CD25+ Treg cells. These data may initiate new procedures for the expansion of Treg cells for clinical use. [source] Segmented filamentous bacteria in a defined bacterial cocktail induce intestinal inflammation in SCID mice reconstituted with CD45RBhigh CD4+ T cellsINFLAMMATORY BOWEL DISEASES, Issue 10 2007Renata Stepankova PhD Abstract Background: The aim was to analyze the influence of intestinal microbiota on the development of intestinal inflammation. We used the model of chronic inflammation that develops spontaneously in the colon of conventional severe combined immunodeficiency (SCID) mice restored with the CD45 RBhigh subset of CD4+T cells isolated from the spleen of normal BALB/c mice. Methods: A CD4+CD45RBhigh subpopulation of T cells was purified from the spleen of conventional BALB/c mice by magnetic separation (MACS) and transferred into immunodeficient SCID mice. Germ-free (GF) SCID mice or SCID mice monoassociated with Enterococcus faecalis, SFB (segmented filamentous bacteria), Fusobacterium mortiferum, Bacteroides distasonis, and in combination Fusobacterium mortiferum + SFB or Bacteroides distasonis + SFB were used as recipients. SCID mice were colonized by a defined cocktail of specific pathogen-free (SPF) bacteria. Mice were evaluated 8,12 weeks after the cell transfer for clinical and morphological signs of inflammatory bowel disease (IBD). Results: After the transfer of the CD4+CD45RBhigh T-cell subpopulation to SCID mice severe colitis was present in conventional animals and in mice colonized with a cocktail of SPF microflora plus SFB. Altered intestinal barrier in the terminal ileum of mice with severe colitis was documented by immunohistology using antibodies to ZO-1 (zona occludens). Conclusions: Only SFB bacteria together with a defined SPF mixture were effective in triggering intestinal inflammation in the model of IBD in reconstituted SCID mice, while no colitis was detected in GF mice or in mice colonized either with SPF microflora or monoassociated only with SFB or colonized by Bacteroides distasonis + SFB or Fusobacterium mortiferum + SFB. (Inflamm Bowel Dis 2007) [source] Down regulation of 3p genes, LTF, SLC38A3 and DRR1, upon growth of human chromosome 3,mouse fibrosarcoma hybrids in severe combined immunodeficiency miceINTERNATIONAL JOURNAL OF CANCER, Issue 1 2006Irina D. Kholodnyuk Abstract We have applied a functional test for tumour antagonizing genes based on human chromosome 3 (chr3),mouse fibrosarcoma A9 MCHs that were studied in vitro and after growth as tumours in severe combined immunodeficiency (SCID) mice. Previously, we reported that 9 out of the 36 SCID-tumours maintained the transferred chr3 ("chr3+" tumours), but lost the expression of the known human TSG fragile histidine triad gene (FHIT) in contrast to 14 other 3p-genes examined. Here we report the results of the duplex RT-PCR analysis of 9 "chr3+" tumours and 3 parental MCHs. We have examined the expression of 34 human 3p-genes from known cancer-related regions of instability, including 13 genes from CER1 defined by us previously at 3p21.33,p21.31 and 10 genes from the LUCA region at 3p21.31. We have found that in addition to FHIT, expression of the LTF gene from CER1 at 3p21.33-p21.31 was lost in all 9 tumours analyzed. The transcript of the solute carrier family 38 member 3 gene (SLC38A3) gene from LUCA region at 3p21.31 was not found in 8 and was greatly reduced in 1 out of these 9 tumours. Expression of the down-regulated in renal cell carcinoma gene (DRR1) gene at 3p14.2 was lost in 7 and down regulated in 2 "chr3+" tumours. In the SCID-tumour derived cell lines treatment with 5-aza-2,-deoxycytidine restored the mRNA expression of LTF, indicating the integrity of DNA sequences. Notably that transcription of the LTF and 2 flanking genes, LRRC2 and TMEM7, as well as transcription of the SLC38A3 gene, were also impaired in all 5 RCC cell lines analyzed. Our data indicate these genes as putative tumour suppressor genes. © 2006 Wiley-Liss, Inc. [source] Ameliorating effect of saporin-conjugated anti-CD11b monoclonal antibody in a murine T-cell-mediated chronic colitisJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 7 2006Takanori Kanai Abstract Background:, Crohn's disease (CD) is an inflammatory bowel disease that is associated with several changes in the immune system, including an increased number of infiltrating macrophages. These macrophages release a variety of pro-inflammatory cytokines, such as tumor necrosis factor-, (TNF-,) which are critically involved in the onset and the development of CD. The present study was performed to explore the initial involvement of macrophages in the development of T-cell-mediated chronic colitis. Methods:, The effects were evaluated of saporin-conjugated anti-CD11b monoclonal antibody (mAb) on the development of chronic colitis in severe combined immunodeficiency (SCID) mice induced by adoptive transfer of CD4+CD45RBhigh T cells as an animal model of CD. Results:, Significantly increased CD11b-expressing macrophages as well as CD4+ T cells were found in inflamed colon from colitic mice. Administration of saporin-conjugated anti-CD11b mAb markedly ameliorated the clinical and histopathological disease. In vivo treatment with saporin-conjugated anti-CD11b mAb decreased CD4+ T-cell infiltration in the colon and suppressed inferferon-, (IFN-,) and TNF-, production by lamina propria CD4+ T cells. Conclusions:, Collectively, the present results suggest an initial role of macrophages in the pathogenesis of T-cell-mediated chronic colitis. Furthermore, the macrophage-specific targeting may be a promising strategy for therapeutic intervention in CD. [source] Blockade of CCR4 in a humanized model of asthma reveals a critical role for DC-derived CCL17 and CCL22 in attracting Th2 cells and inducing airway inflammationALLERGY, Issue 7 2009F. Perros Background:, As Th2 type lymphocytes orchestrate the cardinal features of allergic asthma, inhibiting their recruitment to the lungs could be of therapeutic benefit. Although human Th2 cells express the CCR4 chemokine receptor and increased production of CCR4 ligands has been found in asthmatic airways, studies in animals have reached contradictory conclusions on whether blocking this pathway would be beneficial. Objective:, As a lack of efficacy might be due to differences between mouse and man, we readdressed this question using a humanized severe combined immunodeficiency model of asthma. Methods:, Mice received peripheral blood mononuclear cells from house dust mite (HDM) allergic asthmatic patients and then underwent bronchial challenge with HDM. Results:, This resulted in marked allergic inflammation and bronchial hyper-reactivity. Administration of CCR4 blocking antibody abolished the airway eosinophilia, goblet cell hyperplasia, IgE synthesis and bronchial hyperreactivity. In this chimeric system, human CD11c+ dendritic cells (DCs) were the predominant source of CCR4 ligands, suggesting that DC-derived chemokines attract Th2 cells. In separate experiments using human DCs, in vitro exposure to HDM of DCs from HDM allergic patients but not healthy controls caused CCL17 and CCL22 release that resulted in chemoattraction of polarized human Th2 cells in a CCR4-dependent way. Conclusions:, Taken together, our data provide proof of concept that CCR4 blockade inhibits the salient features of asthma and justify further clinical development of CCR4 antagonists for this disease. [source] Pichia anomala fungaemia in immunocompromised childrenMYCOSES, Issue 5-6 2004M. Bak Pichia anomala; Fungämie; Immunsuppression; Kindern Summary Pichia anomala is an emerging yeast causing serious nosocomial infections in newborn and immunocompromised children. We describe nosocomial port catheter infection due to P. anomala in three children who were receiving cancer chemotherapy, bloodstream infection in a preterm infant and in an infant with severe combined immunodeficiency. All patients were treated with amphotericin B. All isolates were susceptible to amphotericin B and fluconazole. No recurrence was observed during follow-up in four of five patients. The common clinical feature in all of our patients was the presence of prior antimicrobial therapy. Zusammenfassung Pichia anomala gilt als opportunistischer Erreger nosokomialer Infektionen bei Neugeborenen und immunsupprimierten Kindern. Wir beschreiben nosokomiale Katheterinfektionen durch P. anomala bei drei Kindern mit Krebs, bei einer Frühgeburt und bei einem immunsupprimierten Säugling. Alle fünf Patienten hatten vorab antibakterielle Therapie erhalten und wurden durch Amphotericin B erfolgreich behandelt. Alle Isolate waren empfindlich für Amphotericin B und Fluconazol. In der Nachbeobachtungszeit wurde an vier fünf Patienten kein Rezidiv beobachtet. [source] Rituximab for the treatment of post-bone marrow transplantation refractory hemolytic anemia in a child with Omenn's syndromePEDIATRIC TRANSPLANTATION, Issue 5 2007Briuglia Silvana Abstract:, Omenn's syndrome is a rare severe combined immunodeficiency that kills affected subjects before the end of the first year of life unless patients are treated with bone marrow transplantation (BMT). Unfortunately, post-BMT patients may develop autoimmune diseases, such as autoimmune hemolytic anemia (AIHA), which sometimes fails to respond to standard therapies. Rituximab is a chimeric, human, immunoglobulin G1/k monoclonal antibody specific for the CD20 antigen expressed on the surface of B lymphocytes. Rituximab is currently only labeled for treatment of B-cell lymphoproliferative disorders, such as B-cell non-Hodgkin's lymphoma and follicular lymphoma; however, it is also employed in the treatment of a variety of disorders mediated by auto-antibodies, such as AIHA and transplant-related autoimmune disorders. Herein, we describe the case of a 23-month-old male child with Omenn's syndrome, who had undergone BMT and was successfully treated with rituximab (375 mg/m2 intravenously, weekly for three times) for refractory post-BMT hemolytic anemia. Our findings evidence that rituximab should be considered for treatment of post-BMT AIHA refractory to traditional therapy also in children with primary immunodeficiencies; furthermore, rituximab might represent a means to obtain remissions without the toxic effects associated with corticosteroid and immunosuppressive agents. [source] Tuberculin skin test positivity in pediatric allogeneic BMT recipients and donors in TurkeyPEDIATRIC TRANSPLANTATION, Issue 4 2007Betul Tavil Abstract:, The preliminary study was performed to determine the frequency of tuberculin skin test (TST) positivity among 26 patients and their donors screened by TST to investigate whether tuberculin positivity of a recipient or donor influenced the rate of tuberculosis disease, transplant-related events, and to evaluate the effectiveness of isoniazide (INAH) prophylaxis administered to those with positive TST. The frequency of TST positivity was 23% (n = 6) among recipients and also 23% (n = 6) among donors. Two recipients and five donors with positive TST received INAH prophylaxis for six months. Our use of INAH prophylaxis in transplant patients was very conservative because of the risk of drug interaction. The transplantation procedure was not postponed for either recipient or donor TST positivity. Despite the high frequency of tuberculosis in our country, we have not detected any case of tuberculosis in our center, either among the purified protein derivative-screened (n = 26) or non-screened (n = 128) patients except for disseminated tuberculosis infection because of BCG vaccination in two patients with severe combined immunodeficiency. In conclusion, TST positivity in either recipient or donor may not be a contraindication for bone marrow transplantation and the procedure may not be postponed. Pretransplantation TST screening may be needed in countries where tuberculosis is common in the general population. [source] Successful unrelated mismatched cord blood transplantation in an infant with severe combined immunodeficiency and Mycobacterium bovis bacillus Calmette-Guèrin diseasePEDIATRIC TRANSPLANTATION, Issue 4 2006Tang-Her Jaing Abstract:, The case reported here of an infant who presented with Pneumocystis carinii pneumonia, CD4+ lymphopenia, and hypogammaglobulinemia attributable to severe combined immunodeficiency (SCID). This report discussed treatment of Mycobacterium bovis bacillus Calmette-Guèrin disease with unrelated cord blood transplantation in addition to antituberculous therapy, by adoptively transferring donor immunity with induction of mixed chimerism. Because of the unique nature of umbilical cord blood hematopoietic cells, engraftment without conditioning may be possible in SCID patients without fully matched donors. [source] G-CSF-mobilized haploidentical peripheral blood stem cell transplantation in children with poor prognostic nonmalignant disordersAMERICAN JOURNAL OF HEMATOLOGY, Issue 2 2008Fikret Arpac Haploidentical hematopoietic stem cell transplantation (HSCT) is currently one of the alternative curative treatment options for some nonmalignant but also for malignant diseases. However, concerns regarding its safety cause delays in time and a successful outcome. Between 2000 and 2005, twenty-one children with poor prognostic nonmalignant disorders, 13 boys and 8 girls, with a median age of 12 months, underwent 28 haploidentical peripheral HSCT. Immunomagnetic bead depletion device (CliniMACS) was used for indirect T-cell depletion. Indications for transplant were severe combined immunodeficiency (n = 16), osteopetrosis (n = 2), MDS (n = 1), amegakaryocytic thrombocytopenia (n = 1), and aplastic anemia (n = 1). Five patients (24%) had lung infection at the time of transplantation. The patients received a median of 25.67 × 106 G-CSF-mobilized peripheral CD34+ progenitor cells and a median of 4.19 × 104 T-lymphocytes per kilogram of body weight with a T-cell depletion rate of median 4.59 logs. The rate of total engraftment was 66.6%. Median times for leukocyte and platelet engraftment were 14 and 16 days, respectively. The 6-year projected survival was 32% for all patients and 29.76% for patients with severe combined immunodeficiency (SCID). The rates of transplant-related mortality, graft failure, and severe GvHD were 14.2, 33.4%, and 8.3%, respectively. Infection was the main cause of death. The poor outcome may be explained with the poor prognostic factors of our patients such as the type of SCID in most cases (T-B, SCID), the median age over 6 months and the presence of lung infection in some children at the time of transplantation. Am. J. Hematol., 2008. © 2007 Wiley-Liss, Inc. [source] Fas-mediated upregulation of vascular endothelial growth factor and monocyte chemoattractant protein-1 expression in cultured dermal fibroblasts: Role in the inflammatory responseTHE JOURNAL OF DERMATOLOGY, Issue 2 2007Masao FUJIWARA ABSTRACT The Fas,Fas ligand interaction is the most important pathway in starting apoptosis. In addition, several recent reports have emerged documenting non-apoptotic roles for Fas. However, a non-apoptotic role of Fas in dermal fibroblasts remains unknown. The present study investigated whether Fas stimulation not only promotes apoptosis but also stimulates elements of the inflammatory response such as angiogenesis and macrophage infiltration. Fas stimulation was performed by treating cultured human dermal fibroblasts with an agonistic anti-Fas monoclonal antibody (mAb). Anti-Fas mAb-treated fibroblasts showed a significantly greater increase of caspase-3 and caspase-8 activity compared with control fibroblasts. Addition of the anti-Fas mAb induced DNA fragmentation, as confirmed by the DNA ladder assay. Terminal deoxynucleotidyl transferase-mediated 2,-deoxyuridine 5,-triphosphate nick end labeling (TUNEL) staining showed that treatment with the anti-Fas mAb induced an increase of apoptotic fibroblasts in a time-dependent manner. At both mRNA and protein levels, anti-Fas mAb-treated fibroblasts showed significantly higher expression of vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein (MCP)-1 compared with control fibroblasts. A pan-caspase inhibitor (Z-VAD-FMK) significantly inhibited VEGF and MCP-1 expression. After transplantation of fibroblasts into mice with severe combined immunodeficiency, the nodules derived from anti-Fas mAb-treated fibroblasts showed more abundant neovascularization, increased macrophage infiltration, and more apoptotic cells in comparison with nodules derived from control fibroblasts. The results of both in vitro and in vivo studies confirmed significantly higher angiogenic activity and macrophage chemotactic activity of anti-Fas mAb-treated fibroblasts compared with control fibroblasts. [source] Phage ,C31 integrase-mediated genomic integration of the common cytokine receptor gamma chain in human T-cell linesTHE JOURNAL OF GENE MEDICINE, Issue 5 2006Yoshinori Ishikawa Abstract Background X-linked severe combined immunodeficiency (SCID-X1, X-SCID) is a life-threatening disease caused by a mutated common cytokine receptor , chain (,c) gene. Although ex vivo gene therapy, i.e., transduction of the ,c gene into autologous CD34+ cells, has been successful for treating SCID-X1, the retrovirus vector-mediated transfer allowed dysregulated integration, causing leukemias. Here, to explore an alternative gene transfer methodology that may offer less risk of insertional mutagenesis, we employed the ,C31 integrase-based integration system using human T-cell lines, including the ,c-deficient ED40515(-). Methods A ,C31 integrase and a neor gene expression plasmid containing the ,C31 attB sequence were co-delivered by electroporation into Jurkat cells. After G418 selection, integration site analyses were performed using linear amplification mediated-polymerase chain reaction (LAM-PCR). ED40515(-) cells were also transfected with a ,c expression plasmid containing attB, and the integration sites were determined. IL-2 stimulation was used to assess the functionality of the transduced ,c in an ED40515(-)-derived clone. Results Following co-introduction of the ,C31 integrase expression plasmid and the plasmid carrying attB, the efficiency of integration into the unmodified human genome was assessed. Several integration sites were characterized, including new integration sites in intergenic regions on chromosomes 13 and 18 that may be preferred in hematopoietic cells. An ED40515(-) line bearing the integrated ,c gene exhibited stable expression of the ,c protein, with normal IL-2 signaling, as assessed by STAT5 activation. Conclusions This study supports the possible future use of this ,C31 integrase-mediated genomic integration strategy as an alternative gene therapy approach for treating SCID-X1. Copyright © 2006 John Wiley & Sons, Ltd. [source] Crystallization and preliminary X-ray diffraction of human interleukin-7 bound to unglycosylated and glycosylated forms of its ,-receptorACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 10 2007Joseph Wickham Jr The interleukin-7 (IL-7) signaling pathway plays an essential role in the development, proliferation and homeostasis of T and B cells in cell-mediated immunity. Understimulation and overstimulation of the IL-7 signaling pathway leads to severe combined immunodeficiency, autoimmune reactions, heart disease and cancers. Stimulation of the IL-7 pathway begins with IL-7 binding to its ,-receptor, IL-7R,. Protein crystals of unglycosylated and glycosylated complexes of human IL-7,IL-7R, extracellular domain (ECD) obtained using a surface entropy-reduction approach diffract to 2.7 and 3.0,Å, respectively. Anomalous dispersion methods will be used to solve the unglycosylated IL-7,IL-7R, ECD complex structure and this unglycosylated structure will then serve as a model in molecular-replacement attempts to solve the structure of the glycosylated IL-7,,-receptor complex. [source] Pro-apoptotic therapy with the oligonucleotide GenasenseTM (oblimersen sodium) targeting Bcl-2 protein expression enhances the biological anti-tumour activity of rituximabBRITISH JOURNAL OF HAEMATOLOGY, Issue 5 2004Jeyanthi Ramanarayanan Summary New strategies have evolved in the treatment of patients with non-Hodgkin's lymphoma (NHL). Anti-sense oligonucleotides (ASO) and monoclonal antibody (mAb) therapy, though proven to be safe and effective, have not demonstrated to be curative when used as single agents. We tested an innovative combination strategy involving various mAbs and ASO against Bcl-2 (G3139) in aggressive preclinical models. G3139, under optimal transfection conditions, decreased the proliferation rate of lymphoma cells by 60,75% when compared with controls. In addition, apoptosis was demonstrated in Raji (25%) and DHL-4 cells (30%) treated with Genasense following downregulation of Bcl-2 protein. Downregulation of Bcl-2 by G3139 was associated with a higher degree of rituximab-associated, complement-mediated cytotoxicity and antibody dependent cellular cytotoxicity when compared with rituximab alone-treated controls. In vivo studies in severe combined immunodeficiency (SCID) mice clearly demonstrated synergistic activity between G3139 and rituximab. Treatment of lymphoma-bearing SCID mice with G3139 for two consecutive days prior to each rituximab dose resulted in better disease control and survival than treatment with either agent alone or controls. Our findings suggest that Bcl-2 downregulation by G3139, followed by the administration of rituximab is an efficient anti-tumour strategy associated with improved survival in lymphoma-bearing SCID mice. [source] Ras Farnesylation Inhibitor FTI-277 Restores the E-Cadherin/Catenin Cell Adhesion System in Human Cancer Cells and Reduces Cancer MetastasisCANCER SCIENCE, Issue 9 2002Jeong-Seok Nam The E-cadherin/catenin cell adhesion system is often down-regulated in epithelial tumors. This is thought to play an important role in cancer invasion and metastasis, and restoration of this system may suppress metastatic spread of cancer. In this study, the effects of a Ras farnesylation inhibitor (FTI-277) on E-cadherin-mediated cell-cell adhesion and metastatic potential were examined. In cell aggregation assays, FTI-277 stimulated aggregation of colon, liver and breast cancer cells. In vitro cultures of cancer cells showed that FIT-277 induced strong cell-cell contact. Immunoblotting analysis showed that FTI-277 increased E-cadherin/catenin (,, , and ,) expression and strongly stabilized E-cadherin/catenin with the actin cytoskeleton. Northern blotting studies indicated that the observed increase in the E-cadherin/catenin protein content was due to increased expression of their genes. After inoculation of the spleens of mice with severe combined immunodeficiency (SCID) with cancer cells, FTI-277 treatment for 3 weeks markedly reduced splenic primary tumor growth and the rate of liver metastasis compared with control counterparts. Our data demonstrate that FTI-277 can activate functioning of the E-cadherin-mediated cell adhesion system, which is associated with suppression of cancer cell metastasis. Therefore, selective inhibition of Ras activation may be useful for preventing cancer metastasis. [source] A New Quinoline Derivative MS-209 Reverses Multidrug Resistance and Inhibits Multiorgan Metastases by P-glycoprotein-expressing Human Small Cell Lung Cancer CellsCANCER SCIENCE, Issue 7 2001Hiroshi Nokihara Development of distant metastases and acquired multidrug resistance (MDR) are major problems in therapy for human small cell lung cancer (SCLC). MS-209 is a novel quinoline compound, which reverses P-glycoprotein (P-gp)-mediated MDR. We previously reported that MS-209 reversed in vitro MDR of human SCLC (SBC-3/ADM and H69/VP) cells expressing P-gp. In the present study, we determined the therapeutic effect of MS-209 in combination with chemotherapy against multiorgan metastases of MDR SCLC cells. SBC-3/ADM cells expressing P-gp were highly resistant to etoposide (VP-16), adriamycin (ADM), and vincristine (VCR) in vitro, compared with parental SBC-3 cells lacking P-gp expression. MS-209 restored chemosensitivity of SBC-3/ADM cells to VP-16, ADM, and VCR in a dose-dependent manner in vitro. Intravenous injection with SBC-3 or SBC-3/ADM cells produced metastatic colonies in the liver, kidneys and lymph nodes in natural killer (NK) cell-depleted severe combined immunodeficiency (SCID) mice, though SBC-3/ ADM cells more rapidly produced metastases than did SBC-3 cells. Treatment with VP-16 and ADM reduced metastasis formation by SBC-3 cells, whereas the same treatment did not affect metastasis by SBC-3/ADM cells. Although MS-209 alone had no effect on metastasis by SBC-3 or SBC-3/ADM cells, combined use of MS-209 with VP-16 or ADM resulted in marked inhibition of metastasis formation by SBC-3/ADM cells to multiple organs. These findings suggest that MS-209 reversed the MDR of SBC-3/ADM cells, but not SBC-3 cells, growing in the various organs, and inhibited metastasis formation in vivo. Therefore, this chemosensitizing agent, MS-209, may be useful for treatment of refractory SCLC patients with multiorgan metastases. [source] Recombinase-activating gene 1 immunodeficiency: different immunological phenotypes in three siblingsACTA PAEDIATRICA, Issue 6 2009Srdjan Pasic Abstract We report different immunological phenotypes in three siblings from consanguineous family with recombinase-activating gene 1 (RAG1) gene mutations. Null mutations of RAG genes result in severe combined immunodeficiency (SCID) with absent T and B cells. Hypomorphic mutations with retained activity of RAG genes may lead to a ,leaky' SCID with some features of Omenn syndrome (OS) or typical OS. In our three patients, homozygous, hypomorphic RAG1 gene mutation (g.368,369delAA) was detected. Two patients presented with T,B,SCID phenotype while the youngest patient developed T+B+NK+SCID phenotype with expansion of autologous T-cell receptor (TCR) ,,-positive T cells, increased immunoglobulin levels and retained ability for antibody production. Similar to originally reported patients with this newly recognized immune phenotype, our patient developed disseminated cytomegalovirus (CMV) infection and autoimmune cytopenia. Conclusion: In infants with disseminated cytomegalovirus infection and autoimmune cytopenia, even if basic immunologic investigation appears normal, RAG1 immunodeficiency should be considered. [source] Epstein-Barr virus-associated haemophagocytic lymphohistiocytosis in Wiskott-Aldrich syndromeACTA PAEDIATRICA, Issue 7 2003S Pasic A patient with Wiskott-Aldrich syndrome who developed Epstein-Barr virus-associated haemophagocytic lymphohistiocytosis (EBV-HLH) is described in this study. At 4 mo of age the patient developed fever associated with bicytopenia and splenomegaly. Analysis of a bone marrow specimen revealed extensive haemophagocytosis, and in situ hybridization for EBV of the bone marrow specimen using an EBV-encoded RNA probe was positive. Diagnosis of EBV-HLH was established and immunotherapy with HLH-94 protocol was started. HLH has been described in patients with other well-defined primary immunodeficiencies such as X-linked lymphoproliferative syndrome, Chediak-Higashi syndrome and Griscelli disease. Also, HLH was reported recently in severe combined immunodeficiency and DiGeorge syndrome. Conclusion: The possibility of an underlying primary immunodeficiency should be considered in paediatric patients who present with HLH during infancy. [source] | |||||||||||||||||||||||||||||||