RESUMO
BACKGROUND: Significance of monitoring adalimumab trough levels and anti-adalimumab antibodies (AAA) for disease outcome in Crohn's disease (CD) patients remained unclear. AIM: To evaluate the association of adalimumab trough levels and AAA at week 26 with clinical remission at week 52, the effect of azathiopurine on AAA and factors influencing trough levels in CD patients in the DIAMOND trial. METHODS: We performed this study using adalimumab trough levels, AAA at week 26 and 6-thioguanine nucleotide (TGN) in red blood cells at week 12. A multiple regression model and receiver operating analysis was performed to identify factors influencing adalimumab trough levels and AAA, and adalimumab thresholds for predicting disease activity. RESULTS: There was a significant difference of adalimumab trough level at week 26 between patients with disease remission and without at week 52 (7.7 ± 3.3 µg/mL vs 5.4 ± 4.3 µg/mL: P <.001). Adalimumab trough level of 5.0 µg/mL yielded optimal sensitivity and specificity for remission prediction (80.2% and 55.6%, respectively). AAA development at week 26 significantly affected remission at week 52 (P = .021), which was strongly associated with adalimumab trough levels. Female gender and increasing body weight were independently associated with low adalimumab trough levels, and female gender was associated with AAA development. A cut-off 6TGN level of >222.5 p mol/8 ×108 RBCs yielded sensitivity (100%) and specificity (60.6%) for AAA negativity. CONCLUSION: Adalimumab trough levels and AAA occurrence were significantly associated with clinical remission. Higher 6TGN affected AAA negativity. The combination therapy is beneficial in some relevant aspects for CD patients. (UMIN Registration No. 000005146).
Assuntos
Adalimumab/sangue , Anti-Inflamatórios/sangue , Anticorpos/sangue , Doença de Crohn/sangue , Adalimumab/imunologia , Adalimumab/farmacocinética , Adalimumab/uso terapêutico , Anti-Inflamatórios/imunologia , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/uso terapêutico , Doença de Crohn/tratamento farmacológico , Doença de Crohn/imunologia , Quimioterapia Combinada , Feminino , Nucleotídeos de Guanina/sangue , Humanos , Masculino , Mercaptopurina/análogos & derivados , Mercaptopurina/uso terapêutico , Sensibilidade e Especificidade , Tionucleotídeos/sangue , Resultado do TratamentoRESUMO
BACKGROUND: Most array analyses of ulcerative colitis have focused on identifying susceptibility genes for ulcerative colitis. AIM: To clarify the changes in gene expression during inflammation in ulcerative colitis colon mucosa using cDNA macroarray. METHODS: From 23 ulcerative colitis patients, 16 each of inflamed and non-inflamed specimens (total 32 samples for individual analysis) were obtained by colonoscopic biopsy. Eighteen of the 32 samples, used for pairwise analysis, consisted of nine sample pairs, each pair being from the same patient. We examined expression profiles of approximately 1300 genes with cDNA macroarray. Comparisons were made using two kinds of statistics, t-test and significance analysis of microarray in both analyses. The reproducibility of significant genes from the macroarray analysis was confirmed by real-time ploymerase chain reaction. RESULTS: We detected five upregulated genes, categorized into proinflammatory genes (MRP14, GRO gamma and SAA1) and anti-inflammatory genes (TIMP1 and Elafin) in inflamed mucosa, and one upregulated gene (L-FABP) in non-inflamed mucosa. CONCLUSIONS: As the cDNA macroarray analysis in this study exactly reflects the total profile of gene expression in the clinical setting of ulcerative colitis, the genes identified will be directly applicable to diagnostics or as novel therapeutic targets in active ulcerative colitis.
Assuntos
Colite Ulcerativa/genética , DNA Complementar/análise , Genes/genética , Acrossomo , Adulto , Antígenos/genética , Calgranulina B/genética , Proteínas de Transporte/genética , Quimiocina CXCL1 , Quimiocinas CXC/genética , DNA Complementar/genética , Proteínas de Ligação a Ácido Graxo , Humanos , Inflamação/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Isoantígenos , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Secretadas Inibidoras de Proteinases , Proteínas/genética , RNA/análise , RNA/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Proteínas de Plasma Seminal , Inibidor Tecidual de Metaloproteinase-1/genética , Regulação para Cima/genéticaRESUMO
Ulcerative colitis (UC) is an inflammatory bowel disease of undetermined etiology. Mucins, mainly produced by goblet cells, protect colon cells from various kinds of stress. Alteration in the quality or quantity of mucins may be the cause of the disease. Another possible cause is immune reactions to colonic cells. Anti-MUC1 antibodies were detected in the sera of patients with UC. Antibodies would destroy the colonic cells through antibody-dependent cell-mediated cytotoxicity. We reviewed the significance of mucins as well as humoral and cellular immunity in the pathogenesis of UC.
Assuntos
Colite Ulcerativa/imunologia , Mucinas/imunologia , Anticorpos/análise , Formação de Anticorpos , Colite Ulcerativa/fisiopatologia , Humanos , Imunidade Celular , Mucosa Intestinal/imunologiaRESUMO
BACKGROUND: MUC1 is aberrantly expressed on a variety of epithelial tumors. We have reported that MUC1 plays important roles in separation from primary site, invasion into the stromal tissue, and protection from immune responses. The aim of this study is to determine the precise binding of MUC1 to intercellular adhesion molecule 1 (ICAM-1) that accelerates the cancer metastasis. METHODS: A cell aggregation assay between MUC1 cDNA transfectants and ICAM-1 expressing cells was employed. An anti-MUC1 antibody, anti-ICAM-1 antibody or synthetic peptide of MUC1 core protein was added to the assay to inhibit the cell aggregation. RESULTS: MUC1 transfectants showed a significantly higher aggregation rate compared to the control cells. This aggregation was further enhanced by the inhibition of O-glycan biosynthesis. It was inhibited by either an anti-MUC1 antibody recognizing the tandem repeat domain of MUC1 core protein or an anti-ICAM-1 antibody identifying domain 1. It was also inhibited by a synthetic MUC1 peptide of 40 amino acids corresponding to two tandem repeats. CONCLUSIONS: The results revealed that a tandem repeat domain of MUC1 mucin core protein binds to domain 1 of ICAM-1, suggesting a potential role of MUC1- ICAM-1 interaction in the metastasis of epithelial tumors.
Assuntos
Carcinoma/imunologia , Agregação Celular/imunologia , Neoplasias Colorretais/imunologia , Molécula 1 de Adesão Intercelular/imunologia , Mucina-1/imunologia , Metástase Neoplásica/imunologia , Animais , Anticorpos/imunologia , Linfócitos B/imunologia , Sítios de Ligação , Carcinoma/fisiopatologia , Neoplasias Colorretais/fisiopatologia , Fibroblastos/imunologia , Humanos , Molécula 1 de Adesão Intercelular/farmacologia , Mucina-1/farmacologia , Sequências de Repetição em Tandem , Transfecção , Células Tumorais CultivadasRESUMO
A 44-year-old woman noticed edema of the lower limbs in May 1999 and visited our hospital in September 1999 to undergo further examination. On admission, severe hypoalbuminemia (1.9 g/dl) was detected with a negative urinary protein level. Protein leakage into the gastrointestinal tract and deposition of immune complex in the colonic mucosa were shown by the fluorescent antibody method. In addition, anti-centromere antibody, sclerodactyly, and findings indicative of histological sclerotic changes on a skin biopsy were observed. These findings supported a diagnosis of protein-losing gastroenteropathy complicated by scleroderma. Administration of oral corticosteroids was begun one month after admission and the patient experienced diminished visual acuity immediately after steroid pulse therapy in November. Central serous chorioretinopathy (CSC) was diagnosed at the Department of Ophthalmology of our hospital, and the administration of corticosteroids was suspected as a possible cause of CSC. Considering the severity of hypoproteinemia, the corticosteroid treatment was continued despite corticosteroids being strogly suspected as the primary cause of CSC. A complete disappearance of CSC was achieved in 30 days after the onset of symptoms despite continuation of the steroid therapy, and her serum albumin and complement levels both normalized. We concluded that damage to the retinal pigment epithelium secondary to the vascular lesion at the choroidal level plays a causative role in CSC. In the present case, the findings suggested that the deposition of immune complex in choroidal tissues as well as the gastrointestinal tract caused hyperpermeability of choroidal vessels and led to the development of CSC.
Assuntos
Coriorretinite/etiologia , Enteropatias Perdedoras de Proteínas/complicações , Escleroderma Sistêmico/complicações , Adulto , Feminino , Humanos , Metilprednisolona/administração & dosagem , Metilprednisolona/efeitos adversos , Prednisolona/administração & dosagem , Prednisolona/efeitos adversos , Enteropatias Perdedoras de Proteínas/tratamento farmacológico , Pulsoterapia , Escleroderma Sistêmico/tratamento farmacológico , Resultado do TratamentoRESUMO
Barrett's esophagus (BE) is an acquired disorder associated with a high incidence of adenocarcinoma of the lower esophagus. Moreover, it has been reported that short-segment BE may be associated with adenocarcinoma of the esophagogastric junction. The objective of this study was to define the prevalence of BE and the mucin profile in BE, including the short-segment type, and to compare the mucin profile in BE with the profiles of Barrett's adenocarcinoma and distal esophageal adenocarcinoma among Japanese. In total, 650 adult subjects underwent endoscopic examination for evaluation of BE. Although the prevalence of traditional (long segment) BE was 0.62%, the overall prevalence of BE including short-segment type was 15.7%. In Barrett's epithelium, the short-segment type predominantly had gastric type mucin, while the middle- and long-segment types possessed intestinal mucin, especially colonic type mucin (sulfo-Lewis(a)), with high frequency. In Barrett's epithelium with adenocarcinoma, all Barrett's epithelium adjacent to carcinomas showed a predominance of immunoreactivity to sulfo-Lewis(a). In Barrett's adenocarcinomas, colonic type mucin was detected in 100% by monoclonal antibody (MoAb) 91.9H. Small-intestinal mucin and gastric mucin were stained in 50% and 12.5% of the subjects, respectively. Colonic type mucin was also detected with high frequency (80%) in distal esophageal adenocarcinomas without Barrett's epithelium. These data suggest that the epitope, not of small-intestinal type or gastric type mucin, but of colonic type mucin (sulfo-Lewis(a)), may be associated with, at least in part, the malignant phenotype of BE.
Assuntos
Adenocarcinoma/metabolismo , Esôfago de Barrett/metabolismo , Neoplasias Esofágicas/metabolismo , Mucinas/metabolismo , Adenocarcinoma/patologia , Adulto , Idoso , Anticorpos Monoclonais , Esôfago de Barrett/epidemiologia , Esôfago de Barrett/patologia , Neoplasias Esofágicas/patologia , Feminino , Humanos , Imuno-Histoquímica , Japão/epidemiologia , Antígenos do Grupo Sanguíneo de Lewis , Masculino , Pessoa de Meia-Idade , Mucinas/imunologia , Oligossacarídeos/metabolismo , Fenótipo , PrevalênciaRESUMO
CD45-AP associates specifically with CD45, a protein-tyrosine phosphatase essential for antigen receptor-mediated signal transduction. CD45 modulates the activity of Src family protein-tyrosine kinases involved at the onset of antigen receptor-mediated signaling by dephosphorylating their regulatory tyrosyl residues. We have shown that lymphocyte responses to antigen receptor stimulation are impaired in CD45-AP-null mice. To examine the possibility that CD45-AP coordinates the interaction between CD45 and its substrates, we investigated the associations of CD45-AP with several protein-tyrosine kinases. Endogenous CD45-AP coimmunoprecipitated with Lck and ZAP-70 in both CD45-positive T cells and their CD45-negative variants after stimulation by antigen receptor ligation. Concomitantly, CD45 coimmunoprecipitated with Lck and ZAP-70 after T cell receptor-mediated stimulation of CD45-positive cells. Recombinant CD45-AP exhibited specific binding to Lck and ZAP-70 protein-tyrosine kinases, but not to Fyn or Csk, in lysates of both CD45-positive and -negative T cells. Specific interactions were demonstrated between the respective recombinant proteins as well. These results demonstrate that CD45-AP associates directly and selectively with Lck and ZAP-70 in response to T cell receptor-mediated stimulation. The associations of CD45-AP with Lck and ZAP-70 may mediate the functional interactions of these kinases with CD45 during antigen receptor stimulation.
Assuntos
Antígenos Comuns de Leucócito/metabolismo , Proteínas de Membrana , Fosfoproteínas/metabolismo , Proteínas Tirosina Quinases/metabolismo , Receptores de Antígenos de Linfócitos T/fisiologia , Transdução de Sinais/fisiologia , Animais , Western Blotting , Linhagem Celular , Peptídeos e Proteínas de Sinalização Intracelular , Antígenos Comuns de Leucócito/imunologia , Camundongos , Proteínas Recombinantes/metabolismo , Proteína-Tirosina Quinase ZAP-70RESUMO
CD45-AP specifically associates with CD45, a protein tyrosine phosphatase essential for lymphocyte differentiation and antigen receptor-mediated signal transduction. CD45 is thought to mediate antigen receptor signaling by dephosphorylating regulatory tyrosine residues on Src family protein tyrosine kinases such as Lck. However, the mechanism for regulating CD45 protein tyrosine phosphatase activity remains unclear. CD45-AP-null mice were created to examine the role of CD45-AP in CD45-mediated signal transduction. T and B lymphocytes showed reduced proliferation in response to antigen receptor stimulation. Both mixed leukocyte reaction and cytotoxic T lymphocyte functions of T cells were also markedly decreased in CD45-AP-null mice. Interestingly, the interaction between CD45 and Lck was significantly reduced in CD45-AP-null T cells, indicating that CD45-AP directly or indirectly mediates the interaction of CD45 with Lck. Our data indicate that CD45-AP is required for normal antigen receptor signaling and function in lymphocytes.
Assuntos
Antígenos Comuns de Leucócito/metabolismo , Proteínas de Membrana , Fosfoproteínas/fisiologia , Proteínas Tirosina Fosfatases/metabolismo , Transdução de Sinais , Animais , Linfócitos B , Divisão Celular , Peptídeos e Proteínas de Sinalização Intracelular , Antígenos Comuns de Leucócito/biossíntese , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Fosfoproteínas/genética , Proteínas Tirosina Fosfatases/biossíntese , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Linfócitos TRESUMO
CD45-AP is a recently identified CD45-associated protein. The two proteins interact specifically through their respective transmembrane segments. Northern hybridization analysis of CD45+ T lymphocytes and their CD45- variants demonstrated that the production of CD45-AP and CD45 mRNA is regulated independently. On the other hand, Western blotting analysis indicated that the CD45-AP protein has a shorter half-life in the absence of CD45 in three out of four variants. Similar analysis of various types of leukocytes demonstrated that CD45-AP is expressed in T, B, and pre-B cells, but not in plasma cells or cells of the monocyte/macrophage lineage. Two forms of CD45-AP mRNA exist in all types of CD45-AP-expressing lymphocytes analyzed. One form corresponds to the previously reported CD45-AP cDNA and the other form encodes an additional 12 amino acids at the N terminus. The two CD45-AP proteins are identical in their capacity for specific binding to CD45, but employ different mechanisms for endoplasmic reticulum membrane translocation.
Assuntos
Proteínas de Membrana/análise , Proteínas de Membrana/biossíntese , Fosfoproteínas/análise , Fosfoproteínas/biossíntese , Linfócitos T/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Linhagem Celular , Clonagem Molecular , Biblioteca Gênica , Peptídeos e Proteínas de Sinalização Intracelular , Antígenos Comuns de Leucócito/análise , Antígenos Comuns de Leucócito/biossíntese , Antígenos Comuns de Leucócito/metabolismo , Leucócitos Mononucleares/metabolismo , Camundongos , Dados de Sequência Molecular , Fosfoproteínas/metabolismo , Ligação Proteica/imunologia , Biossíntese de Proteínas/imunologia , RNA Mensageiro/biossíntese , Transcrição Gênica/imunologiaRESUMO
It is known that the expression levels of intercellular adhesion molecule-1 (ICAM-1) in adult T cell leukemia(ATL) cells are high, whereas those in T-lymphoid cells are not. In order to investigate the factors that influence the induction of ICAM-1 molecules, Northern blot analysis to measure the expression level of ICAM-1 mRNAs and Southern blot hybridization to analyze the integration of human T-cell-leukemia virus type 1 (HTLV-1) provirus were done. The levels of ICAM-1 mRNA expression of ATL cells were generally higher than those of T-lymphoid cells. However, ILT-mat cells and ATL16T(-) cells, although they were ATL cells, showed rather low surface ICAM-1 expression and ICAM-1 mRNA expression. Southern blot hybridization showed that only two and four bands were found in ILT-mat and ATL16T(-) cells, respectively, whereas > 10 bands were detected in other ATL cells. These results suggest that monoclonal integration of HTLV-1 provirus to the genome of T cell, especially the number of integration sites, is one of the factors for induction of ICAM-1 molecules.
Assuntos
Vírus Linfotrópico T Tipo 1 Humano/isolamento & purificação , Molécula 1 de Adesão Intercelular/metabolismo , Leucemia-Linfoma de Células T do Adulto/imunologia , Leucemia-Linfoma de Células T do Adulto/virologia , Adulto , Sequência de Bases , Linhagem Celular , Primers do DNA/genética , Feminino , Vírus Linfotrópico T Tipo 1 Humano/genética , Humanos , Molécula 1 de Adesão Intercelular/genética , Leucemia-Linfoma de Células T do Adulto/patologia , Pessoa de Meia-Idade , NF-kappa B/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Pele/imunologia , Pele/patologia , Pele/virologia , Linfócitos T/imunologia , Células Tumorais Cultivadas , Integração Viral/genéticaRESUMO
This paper reports a rare case of the limited form of Wegener's granulomatosis (WG) with pulmonary giant bulla, which was pathologically identified only in the lung and showed a high level of soluble intercellular adhesion molecule-1 (ICAM-1) but not anti-neutrophil cytoplasmic antibody (ANCA). A 46 year-old male was admitted for the further examination of right anterior chest pain and dyspnea. Chest X-ray and CT examination showed giant bulla accompanied with the invasive lesions in upper lobe of right lung. Partial lobectomy was done. Granulomatous and necrotizing vasculitis characteristics of WG were confirmed by the histopathology of resected tissues. Immunological analysis on admission showed a high level of soluble ICAM-1 and ANCA negative, but that of soluble ICAM-1 was reduced after surgical operation and remained within normal range during an administration of prednisolone and cyclophosphamide. These results suggest that soluble ICAM-1 may be one of the useful parameters for a diagnosis of WG and for an estimation of its treatments, especially in the cases of ANCA negative WG.
Assuntos
Autoanticorpos/sangue , Granulomatose com Poliangiite/imunologia , Molécula 1 de Adesão Intercelular/sangue , Enfisema Pulmonar/complicações , Anticorpos Anticitoplasma de Neutrófilos , Granulomatose com Poliangiite/complicações , Humanos , Masculino , Pessoa de Meia-Idade , SolubilidadeRESUMO
We have treated a case of chronic fatigue syndrome with atopic diathesis was had suffered general malaise, low grade fever, swelling of the lymph nodes, myalgias and arthralgias for a long time. A 29-year-old female, who had been treated for atopic dermatitis for 5 years, complained of general malaise in May 1990. She was admitted to the nearest hospital in December 1990 because of low grade fever, swelling of the lymph nodes and an elevation of antinuclear antibody (2520x). She was transferred to our hospital in May 1991. A diagnosis of collagen disease was not compatible with her condition. In addition to general malaise, fever and lymph node swelling, headache, myalgias, muscle weakness, arthralgias and insomnia were observed, and a diagnosis of chronic fatigue syndrome was made based on the working case definition proposed by Holmes et al. Although eosinophilia, a high serum level of IgE, and elevation of RAST scores, low NK and ADCC activity, and a reduced level of NK cells in the peripheral blood were detected, serum antibodies to a number of viruses were in the normal range. Treatments with non-steroid anti-inflammatory drugs, minor tranquilizers and antidepressant drugs were not effective at all. An administration of magnesium sulphate was intravenously performed once a week in order to improve her condition, especially severe general malaise. After about 6-week's administration of magnesium sulphate, she noticed reduced easy fatigability and an improvement in her impaired daily activities. Finally she was able to leave the hospital in January 1992.(ABSTRACT TRUNCATED AT 250 WORDS)