Pub Date : 2002-02-01DOI: 10.1046/j.1365-2249.2002.01754.x
S. Lytton, U. Berg, A. Németh, M. Ingelman-Sundberg
Treatment with the immunosuppressive drugs cyclosporin and tacrolimus, the mainstays of anti‐graft rejection and autoimmune disease therapy, is limited by their hepato‐ and nephrotoxicity. The metabolic conversion of these compounds to more easily excretable products is catalysed mainly by hepatic cytochrome P4503A4 (CYP3A4) but also involves extrahepatic CYP3A5 and other P450 forms. We set out to study whether or not exposure to cyclosporin and FK506 in children undergoing organ transplantation leads to formation of autoantibodies against P450s. Immunoblotting analysis revealed anti‐CYP reactivity in 16% of children on CyA for anti‐graft rejection or treatment of nephrosis (n = 67), 31% of kidney transplant patients switched from CyA to FK506 (n = 16), and 21% of kidney and or liver transplant patients on FK506 (n = 14). In contrast, the frequency of reactive immunoblots was only 8·5% among the normal paediatric controls (n = 25) and 7% among adult kidney transplant patients on CyA or FK506 (n = 30). The CYP2C9+ sera were able to immunoprecipitate in vitro translated CYP2C9 and the immunoblot reactivity showed striking correlation to peaks in the age at onset of drug exposure. Sera were isoform selective as evidenced from Western blotting using human liver microsomes and heterologously expressed human P450s. These findings suggest that anti‐cytochrome P450 autoantibodies, identified on the basis of their specific binding in immunoblots, are significantly increased among children on immunosuppressive drugs and in some cases are associated with drug toxicity and organ rejection.
{"title":"Autoantibodies against cytochrome P450s in sera of children treated with immunosuppressive drugs","authors":"S. Lytton, U. Berg, A. Németh, M. Ingelman-Sundberg","doi":"10.1046/j.1365-2249.2002.01754.x","DOIUrl":"https://doi.org/10.1046/j.1365-2249.2002.01754.x","url":null,"abstract":"Treatment with the immunosuppressive drugs cyclosporin and tacrolimus, the mainstays of anti‐graft rejection and autoimmune disease therapy, is limited by their hepato‐ and nephrotoxicity. The metabolic conversion of these compounds to more easily excretable products is catalysed mainly by hepatic cytochrome P4503A4 (CYP3A4) but also involves extrahepatic CYP3A5 and other P450 forms. We set out to study whether or not exposure to cyclosporin and FK506 in children undergoing organ transplantation leads to formation of autoantibodies against P450s. Immunoblotting analysis revealed anti‐CYP reactivity in 16% of children on CyA for anti‐graft rejection or treatment of nephrosis (n = 67), 31% of kidney transplant patients switched from CyA to FK506 (n = 16), and 21% of kidney and or liver transplant patients on FK506 (n = 14). In contrast, the frequency of reactive immunoblots was only 8·5% among the normal paediatric controls (n = 25) and 7% among adult kidney transplant patients on CyA or FK506 (n = 30). The CYP2C9+ sera were able to immunoprecipitate in vitro translated CYP2C9 and the immunoblot reactivity showed striking correlation to peaks in the age at onset of drug exposure. Sera were isoform selective as evidenced from Western blotting using human liver microsomes and heterologously expressed human P450s. These findings suggest that anti‐cytochrome P450 autoantibodies, identified on the basis of their specific binding in immunoblots, are significantly increased among children on immunosuppressive drugs and in some cases are associated with drug toxicity and organ rejection.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"26 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2002-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84773475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-02-01DOI: 10.1046/j.1365-2249.2002.01765.x
M. Faas, H. Moes, J. Fijen, A. Kobold, J. Tulleken, J. Zijlstra
In the present study, we investigated the effect of RWJ‐67657, a p38 MAP kinase inhibitor, upon in vivo LPS‐induced monocyte cytokine production and upon monocyte LPS‐hyporesponsiveness. Thirty minutes before a single injection of LPS (4 ng/kg BW), healthy male volunteers received a single oral dose of RWJ‐67657 at increasing dosages (0–1400 mg). Blood samples (pre‐medication, 3, 6 and 24 h after LPS) were immediately incubated with LPS (reflecting LPS‐hyporesponsiveness) or without LPS (reflecting in vivo monocyte stimulation) for 4 h at 37°C. Following red blood cells lysis and white blood cell permeabilization, cells were labelled with α‐CD14‐FITC and α‐IL‐1β, α‐IL‐12 or α‐TNFα (PE‐labelled), fixed, and analysed using flow cytometry. In vivo LPS injection resulted in an increased percentage of circulating monocytes producing IL‐1β, TNFα and IL‐12 only at 3 h after the LPS injection. This was dose‐dependently inhibited by RWJ‐67657 treatment. LPS‐hyporesponsiveness to in vitro LPS treatment was most prominent at 3 and 6 h after the in vivo LPS injection; compared with pre‐medication monocytes, at these intervals a reduced percentage of monocytes produced IL‐1β, TNFα or IL‐12 after the in vitro LPS stimulus. At t = 6 h, this LPS‐hyporesponsiveness could dose‐dependently be inhibited by RWJ‐67657 treatment of the volunteers. We therefore conclude that p38 MAP kinase inhibition with RWJ‐67657 inhibited monocyte production of cytokines following in vivo LPS injection. Treatment with RWJ‐67657 also reversed the LPS‐hyporesponsiveness. Whether this result can be extended to the clinical situation remains to be elucidated. Patients with sepsis or an otherwise high risk for multi‐organ failure are potential study groups.
{"title":"Monocyte intracellular cytokine production during human endotoxaemia with or without a second in vitro LPS challenge: effect of RWJ‐67657, a p38 MAP‐kinase inhibitor, on LPS‐hyporesponsiveness","authors":"M. Faas, H. Moes, J. Fijen, A. Kobold, J. Tulleken, J. Zijlstra","doi":"10.1046/j.1365-2249.2002.01765.x","DOIUrl":"https://doi.org/10.1046/j.1365-2249.2002.01765.x","url":null,"abstract":"In the present study, we investigated the effect of RWJ‐67657, a p38 MAP kinase inhibitor, upon in vivo LPS‐induced monocyte cytokine production and upon monocyte LPS‐hyporesponsiveness. Thirty minutes before a single injection of LPS (4 ng/kg BW), healthy male volunteers received a single oral dose of RWJ‐67657 at increasing dosages (0–1400 mg). Blood samples (pre‐medication, 3, 6 and 24 h after LPS) were immediately incubated with LPS (reflecting LPS‐hyporesponsiveness) or without LPS (reflecting in vivo monocyte stimulation) for 4 h at 37°C. Following red blood cells lysis and white blood cell permeabilization, cells were labelled with α‐CD14‐FITC and α‐IL‐1β, α‐IL‐12 or α‐TNFα (PE‐labelled), fixed, and analysed using flow cytometry. In vivo LPS injection resulted in an increased percentage of circulating monocytes producing IL‐1β, TNFα and IL‐12 only at 3 h after the LPS injection. This was dose‐dependently inhibited by RWJ‐67657 treatment. LPS‐hyporesponsiveness to in vitro LPS treatment was most prominent at 3 and 6 h after the in vivo LPS injection; compared with pre‐medication monocytes, at these intervals a reduced percentage of monocytes produced IL‐1β, TNFα or IL‐12 after the in vitro LPS stimulus. At t = 6 h, this LPS‐hyporesponsiveness could dose‐dependently be inhibited by RWJ‐67657 treatment of the volunteers. We therefore conclude that p38 MAP kinase inhibition with RWJ‐67657 inhibited monocyte production of cytokines following in vivo LPS injection. Treatment with RWJ‐67657 also reversed the LPS‐hyporesponsiveness. Whether this result can be extended to the clinical situation remains to be elucidated. Patients with sepsis or an otherwise high risk for multi‐organ failure are potential study groups.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2002-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84000351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-02-01DOI: 10.1046/j.1365-2249.2002.01745.x
S. Lifshitz, R. Dagan, M. Shani-Sekler, N. Grossman, G. Fleminger, M. Friger, Y. M. Nebenzahl
Vulnerability to Streptococcus pneumoniae is most pronounced in children. The microbial virulence factors and the features of the host immune response contributing to this phenomenon are not completely understood. In the current study, the humoral immune response to separated Strep. pneumoniae surface proteins and the ability to interfere with Strep. pneumoniae adhesion to cultured epithelial cells were analysed in adults and in children. Sera collected from healthy adults recognized Strep. pneumoniae separated lectin and nonlectin surface proteins in Western blot analysis and inhibited on average 80% of Strep. pneumoniae adhesion to epithelial cells in a concentration‐dependent manner. However, sera longitudinally collected from healthy children attending day care centres from 18 months of age and over the course of the following 2 years revealed: (a) development of antibodies to previously unrecognized Strep. pneumoniae surface proteins with age; (b) a quantitative increase in antibody responses, measured by densitometry, towards separated Strep. pneumoniae surface proteins with age; and (c) inhibition of Strep. pneumoniae adhesion to epithelial cells, which was 50% on average at 18 months of age, increased significantly to an average level of 80% inhibition at 42 months of age equalling adult sera inhibitory values. The results obtained in the current study, from the longitudinally collected sera from healthy children with documented repeated Strep. pneumoniae colonization, show that repeated exposures are insufficient to elicit an immune response to Strep. pneumoniae proteins at 18 months of age. This inability to recognize Strep. pneumoniae surface proteins may stem from the inefficiency of T‐cell‐dependent B‐cell responses at this age and/or from the low immunogenicity of the proteins.
{"title":"Age‐dependent preference in human antibody responses to Streptococcus pneumoniae polypeptide antigens","authors":"S. Lifshitz, R. Dagan, M. Shani-Sekler, N. Grossman, G. Fleminger, M. Friger, Y. M. Nebenzahl","doi":"10.1046/j.1365-2249.2002.01745.x","DOIUrl":"https://doi.org/10.1046/j.1365-2249.2002.01745.x","url":null,"abstract":"Vulnerability to Streptococcus pneumoniae is most pronounced in children. The microbial virulence factors and the features of the host immune response contributing to this phenomenon are not completely understood. In the current study, the humoral immune response to separated Strep. pneumoniae surface proteins and the ability to interfere with Strep. pneumoniae adhesion to cultured epithelial cells were analysed in adults and in children. Sera collected from healthy adults recognized Strep. pneumoniae separated lectin and nonlectin surface proteins in Western blot analysis and inhibited on average 80% of Strep. pneumoniae adhesion to epithelial cells in a concentration‐dependent manner. However, sera longitudinally collected from healthy children attending day care centres from 18 months of age and over the course of the following 2 years revealed: (a) development of antibodies to previously unrecognized Strep. pneumoniae surface proteins with age; (b) a quantitative increase in antibody responses, measured by densitometry, towards separated Strep. pneumoniae surface proteins with age; and (c) inhibition of Strep. pneumoniae adhesion to epithelial cells, which was 50% on average at 18 months of age, increased significantly to an average level of 80% inhibition at 42 months of age equalling adult sera inhibitory values. The results obtained in the current study, from the longitudinally collected sera from healthy children with documented repeated Strep. pneumoniae colonization, show that repeated exposures are insufficient to elicit an immune response to Strep. pneumoniae proteins at 18 months of age. This inability to recognize Strep. pneumoniae surface proteins may stem from the inefficiency of T‐cell‐dependent B‐cell responses at this age and/or from the low immunogenicity of the proteins.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"132 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2002-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82342812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-02-01DOI: 10.1046/j.1365-2249.2002.01726.x
I. Wakelkamp, M. Gerding, J. V. D. Meer, M. Prummel, W. Wiersinga
Adhesion molecules play a key role in autoimmune disorders, and serum concentrations of soluble adhesion molecules are increased in Graves’ ophthalmopathy (GO). Whether this is due to the strong association with smoking is unknown. It is also not known if the severity or activity of GO determine the serum levels of adhesion molecules. We measured serum concentrations of sICAM‐1, sVCAM‐1 and sELAM‐1 in 62 euthyroid Graves’ patients with untreated GO, in 62 healthy controls matched for sex, age and smoking habits, and in 26 euthyroid Graves’ patients without GO. GO severity was assessed by the Total Eye Score and the activity by the Clinical Activity Score. Adhesion molecules were measured by highly sensitive ELISAs. GO patients had higher levels than controls (median values in ng/ml with range): sICAM‐1 300 [171–575] versus 244 [119–674], P < 0·001; sVCAM‐1 457 [317–1060] versus 410 [238–562], P < 0·001; and sELAM‐1 61 [19–174] versus 53 [23–118], P = 0·021. Euthyroid Graves’ disease patients without GO had levels similar to controls: sICAM‐1 273 138–453), sVCAM‐1 386 [260–1041] and sELAM‐1 46 [22–118]. Smoking had an independent effect and was associated with higher levels of sICAM‐1 and lower levels of sVCAM‐1 in both GO patients and controls; sELAM‐1 levels were comparable. In the 62 GO patients, sICAM‐1 correlated significantly with severity of eye disease (r = 0·40, P = 0·002). No correlation was found with the duration of GO, the Clinical Activity Score or TBII levels. Multivariate analysis of all 150 subjects showed that the presence of GO and smoking are independent determinants of sICAM‐1 and sVCAM‐1 concentrations. In GO patients, the Total Eye Score was a stronger determinant than smoking. It is concluded that (i) smoking is associated with increased sICAM‐1 and decreased sVCAM‐1 levels; (ii) independent from smoking, euthyroid GO patients have higher levels of sICAM‐1, sVCAM‐1 and sELAM‐1 than patients with euthyroid Graves’ disease or healthy controls; (iii) the major determinant of sICAM‐1 in GO patients is the severity of their eye disease.
黏附分子在自身免疫性疾病中起关键作用，Graves眼病(GO)患者血清中可溶性黏附分子浓度升高。这是否与吸烟密切相关尚不清楚。氧化石墨烯的严重程度或活性是否决定黏附分子的血清水平也尚不清楚。我们测量了62例未治疗氧化石墨烯的甲状腺功能正常Graves患者、62例性别、年龄和吸烟习惯相匹配的健康对照以及26例未治疗氧化石墨烯的甲状腺功能正常Graves患者的血清中sICAM‐1、sVCAM‐1和sELAM‐1的浓度。GO的严重程度由总视力评分评估，活动度由临床活动评分评估。采用高灵敏度elisa检测粘附分子。GO患者的水平高于对照组(中位数为ng/ml，有范围):sICAM‐1 300 [171-575]vs . 244 [119-674]， P < 0.001;sVCAM‐1 457 [317-1060]vs . 410 [238-562]， P < 0.001;sELAM‐1 61[19-174]对53 [23-118]，P = 0.021。无氧化石墨烯的甲状腺功能亢进Graves病患者的水平与对照组相似:sICAM‐1 273(138-453)、sVCAM‐1 386(260-1041)和sELAM‐1 46(22-118)。吸烟具有独立的影响，并且在GO患者和对照组中与较高水平的sICAM‐1和较低水平的sVCAM‐1相关;sELAM‐1水平具有可比性。在62例GO患者中，sICAM‐1与眼病严重程度显著相关(r = 0.40, P = 0.002)。未发现与GO持续时间、临床活动评分或TBII水平相关。对所有150名受试者的多变量分析表明，氧化石墨烯和吸烟是sICAM‐1和sVCAM‐1浓度的独立决定因素。在GO患者中，总视力评分是比吸烟更强的决定因素。结论:(1)吸烟与sICAM‐1水平升高和sVCAM‐1水平降低有关;(ii)与吸烟无关，甲状腺功能正常的GO患者的sICAM‐1、sVCAM‐1和sELAM‐1水平高于甲状腺功能正常的Graves病患者或健康对照者;(iii) GO患者中sICAM‐1的主要决定因素是其眼病的严重程度。
{"title":"Smoking and disease severity are independent determinants of serum adhesion molecule levels in Graves’ ophthalmopathy","authors":"I. Wakelkamp, M. Gerding, J. V. D. Meer, M. Prummel, W. Wiersinga","doi":"10.1046/j.1365-2249.2002.01726.x","DOIUrl":"https://doi.org/10.1046/j.1365-2249.2002.01726.x","url":null,"abstract":"Adhesion molecules play a key role in autoimmune disorders, and serum concentrations of soluble adhesion molecules are increased in Graves’ ophthalmopathy (GO). Whether this is due to the strong association with smoking is unknown. It is also not known if the severity or activity of GO determine the serum levels of adhesion molecules. We measured serum concentrations of sICAM‐1, sVCAM‐1 and sELAM‐1 in 62 euthyroid Graves’ patients with untreated GO, in 62 healthy controls matched for sex, age and smoking habits, and in 26 euthyroid Graves’ patients without GO. GO severity was assessed by the Total Eye Score and the activity by the Clinical Activity Score. Adhesion molecules were measured by highly sensitive ELISAs. GO patients had higher levels than controls (median values in ng/ml with range): sICAM‐1 300 [171–575] versus 244 [119–674], P < 0·001; sVCAM‐1 457 [317–1060] versus 410 [238–562], P < 0·001; and sELAM‐1 61 [19–174] versus 53 [23–118], P = 0·021. Euthyroid Graves’ disease patients without GO had levels similar to controls: sICAM‐1 273 138–453), sVCAM‐1 386 [260–1041] and sELAM‐1 46 [22–118]. Smoking had an independent effect and was associated with higher levels of sICAM‐1 and lower levels of sVCAM‐1 in both GO patients and controls; sELAM‐1 levels were comparable. In the 62 GO patients, sICAM‐1 correlated significantly with severity of eye disease (r = 0·40, P = 0·002). No correlation was found with the duration of GO, the Clinical Activity Score or TBII levels. Multivariate analysis of all 150 subjects showed that the presence of GO and smoking are independent determinants of sICAM‐1 and sVCAM‐1 concentrations. In GO patients, the Total Eye Score was a stronger determinant than smoking. It is concluded that (i) smoking is associated with increased sICAM‐1 and decreased sVCAM‐1 levels; (ii) independent from smoking, euthyroid GO patients have higher levels of sICAM‐1, sVCAM‐1 and sELAM‐1 than patients with euthyroid Graves’ disease or healthy controls; (iii) the major determinant of sICAM‐1 in GO patients is the severity of their eye disease.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"142 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2002-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77428366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-02-01DOI: 10.1046/j.1365-2249.2002.01751.x
R. Schmits, B. Kubuschok, S. Schuster, K. Preuss, M. Pfreundschuh
The analysis of the antibody repertoire of patients with giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) might identify target antigens of the autoimmune response with potential relevance to our understanding of the pathogenesis of the disease and to the development of serodiagnostic tests. To detect such antigens, we screened a cDNA library derived from normal human testis for antigens reacting with IgG antibodies in the 1 : 250 diluted sera of three patients with untreated GCA using SEREX, the serological identification of antigens by recombinant cDNA expression cloning. Of 100 000 clones screened with each serum, six, 28 and six clones, respectively, were positive, representing a total of 33 different antigens. Most of the antigens reacted only with the serum used for identification and/or at a similar frequency with normal control sera. However, lamin C and the nuclear antigen of 14 kD reacted specifically with 32% of GCA/PMR, but with none of the control sera, while human cytokeratin 15, mitochondrial cytochrome oxidase subunit II, and a new gene product were detected preferentially, but not exclusively by sera from GCA/PMR patients. We conclude that patients with GCA/PMR develop antibodies against a broad spectrum of human autoantigens. Antibodies against human lamin C, the nuclear autoantigen of 14 kD as well as human cytokeratin 15, mitochondrial cytochrome oxidase subunit II and the product of a new gene should be investigated further to determine their value as tools for the diagnosis and/or the definition of clinical subgroups of patients with GCA/PMR.
{"title":"Analysis of the B cell repertoire against autoantigens in patients with giant cell arteritis and polymyalgia rheumatica","authors":"R. Schmits, B. Kubuschok, S. Schuster, K. Preuss, M. Pfreundschuh","doi":"10.1046/j.1365-2249.2002.01751.x","DOIUrl":"https://doi.org/10.1046/j.1365-2249.2002.01751.x","url":null,"abstract":"The analysis of the antibody repertoire of patients with giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) might identify target antigens of the autoimmune response with potential relevance to our understanding of the pathogenesis of the disease and to the development of serodiagnostic tests. To detect such antigens, we screened a cDNA library derived from normal human testis for antigens reacting with IgG antibodies in the 1 : 250 diluted sera of three patients with untreated GCA using SEREX, the serological identification of antigens by recombinant cDNA expression cloning. Of 100 000 clones screened with each serum, six, 28 and six clones, respectively, were positive, representing a total of 33 different antigens. Most of the antigens reacted only with the serum used for identification and/or at a similar frequency with normal control sera. However, lamin C and the nuclear antigen of 14 kD reacted specifically with 32% of GCA/PMR, but with none of the control sera, while human cytokeratin 15, mitochondrial cytochrome oxidase subunit II, and a new gene product were detected preferentially, but not exclusively by sera from GCA/PMR patients. We conclude that patients with GCA/PMR develop antibodies against a broad spectrum of human autoantigens. Antibodies against human lamin C, the nuclear autoantigen of 14 kD as well as human cytokeratin 15, mitochondrial cytochrome oxidase subunit II and the product of a new gene should be investigated further to determine their value as tools for the diagnosis and/or the definition of clinical subgroups of patients with GCA/PMR.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"41 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2002-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77935837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-02-01DOI: 10.1046/j.1365-2249.2002.01740.x
N. Katoh, S. Hirano, M. Suehiro, K. Ikenaga, H. Yasuno
Matrix metalloproteinases and their specific inhibitors, tissue inhibitors of metalloproteinases (TIMPs), contribute to inflammation‐induced tissue destruction and subsequent remodeling for maintenance of tissue homeostasis. Since the production of these enzymes and their inhibitors is regulated by mediators such as proinflammatory cytokines and growth factors, elevated levels of serum TIMPs and/or MMPs have been documented in patients with several inflammatory disorders. In this study, we examined the role of TIMPs and MMPs in the pathogenesis of atopic dermatitis (AD) by evaluating the serum levels of TIMP‐1 and MMP‐3 in 40 patients with AD and 20 control subjects by ELISA. The serum TIMP‐1 levels were significantly higher in AD patients in exacerbation status than in nonatopic subjects, whereas serum MMP‐3 levels were not significantly different between them. As a result, AD patients revealed significantly elevated TIMP‐1/MMP‐3 ratios. The levels of serum TIMP‐1 were significantly reduced in AD patients following conventional treatments. Significantly higher values of peripheral eosinophil counts, serum levels of IgE and lactate dehydrogenase, eruption score, and eruption area were noted in the AD patients with elevated TIMP‐1 levels when compared with those with normal values. Moreover, the points of chronic eruptions such as lichenification and prurigo were significantly higher in the patients with elevated TIMP‐1 levels than those with normal TIMP‐1, while those of acute lesions such as oozy/microvesicles and oedema were not different between these groups. Serum TIMP‐1 level may be a useful marker to estimate the long‐term disease activity of AD.
{"title":"Increased levels of serum tissue inhibitor of metalloproteinase‐1 but not metalloproteinase‐3 in atopic dermatitis","authors":"N. Katoh, S. Hirano, M. Suehiro, K. Ikenaga, H. Yasuno","doi":"10.1046/j.1365-2249.2002.01740.x","DOIUrl":"https://doi.org/10.1046/j.1365-2249.2002.01740.x","url":null,"abstract":"Matrix metalloproteinases and their specific inhibitors, tissue inhibitors of metalloproteinases (TIMPs), contribute to inflammation‐induced tissue destruction and subsequent remodeling for maintenance of tissue homeostasis. Since the production of these enzymes and their inhibitors is regulated by mediators such as proinflammatory cytokines and growth factors, elevated levels of serum TIMPs and/or MMPs have been documented in patients with several inflammatory disorders. In this study, we examined the role of TIMPs and MMPs in the pathogenesis of atopic dermatitis (AD) by evaluating the serum levels of TIMP‐1 and MMP‐3 in 40 patients with AD and 20 control subjects by ELISA. The serum TIMP‐1 levels were significantly higher in AD patients in exacerbation status than in nonatopic subjects, whereas serum MMP‐3 levels were not significantly different between them. As a result, AD patients revealed significantly elevated TIMP‐1/MMP‐3 ratios. The levels of serum TIMP‐1 were significantly reduced in AD patients following conventional treatments. Significantly higher values of peripheral eosinophil counts, serum levels of IgE and lactate dehydrogenase, eruption score, and eruption area were noted in the AD patients with elevated TIMP‐1 levels when compared with those with normal values. Moreover, the points of chronic eruptions such as lichenification and prurigo were significantly higher in the patients with elevated TIMP‐1 levels than those with normal TIMP‐1, while those of acute lesions such as oozy/microvesicles and oedema were not different between these groups. Serum TIMP‐1 level may be a useful marker to estimate the long‐term disease activity of AD.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"62 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2002-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74874267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-02-01DOI: 10.1046/j.1365-2249.2002.01716.x
J. A. Cabanillas, R. Cambronero, A. Pacheco-Castro, M. García-Rodríguez, J. M. Martín-Fernández, G. Fontán, J. R. Regueiro
Common variable immunodeficiency (CVID) is a very frequent but heterogeneous syndrome of antibody formation. The primary defect remains unknown, but many reports describe peripheral blood T lymphocyte dysfunctions in a substantial proportion of CVID patients, which may impair T–B cell collaboration. In order to investigate whether such putative defects were intrinsic to T cells or, rather, secondary to quantitative differences in T cell subset distribution, or to other described disorders, we have used Herpesvirus saimiri (HVS) for the targeted transformation of CVID CD4+ and CD8+ T cells and subsequent functional evaluation by flow cytometry of their capacity to generate cell surface (CD154, CD69) or soluble (IL‐2, TNF‐α, IFN‐γ) help after CD3 engagement. Unexpectedly, the results showed that 40 different CVID blood samples exposed to HVS gave rise with a significantly increased frequency to transformed CD4+ T cell lines, compared to 40 age‐matched controls (27%versus 3%, P≤ 0·00002) suggesting the existence of a CVID‐specific signalling difference which affects CD4+ cell transformation efficiency. The functional analysis of 10 CD4+ and 15 CD8+ pure transformed T cell lines from CVID patients did not reveal any statistically significant difference as compared to controls. However, half of the CD4+ transformed cell lines showed CD154 (but not CD69) induction (mean value of 46·8%) under the lower limit of the normal controls (mean value of 82·4%, P≤ 0·0001). Exactly the same five cell lines showed, in addition, a significantly low induction of IL‐2 (P≤ 0·04), but not of TNF‐α or IFN‐γ. None of these differences were observed in the remaining CD4+ cell lines or in any of the transformed CD8+ cell lines. We conclude that certain CVID patients show selective and intrinsic impairments for the generation of cell surface and soluble help by CD4+ T cells, which may be relevant for B lymphocyte function. The transformed T cell lines will be useful to establish the biochemical mechanisms responsible for the described impairments.
{"title":"Characterization of Herpesvirus saimiri‐transformed T lymphocytes from common variable immunodeficiency patients","authors":"J. A. Cabanillas, R. Cambronero, A. Pacheco-Castro, M. García-Rodríguez, J. M. Martín-Fernández, G. Fontán, J. R. Regueiro","doi":"10.1046/j.1365-2249.2002.01716.x","DOIUrl":"https://doi.org/10.1046/j.1365-2249.2002.01716.x","url":null,"abstract":"Common variable immunodeficiency (CVID) is a very frequent but heterogeneous syndrome of antibody formation. The primary defect remains unknown, but many reports describe peripheral blood T lymphocyte dysfunctions in a substantial proportion of CVID patients, which may impair T–B cell collaboration. In order to investigate whether such putative defects were intrinsic to T cells or, rather, secondary to quantitative differences in T cell subset distribution, or to other described disorders, we have used Herpesvirus saimiri (HVS) for the targeted transformation of CVID CD4+ and CD8+ T cells and subsequent functional evaluation by flow cytometry of their capacity to generate cell surface (CD154, CD69) or soluble (IL‐2, TNF‐α, IFN‐γ) help after CD3 engagement. Unexpectedly, the results showed that 40 different CVID blood samples exposed to HVS gave rise with a significantly increased frequency to transformed CD4+ T cell lines, compared to 40 age‐matched controls (27%versus 3%, P≤ 0·00002) suggesting the existence of a CVID‐specific signalling difference which affects CD4+ cell transformation efficiency. The functional analysis of 10 CD4+ and 15 CD8+ pure transformed T cell lines from CVID patients did not reveal any statistically significant difference as compared to controls. However, half of the CD4+ transformed cell lines showed CD154 (but not CD69) induction (mean value of 46·8%) under the lower limit of the normal controls (mean value of 82·4%, P≤ 0·0001). Exactly the same five cell lines showed, in addition, a significantly low induction of IL‐2 (P≤ 0·04), but not of TNF‐α or IFN‐γ. None of these differences were observed in the remaining CD4+ cell lines or in any of the transformed CD8+ cell lines. We conclude that certain CVID patients show selective and intrinsic impairments for the generation of cell surface and soluble help by CD4+ T cells, which may be relevant for B lymphocyte function. The transformed T cell lines will be useful to establish the biochemical mechanisms responsible for the described impairments.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"96 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2002-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85778021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-02-01DOI: 10.1046/j.1365-2249.2002.01733.x
M. Satoh, H. Toma, Yoshiya Sato, M. Takara, Y. Shiroma, S. Kiyuna, K. Hirayama
Strongyloidiasis, a human intestinal infection caused by Strongyloides stercoralis (S. stercoralis), is difficult to cure with drugs. In particular, a decrease of the efficacy of treatment has been reported in patients dually infected with S. stercoralis and human T‐cell leukaemia virus type I (HTLV‐I), both of which are endemic in Okinawa, Japan. However, the factors influencing this resistance remain unclear. In the present study, patients infected with S. stercoralis, with or without HTLV‐I infection, were treated with albendazole, followed up for one year and separated into two groups, cured and non‐cured. The cure rate of S. stercoralis was lower in HTLV‐I carriers (P < 0·05). Serum levels of S. stercoralis‐specific IgA, IgE, IgG, IgG1 and IgG4 antibodies were estimated, and a decrease of IgE (P < 0·05) and an increase of IgG4 (P < 0·05) were observed in the non‐cured group, especially in HTLV‐I carriers. RT‐PCR of cytokines using peripheral blood mononuclear cells revealed that S. stercoralis patients with HTLV‐I showed a high frequency of expression of IFN‐γ and TGF‐β1, whereas those without HTLV‐I showed no expression of these cytokines. IFN‐γ‐ and TGF‐β1‐positive HTLV‐I carriers showed a decrease of IgE (P < 0·05), an increase of IgG4 (P < 0·01) and a lower cure rate (P < 0·01) compared with those who were negative for both cytokines. These results suggest that persistent infection with HTLV‐I affected S. stercoralis‐specific immunity and reduced therapeutic efficacy.
{"title":"Reduced efficacy of treatment of strongyloidiasis in HTLV‐I carriers related to enhanced expression of IFN‐γ and TGF‐β1","authors":"M. Satoh, H. Toma, Yoshiya Sato, M. Takara, Y. Shiroma, S. Kiyuna, K. Hirayama","doi":"10.1046/j.1365-2249.2002.01733.x","DOIUrl":"https://doi.org/10.1046/j.1365-2249.2002.01733.x","url":null,"abstract":"Strongyloidiasis, a human intestinal infection caused by Strongyloides stercoralis (S. stercoralis), is difficult to cure with drugs. In particular, a decrease of the efficacy of treatment has been reported in patients dually infected with S. stercoralis and human T‐cell leukaemia virus type I (HTLV‐I), both of which are endemic in Okinawa, Japan. However, the factors influencing this resistance remain unclear. In the present study, patients infected with S. stercoralis, with or without HTLV‐I infection, were treated with albendazole, followed up for one year and separated into two groups, cured and non‐cured. The cure rate of S. stercoralis was lower in HTLV‐I carriers (P < 0·05). Serum levels of S. stercoralis‐specific IgA, IgE, IgG, IgG1 and IgG4 antibodies were estimated, and a decrease of IgE (P < 0·05) and an increase of IgG4 (P < 0·05) were observed in the non‐cured group, especially in HTLV‐I carriers. RT‐PCR of cytokines using peripheral blood mononuclear cells revealed that S. stercoralis patients with HTLV‐I showed a high frequency of expression of IFN‐γ and TGF‐β1, whereas those without HTLV‐I showed no expression of these cytokines. IFN‐γ‐ and TGF‐β1‐positive HTLV‐I carriers showed a decrease of IgE (P < 0·05), an increase of IgG4 (P < 0·01) and a lower cure rate (P < 0·01) compared with those who were negative for both cytokines. These results suggest that persistent infection with HTLV‐I affected S. stercoralis‐specific immunity and reduced therapeutic efficacy.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"46 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2002-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82807474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-02-01DOI: 10.1046/j.1365-2249.2002.01743.x
F. Arnalich, D. López-Maderuelo, R. Codoceo, Julia López, L. M. Solís-Garrido, C. Capiscol, C. Fernández‐Capitán, R. Madero, C. Montiel
This study aims to determine the influence of the polymorphism within the intron 2 of the interleukin‐1 receptor antagonist gene (IL‐1RN*) on the outcome of severe sepsis, and to assess its functional significance by correlating this polymorphism with the total production of interleukin‐1 receptor antagonist (IL‐1Ra) protein determined in stimulated peripheral blood mononuclear cells (PBMC). A group of 78 patients with severe sepsis (51 survivors and 27 nonsurvivors) was compared with a healthy control group of 130 blood donors, and 56 patients with uncomplicated pneumonia. We found a significant association between IL‐1RN* polymorphism and survival. Thus, after adjusting for age and APACHE II score, multiple logistic regression analysis showed that patients homozygotes for the allele *2 had a 6·47‐fold increased risk of death (95% CI 1·01–41·47, P = 0·04). Besides, compared with patients homozygous or heterozygous for the allele *1, IL‐1RN*2 homozygotes produced significantly lower levels of IL‐1Ra from their PBMC. Our results suggest that insufficient production of this cytokine might contribute, among other factors, to the higher mortality rate found in severe sepsis patients with the IL‐1RN*2 homozygous genotype.
{"title":"Interleukin‐1 receptor antagonist gene polymorphism and mortality in patients with severe sepsis","authors":"F. Arnalich, D. López-Maderuelo, R. Codoceo, Julia López, L. M. Solís-Garrido, C. Capiscol, C. Fernández‐Capitán, R. Madero, C. Montiel","doi":"10.1046/j.1365-2249.2002.01743.x","DOIUrl":"https://doi.org/10.1046/j.1365-2249.2002.01743.x","url":null,"abstract":"This study aims to determine the influence of the polymorphism within the intron 2 of the interleukin‐1 receptor antagonist gene (IL‐1RN*) on the outcome of severe sepsis, and to assess its functional significance by correlating this polymorphism with the total production of interleukin‐1 receptor antagonist (IL‐1Ra) protein determined in stimulated peripheral blood mononuclear cells (PBMC). A group of 78 patients with severe sepsis (51 survivors and 27 nonsurvivors) was compared with a healthy control group of 130 blood donors, and 56 patients with uncomplicated pneumonia. We found a significant association between IL‐1RN* polymorphism and survival. Thus, after adjusting for age and APACHE II score, multiple logistic regression analysis showed that patients homozygotes for the allele *2 had a 6·47‐fold increased risk of death (95% CI 1·01–41·47, P = 0·04). Besides, compared with patients homozygous or heterozygous for the allele *1, IL‐1RN*2 homozygotes produced significantly lower levels of IL‐1Ra from their PBMC. Our results suggest that insufficient production of this cytokine might contribute, among other factors, to the higher mortality rate found in severe sepsis patients with the IL‐1RN*2 homozygous genotype.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"28 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2002-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82063453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-02-01DOI: 10.1046/j.1365-2249.2002.01766.x
F. Pagès, S. Lebel‐Binay, Annick Vieillefond, L. Deneux, M. Cambillau, O. Soubrane, B. Debré, D. Tardy, J. Lemonne, J. Abastado, W. Fridman, N. Thiounn
We conducted a phase I/II clinical trial of the safety and efficacy of intravesical administration of autologous IFN‐γ‐activated macrophages (MAK) in patients with superficial bladder cancer. Monocyte‐derived MAK cells were prepared in vitro and patients received six instillations of 1·4 × 108 to 2·5 × 108 cells, once a week, for five consecutive weeks. Treatment was well tolerated, with seven grade 1 and five Grade 2 protocol‐related adverse effects. Nine out of 17 included patients had no recurrences during the year following the first instillation of MAK. The aim of the present study was to search for immune parameters related to local immunostimulation induced by MAK. Monitoring of the patients showed that urinary IL‐8, GM‐CSF and, to a lesser extent, IL‐18 were increased following MAK instillations, with inter‐individual differences. The urinary IL‐8 level was about 10‐fold higher than that observed for other cytokines, and its biological activity was reflected by a concomitant increase of urinary elastase, indicating neutrophil activation and degranulation. We also showed that nine out of 12 patients investigated presented an increase of urinary neopterin, a marker of IFN‐γ‐activated macrophages, 7 days after MAK instillation, while serum neopterin levels were almost stable. These results are in line with persistence of activated macrophages in the bladder wall after infusions. Moreover, there was evidence of macrophages in urine smears 2 months after the sixth MAK instillation, and the score of macrophages correlated with the quantity of neutrophils in the urine. Overall, this study provides evidence of a local immunostimulation induced by this novel and safe immunotherapeutic approach of MAK instillations in patients with superficial bladder cancer.
{"title":"Local immunostimulation induced by intravesical administration of autologous interferon‐gamma‐activated macrophages in patients with superficial bladder cancer","authors":"F. Pagès, S. Lebel‐Binay, Annick Vieillefond, L. Deneux, M. Cambillau, O. Soubrane, B. Debré, D. Tardy, J. Lemonne, J. Abastado, W. Fridman, N. Thiounn","doi":"10.1046/j.1365-2249.2002.01766.x","DOIUrl":"https://doi.org/10.1046/j.1365-2249.2002.01766.x","url":null,"abstract":"We conducted a phase I/II clinical trial of the safety and efficacy of intravesical administration of autologous IFN‐γ‐activated macrophages (MAK) in patients with superficial bladder cancer. Monocyte‐derived MAK cells were prepared in vitro and patients received six instillations of 1·4 × 108 to 2·5 × 108 cells, once a week, for five consecutive weeks. Treatment was well tolerated, with seven grade 1 and five Grade 2 protocol‐related adverse effects. Nine out of 17 included patients had no recurrences during the year following the first instillation of MAK. The aim of the present study was to search for immune parameters related to local immunostimulation induced by MAK. Monitoring of the patients showed that urinary IL‐8, GM‐CSF and, to a lesser extent, IL‐18 were increased following MAK instillations, with inter‐individual differences. The urinary IL‐8 level was about 10‐fold higher than that observed for other cytokines, and its biological activity was reflected by a concomitant increase of urinary elastase, indicating neutrophil activation and degranulation. We also showed that nine out of 12 patients investigated presented an increase of urinary neopterin, a marker of IFN‐γ‐activated macrophages, 7 days after MAK instillation, while serum neopterin levels were almost stable. These results are in line with persistence of activated macrophages in the bladder wall after infusions. Moreover, there was evidence of macrophages in urine smears 2 months after the sixth MAK instillation, and the score of macrophages correlated with the quantity of neutrophils in the urine. Overall, this study provides evidence of a local immunostimulation induced by this novel and safe immunotherapeutic approach of MAK instillations in patients with superficial bladder cancer.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"30 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2002-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74979551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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