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1.
Br J Radiol ; 93(1114): 20200463, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32795181

RESUMO

OBJECTIVE: The aim of this study was to evaluate if small group teaching in Radiology impacted Anatomy scores in the summative end of year examination. METHODS: Small group teaching in Radiology was incorporated into Anatomy of year one medical students during the academic years 2016/17 and 2017/18. Examination outcome for 2 years before and 1 year after the study period were compared.Question papers for end of year summative examinations were retrieved; questions relating to Anatomy were identified and anonymised scores for students were obtained. RESULTS: Student numbers ranged 238 to 290/year. Mean Anatomy scores ranged 62-74%, this compared with mean total exam score of 62-65%. No significant difference in Anatomy and Total examination scores for 2015, 2016 and 2019. Mean (SD) Anatomy scores were significantly higher than the Total examination scores for the study period of 2017 and 2018 [68.97 (17.32) vs 63.12 (11.51) and 73.77 (17.85) vs 64.99 (10.31) (p < 0.001)]. Combined Anatomy scores 2017 and 2018 were significantly higher than 2015 and 2016, difference of 5.50 (95% C.I. 3.31-7.70; p < 0.001). CONCLUSION: This is the first study to objectively demonstrate Radiology small group teaching significantly improved Anatomy scores for medical students in the summative end of year examination. ADVANCES IN KNOWLEDGE: No evidence in the literature that Radiology teaching improves examination outcomes for medical students.This is the first study to directly link Radiology teaching with improved Anatomy examination result.Small group teaching in Radiology is a feasible way to teach Anatomy.


Assuntos
Anatomia/educação , Educação de Graduação em Medicina , Avaliação Educacional , Radiologia/educação , Currículo , Feminino , Humanos , Masculino , Escócia , Adulto Jovem
2.
Ann Rheum Dis ; 71(6): 1049-54, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22294633

RESUMO

OBJECTIVES: Proteinase-activated receptor 2 (PAR(2)) is a G protein-coupled receptor activated by serine proteinases with proinflammatory activity. A study was undertaken to investigate the presence and functional significance of PAR(2) expression on rheumatoid arthritis (RA)-derived leucocyte subsets. METHODS: Venous blood was obtained from patients with RA and osteoarthritis (OA) as well as healthy control subjects. Surface expression of PAR(2) on peripheral blood mononuclear cells (PBMCs) was analysed by flow cytometry and interleukin 6 (IL-6) generation by ELISA. RESULTS: Patients with RA had elevated but variable surface expression of PAR(2) on CD14+ monocytes compared with control subjects (median (1st to 3rd quartiles) 1.76% (0.86-4.10%) vs 0.06% (0.03-0.81%), p<0.0001). CD3+ T cells showed a similar pattern with significantly higher PAR(2) expression in patients with RA compared with controls (3.05% (0.36-11.82%) vs 0.08% (0.02-0.28%), p<0.0001). For both subsets, PAR(2) expression was significantly higher (p<0.00001) in patients with high levels of disease activity: PAR(2) expression for both CD14+ and CD3+ cells correlated to C reactive protein and erythrocyte sedimentation rate. Furthermore, in a cohort of patients with newly diagnosed RA, elevated PAR(2) expression in both CD14+ and CD3+ cells was significantly reduced 3 months after methotrexate or sulfasalazine treatment and this reduction correlated significantly with the reduction in the 28-joint Disease Activity Scale score (p<0.05). PAR(2) expression on cells from patients with OA was low, similar to levels seen in control subjects. Generation of IL-6 by monocytes in response to a selective PAR(2) agonist was significantly greater in patients with RA than in patients with OA and control subjects (p<0.05). CONCLUSIONS: These findings are consistent with a pathogenic role for PAR(2) in RA.


Assuntos
Artrite Reumatoide/imunologia , Monócitos/imunologia , Receptor PAR-2/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/metabolismo , Complexo CD3/metabolismo , Células Cultivadas , Estudos Transversais , Feminino , Citometria de Fluxo , Expressão Gênica/imunologia , Humanos , Interleucina-6/imunologia , Interleucina-6/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Osteoartrite/imunologia , Osteoartrite/metabolismo , Receptor PAR-2/genética , Receptor PAR-2/metabolismo
3.
Growth Horm IGF Res ; 18(5): 369-378, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18378173

RESUMO

OBJECTIVE: To investigate the relationship between markers of inflammation with physical growth and systemic markers of GH secretion in JIA. DESIGN: This is a cross sectional prospective study of patients with JIA recruited during therapeutic arthrocentesis of 17 children with JIA (F,10): 8 oligoarticular (OJIA) and 9 polyarticular (PJIA). RESULTS: Median adjusted height (AHt) SDS was -0.3 (-2.2 to 1.6). Serum ALS SDS (median -1.3, range -2.7 to -0.6) was reduced compared with serum IGFBP-3 SDS (median -0.5, range -7.7 to 2.3) and IGF-1 SDS (median -0.2, range -0.5 to 0.5). Log serum IL5 (95% CI -3.25, -0.81) and log serum IL15 (95% CI -9.58, -4.10) were independent factors associated with AHt SDS. Inflammatory cytokines individually showed no association with IGF-1, IGFBP-1, -2, -3 and ALS. CONCLUSION: Children with JIA and mild degree of growth retardation show decreased ALS and IGFBP-3. Cytokines did not show an association to systemic markers of GH secretion. However, this study reports the novel, preliminary association between serum levels of IL5 and IL15 and the extent of short stature.


Assuntos
Artrite Juvenil/sangue , Citocinas/sangue , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/sangue , Adolescente , Artrite Juvenil/imunologia , Estatura , Criança , Pré-Escolar , Estudos Transversais , Feminino , Transtornos do Crescimento/metabolismo , Humanos , Inflamação/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Interleucina-5/sangue , Interleucina-6/sangue , Masculino , Estudos Prospectivos , Puberdade
4.
Ann Rheum Dis ; 67(4): 518-23, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17704067

RESUMO

OBJECTIVE: In countries where parasitic infections are endemic, autoimmune disease is relatively rare, leading to the hypothesis that parasite-derived immunomodulators may protect against its development. Consistent with this, we have previously demonstrated that ES-62, a 62 kDa phosphorylcholine (PC)-containing glycoprotein that is secreted by filarial nematodes, can exert anti-inflammatory action in the murine collagen-induced arthritis (CIA) model and human rheumatoid arthritis-derived synovial tissue cultures. As a first step to developing ES-62-based drugs, the aim of this study was to determine whether the PC-moiety of ES-62 was responsible for its anti-inflammatory actions. METHODS: We compared the anti-inflammatory activity of a PC-free form of recombinant ES-62 (rES-62) and a synthetic PC-ovalbumin conjugate (OVA-PC) with that of native ES-62 in the CIA model and synovial tissues from patients with rheumatoid arthritis. RESULTS: The anti-inflammatory actions of ES-62 in CIA appear to be dependent on the PC moiety as indicated by the reduction in severity of disease and also suppression of collagen-specific T helper 1 cytokine production observed when testing OVA-PC, but not rES-62. Interestingly, the anti-inflammatory activity of PC did not correlate with a reduction in anti-collagen IgG2a levels. Also, the ES-62-mediated suppression of interferon-gamma from human patient tissues could be mimicked by OVA-PC but not rES-62 or ovalbumin. CONCLUSIONS: In countries where filariasis is endemic the reduced detection of inflammatory diseases, such as rheumatoid arthritis may be because of the anti-inflammatory action of the PC moieties of ES-62. PC may thus provide the starting point for the development of novel, safe immunomodulatory therapies.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/imunologia , Proteínas de Helminto/uso terapêutico , Fatores Imunológicos/uso terapêutico , Fosforilcolina/imunologia , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/imunologia , Artrite Experimental/imunologia , Células Cultivadas , Citocinas/sangue , Proteínas de Helminto/química , Proteínas de Helminto/imunologia , Humanos , Imunoglobulina G/sangue , Fatores Imunológicos/química , Fatores Imunológicos/imunologia , Mediadores da Inflamação/sangue , Masculino , Camundongos , Camundongos Endogâmicos DBA , Proteínas Recombinantes/química , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/uso terapêutico , Membrana Sinovial/imunologia , Técnicas de Cultura de Tecidos
5.
Ann Rheum Dis ; 65(8): 1099-101, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16837493

RESUMO

BACKGROUND: Immunoregulatory genes and Gram negative gut bacteria are thought to be important in disease expression in ankylosing spondylitis (AS). OBJECTIVE: To compare the frequency of two common and functional TLR4 mutations (Asp299Gly, and Thr399Ile) between patients with AS and HLA-B27 healthy controls. METHODS: The TLR4 genotypes of patients and healthy HLA-B27 controls were determined using allele-specific PCR and restriction fragment length polymorphism analysis. Asp299Gly genotype was determined in 193 patients and 125 HLA-B27 positive controls and Thr399Ile genotype in 184 patients and 113 HLA-B27 controls. Allele frequencies were compared using a chi(2) test of association. RESULTS: 29/193 (15%) patients with AS had a polymorphism in the Asp299 site compared with 18/125 (14.4%) healthy HLA-B27 controls. Of the patients genotyped for the Thr399Ile allele, 29/184 (15.8%) carried the polymorphism compared with 19/113 (16.8%) HLA-B27 controls. No significant difference between the frequencies of the Asp299Gly genotype or the Thr399Ile genotype between patients with AS and healthy HLA-B27 controls was found. No significant difference in allele frequency was found at either site. CONCLUSION: Two common TLR4 polymorphisms, which cause a functional deficiency in host immune response to Gram negative bacteria, are not overrepresented in patients with AS.


Assuntos
Mutação/genética , Polimorfismo de Nucleotídeo Único , Espondilite Anquilosante/genética , Receptor 4 Toll-Like/genética , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Análise Mutacional de DNA , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Antígeno HLA-B27/imunologia , Humanos , Tamanho da Amostra , Espondilite Anquilosante/imunologia
6.
Genes Immun ; 6(3): 211-6, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15789055

RESUMO

Interleukin (IL)-18 is an important mediator of innate and adaptive immunity. We searched for an association of IL-18 promoter single-nucleotide polymorphisms (SNP) with rheumatoid arthritis (RA) in Caucasians. The entire study population was composed of two independent cohorts from Germany (n=200) and Scotland (n=410). Presence of IL-18 SNP at positions -607 and -137 was determined by allele-specific PCR in 327 RA patients and 283 healthy donors (HD). Diplotype distributions of both loci were in Hardy-Weinberg equilibrium (HWE) in the German and Scottish HD cohorts. In contrast, locus -607 was in HW disequilibrium in German, and locus -137 in Scottish RA patients. Diplotypic exact chi(2) tests suggested that -607CC was overrepresented in German, and -137CC in Scottish RA patients, but conservative chi(2) trend analyses could not prove any significant disease association of these single loci. SNP -607 and -137 were in strong linkage disequilibrium. The -607C(*)-137C haplotype was more prevalent in German RA (3.2 vs 1.2%) and in Scottish RA patients (4.1 vs 0.9%) than in the respective HD cohorts. These observations suggest that SNP of both positions contribute to the genetic background of RA pathogenesis.


Assuntos
Artrite Reumatoide/genética , Interleucina-18/genética , Polimorfismo Genético , Regiões Promotoras Genéticas , Artrite Reumatoide/metabolismo , Alemanha , Haplótipos , Humanos , Interleucina-18/metabolismo , Escócia , População Branca
9.
J Immunol ; 167(5): 2879-86, 2001 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-11509635

RESUMO

IL-18 expression and functional activity has been identified in several autoimmune and infectious diseases. To clarify the potential role of IL-18 during early innate immune responses, we have explored the capacity of IL-18 to activate neutrophils. Human peripheral blood-derived neutrophils constitutively expressed IL-18R (alpha and beta) commensurate with the capacity to rapidly respond to IL-18. IL-18 induced cytokine and chemokine release from neutrophils that was protein synthesis dependent, up-regulated CD11b expression, induced granule release, and enhanced the respiratory burst following exposure to fMLP, but had no effect upon the rate of neutrophil apoptosis. The capacity to release cytokine and chemokine was significantly enhanced in neutrophils derived from rheumatoid arthritis synovial fluid, indicating differential responsiveness to IL-18 dependent upon prior neutrophil activation in vivo. Finally, IL-18 administration promoted neutrophil accumulation in vivo, whereas IL-18 neutralization suppressed the severity of footpad inflammation following carrageenan injection. The latter was accompanied by reduction in tissue myeloperoxidase expression and suppressed local TNF-alpha production. Together, these data define a novel role for IL-18 in activating neutrophils and thereby promoting early innate immune responses.


Assuntos
Interleucina-18/imunologia , Neutrófilos/imunologia , Animais , Apoptose/efeitos dos fármacos , Artrite Reumatoide/imunologia , Sequência de Bases , Degranulação Celular/efeitos dos fármacos , Citocinas/biossíntese , Citocinas/genética , Primers do DNA/genética , Humanos , Técnicas In Vitro , Inflamação/etiologia , Inflamação/imunologia , Inflamação/prevenção & controle , Interleucina-18/farmacologia , Interleucina-18/fisiologia , Subunidade alfa de Receptor de Interleucina-18 , Antígeno de Macrófago 1/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/fisiologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Interleucina/genética , Receptores de Interleucina-18 , Explosão Respiratória/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
11.
J Immunol ; 167(1): 277-82, 2001 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-11418660

RESUMO

IL-15 is a pleiotropic cytokine that plays important roles in both innate and adaptive immunity. It is associated with a range of immunopathology, including rheumatoid arthritis and allograft rejection. IL-15 functions through the trimeric IL-15R complex, which consists of a high affinity binding alpha-chain and the common IL-2R beta- and gamma-chains. Characterization of IL-15/IL-15R interactions may facilitate the development of improved IL-15 antagonists for therapeutic interventions. We previously constructed soluble murine IL-15Ralpha (sIL-15Ralpha) by deleting the cytoplasmic and transmembrane domains. To localize the functional domain of IL-15Ralpha, we have now constructed various truncated versions of sIL-15Ralpha. The shortest region retaining IL-15 binding activity is a 65-aa sequence spanning the Sushi domain of IL-15Ralpha. Sushi domains, common motifs in protein-protein interactions, contain four cysteines forming two disulfide bonds in a 1-3 and 2-4 pattern. Amino acid substitution of the first or fourth cysteine in sIL-15Ralpha completely abolished its IL-15 binding activity. This also abrogated the ability of sIL-15Ralpha to neutralize IL-15-induced proinflammatory cytokine production and anti-apoptotic response in vitro. Furthermore, the mutant sIL-15Ralpha lost its ability to inhibit carrageenan-induced local inflammation and allogenic cell-induced T cell proliferation and cytokine production in vivo. Thus, the Sushi domain is critical for the functional activity of sIL-15Ralpha.


Assuntos
Motivos de Aminoácidos/imunologia , Edema/imunologia , Edema/prevenção & controle , Interleucina-15/metabolismo , Isoantígenos/imunologia , Receptores de Interleucina-2/fisiologia , Doença Aguda , Motivos de Aminoácidos/genética , Animais , Apoptose/genética , Apoptose/imunologia , Carragenina/administração & dosagem , Dissulfetos/metabolismo , Edema/patologia , Feminino , Injeções Subcutâneas , Interleucina-15/antagonistas & inibidores , Isoantígenos/administração & dosagem , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Camundongos , Mutagênese Sítio-Dirigida , Necrose , Ligação Proteica/genética , Ligação Proteica/imunologia , Estrutura Terciária de Proteína/genética , Receptores de Interleucina-15 , Receptores de Interleucina-2/genética , Receptores de Interleucina-2/metabolismo , Solubilidade , Baço/citologia , Baço/transplante , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/patologia
12.
J Immunol ; 167(1): 553-61, 2001 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-11418694

RESUMO

IL-2 responses are susceptible to suppression by TGFbeta, a cytokine widely implicated in suppression of inflammatory responses and secreted by many different tumor cell types. There have been conflicting reports regarding inhibition of IL-2-induced STAT3 and STAT5 phosphorylation by TGFbeta and subsequent suppression of immune responses. Using TGFbeta-producing multiple myeloma tumor cells we demonstrate that tumor-derived TGFbeta can block IL-2-induced proliferation and STAT3 and STAT5 phosphorylation in T cells. High affinity IL-2R expression was required for the suppression of IL-2 responses as a novel CD25(-) T cell line proliferated and phosphorylated STAT3 when cultured with tumor cells or rTGFbeta1. Activating T cells with IL-15, which does not use the high affinity IL-2R, completely restored the ability of T cells to phosphorylate STAT3 and STAT5 when cultured with tumor cells. IL-15-treated T cells proliferated normally when cocultured with tumor cells or rTGFbeta1, whereas IL-2 responses were consistently inhibited. Preincubation with IL-15 also restored the ability of T cells to respond to IL-2 by phosphorylating STAT3 and STAT5, and proliferating normally in the presence of tumor cells. IL-2 pretreatment did not restore T cell function. IL-15 also restored T cell responses by T cells from multiple myeloma patients, and against freshly isolated bone marrow tumor samples. Thus, activation of T cells by IL-15 renders T cells resistant to suppression by TGFbeta1-producing tumor cells and rTGFbeta1. This finding may be exploited in the design of new immunotherapy approaches that will rely on T cells avoiding tumor-induced suppression.


Assuntos
Proteínas de Ligação a DNA/antagonistas & inibidores , Imunossupressores/antagonistas & inibidores , Interleucina-15/fisiologia , Interleucina-2/antagonistas & inibidores , Ativação Linfocitária/imunologia , Proteínas do Leite , Proteínas de Neoplasias/fisiologia , Linfócitos T/imunologia , Transativadores/antagonistas & inibidores , Fator de Crescimento Transformador beta/fisiologia , Células Cultivadas , Técnicas de Cocultura , Proteínas de Ligação a DNA/metabolismo , Humanos , Imunossupressores/farmacologia , Interleucina-15/biossíntese , Interleucina-2/fisiologia , Ativação de Macrófagos , Monócitos/imunologia , Monócitos/metabolismo , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/patologia , Proteínas de Neoplasias/antagonistas & inibidores , Fosforilação , Receptores de Interleucina-2/biossíntese , Fator de Transcrição STAT3 , Fator de Transcrição STAT5 , Transdução de Sinais/imunologia , Linfócitos T/patologia , Transativadores/metabolismo , Fator de Crescimento Transformador beta/antagonistas & inibidores , Células Tumorais Cultivadas
13.
Eur J Immunol ; 30(11): 3147-56, 2000 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11093129

RESUMO

The functional division of CD4(+) T cells into Th1 and Th2 subsets is generally accepted but the mechanisms leading to their preferential induction remain elusive. Cytokines are considered the main determining factors in the initial differentiation of precursor T cells into these distinct subsets. Thus, IL-12 drives Th1 cells whereas IL-4 drives Th2 cells. Recently IL-18, originally designated as IFN-gamma-inducing factor, has been reported to synergize with IL-12 in the induction of Th1 cells. We report here that IL-18 can also induce T cells to differentiate into Th2 cells, in the presence of TCR activation, either alone or together with IL-4. This effect of IL-18 is mediated primarily on CD4(+) T cells compared with CD8(+) T cells and is inhibited in the presence of IL-12. IL-18, however, has no effect on functionally committed Th2 cells.( )Moreover, the effect of IL-18 on Th2 cell development is differentially manifest in different mouse strains, suggesting profound underlying genetic influences. BALB/c mice infected with Leishmania major and treated with recombinant IL-18 developed exacerbated disease and enhanced Th2 response compared with untreated controls. These data therefore provide a novel mechanism for Th2 cell development. Thus, IL-18, a cytokine constitutively expressed by cells of the innate response, is capable of inducing Th2 cell differentiation in the absence of IL-4.


Assuntos
Interleucina-18/imunologia , Células Th1/imunologia , Células Th2/imunologia , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/imunologia , Interleucina-12/imunologia , Interleucina-12/farmacologia , Interleucina-18/farmacologia , Camundongos , Células Th1/citologia , Células Th2/citologia
15.
J Clin Invest ; 104(10): 1393-401, 1999 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-10562301

RESUMO

IL-18 is a novel cytokine with pleiotropic activities critical to the development of T-helper 1 (Th1) responses. We detected IL-18 mRNA and protein within rheumatoid arthritis (RA) synovial tissues in significantly higher levels than in osteoarthritis controls. Similarly, IL-18 receptor expression was detected on synovial lymphocytes and macrophages. Together with IL-12 or IL-15, IL-18 induced significant IFN-gamma production by synovial tissues in vitro. IL-18 independently promoted GM-CSF and nitric oxide production, and it induced significant TNF-alpha synthesis by CD14(+) macrophages in synovial cultures; the latter effect was potentiated by IL-12 or IL-15. TNF-alpha and IFN-gamma synthesis was suppressed by IL-10 and TGF-beta. IL-18 production in primary synovial cultures and purified synovial fibroblasts was, in turn, upregulated by TNF-alpha and IL-1beta, suggesting that monokine expression can feed back to promote Th1 cell development in synovial membrane. Finally, IL-18 administration to collagen/incomplete Freund's adjuvant-immunized DBA/1 mice facilitated the development of an erosive, inflammatory arthritis, suggesting that IL-18 can be proinflammatory in vivo. Together, these data indicate that synergistic combinations of IL-18, IL-12, and IL-15 may be of importance in sustaining both Th1 responses and monokine production in RA.


Assuntos
Artrite Reumatoide/fisiopatologia , Regulação da Expressão Gênica , Interleucina-18/genética , Células Th1/imunologia , Animais , Artrite Experimental/imunologia , Artrite Experimental/patologia , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Complexo CD3/análise , Linhagem Celular , Ensaio de Imunoadsorção Enzimática , Humanos , Inflamação , Interferon gama/genética , Interleucina-12/farmacologia , Interleucina-15/farmacologia , Interleucina-18/análise , Interleucina-18/fisiologia , Subunidade alfa de Receptor de Interleucina-18 , Macrófagos/imunologia , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos DBA , Osteoartrite/imunologia , Osteoartrite/patologia , Osteoartrite/fisiopatologia , Biossíntese de Proteínas , RNA Mensageiro/genética , Receptores de Interleucina/análise , Receptores de Interleucina/genética , Receptores de Interleucina-18 , Líquido Sinovial/química , Líquido Sinovial/imunologia , Membrana Sinovial/imunologia , Membrana Sinovial/patologia , Transcrição Gênica , Fator de Necrose Tumoral alfa/genética
16.
Transplantation ; 64(4): 589-93, 1997 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-9293870

RESUMO

BACKGROUND: During allograft rejection, up-regulation of cytokine-inducible nitric oxide synthase (iNOS) leads to the production of large amounts of nitric oxide (NO). The net effect of NO on the alloimmune response is, however, difficult to predict because of its diverse biological effects, which include potentially opposing roles as an effector and immunoregulatory molecule. METHODS: In this study, the role of iNOS on the in vitro and in vivo alloimmune response was defined using mutant mice that lack a functional iNOS gene. The ability of spleen cells obtained from iNOS-deficient mutants to proliferate and to produce cytokines in response to irradiated BALB/c stimulator cells was determined, and the rate at which iNOS-deficient mice were able to reject BALB/c skin allografts was observed. RESULTS: Spleen cells from homozygous iNOS-deficient (129xMF1)F1 mice, when compared with cells from heterozygous control mice, showed an increased in vitro proliferative response and produced substantially higher levels of interferon-gamma, and also more interleukin-2 and interleukin-12, in response to allogeneic stimulation. The kinetics of BALB/c skin graft rejection were comparable in heterozygous control animals and iNOS-deficient mice. Moreover, no net effect of iNOS on skin allograft rejection was apparent in mice treated with depleting monoclonal antibodies (mAb) to CD4 or CD8 T cells, either alone or in combination, or in mice treated with both anti-CD8 mAb and a neutralizing anti-tumor necrosis factor mAb. CONCLUSIONS: These results show that iNOS has an immunomodulatory effect on the in vitro alloimmune response but lack of iNOS has no net influence on the kinetics of murine skin allograft rejection in either unmodified recipients or recipients in which the early contribution of T-cell subsets and tumor necrosis factor-alpha to graft rejection has been abrogated.


Assuntos
Óxido Nítrico Sintase/metabolismo , Transplante de Pele/imunologia , Animais , Anticorpos Monoclonais/farmacologia , Feminino , Rejeição de Enxerto/enzimologia , Rejeição de Enxerto/metabolismo , Isoantígenos/imunologia , Cinética , Ativação Linfocitária/imunologia , Ativação de Macrófagos/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico Sintase/deficiência , Subpopulações de Linfócitos T/imunologia , Transplante Homólogo/imunologia , Fator de Necrose Tumoral alfa/imunologia
17.
Eur J Immunol ; 26(6): 1217-21, 1996 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-8647195

RESUMO

Interleukin-12 (IL-12) is a key immunoregulatory cytokine which promotes cell-mediated immunity. Its influence on the humoral immune response is less clearly defined. In this study, the effect of systemic IL-12 treatment on the T cell-dependent humoral immune response in the rat was examined using an experimental system in which PVG-RT1u congenic rats were immunized with class I Aa alloantigen in the form of a blood transfusion from the recombinant PVG.R8 rat strain. Administration of IL-12 following allo-immunization augmented the humoral immune response as determined by increased levels of cytotoxic anticlass I major histocompatibility complex antibodies. However, the effect of IL-12 on individual IgG isotypes was highly selective. Levels of allospecific antibodies of the IgG2b and IgG2c subclasses were markedly increased, whereas IgG1 alloantibody levels were profoundly reduced. The observed alterations in alloantibody response were dependent, in large part, on the stimulatory effect of IL-12 on interferon (IFN)-gamma production by T lymphocytes and natural killer cells, since they were abrogated by co-administration of neutralizing anti-IFN-gamma monoclonal antibody following alloantigen immunization.


Assuntos
Antígenos de Histocompatibilidade Classe I/imunologia , Imunoglobulina G/genética , Isotipos de Imunoglobulinas/genética , Interferon gama/fisiologia , Interleucina-12/farmacologia , Isoanticorpos/genética , Animais , Citotoxicidade Celular Dependente de Anticorpos , Rejeição de Enxerto , Masculino , Ratos , Ratos Endogâmicos Lew , Células Th1/imunologia
18.
J Pathol ; 169(2): 203-6, 1993 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-8095298

RESUMO

The relationship between damage to cutaneous melanocytes and antimelanocyte autoimmunity in vitiligo is unclear. We have demonstrated abnormal expression of MHC class II molecules by perilesional melanocytes in 13/21 patients with vitiligo and a six-fold increase in the number expressing the intercellular adhesion molecule ICAM-1. These molecules have important roles in normal antigen presentation and activation of helper T lymphocytes, and their expression by melanocytes may contribute to the abnormal immune response in vitiligo. MHC class II is not expressed by melanocytes in psoriasis and is unlikely to be induced in vitiligo by cytokines released from activated non-melanocyte-specific T lymphocytes.


Assuntos
Doenças Autoimunes/imunologia , Moléculas de Adesão Celular/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Melanócitos/imunologia , Vitiligo/imunologia , Humanos , Imuno-Histoquímica , Molécula 1 de Adesão Intercelular , Psoríase/imunologia
20.
Thromb Haemost ; 65(1): 7-10, 1991 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-2024240

RESUMO

56 haemophiliacs selected on the basis of HIV-1 antibody status, liver disease grade and mean annual dose of clotting factor concentrate used were studied. Spontaneous and stimulated IgG and IgM production in vitro were measured. HIV-1 infection was associated with increased spontaneous immunoglobulin production and an impaired response to pokeweed mitogen and Staph Aureus protein A. Implying a shift in the proportions of partially and fully activated B cells. In the absence of HIV-1 infection there was a shift to a greater proportion of partially activated B cells in patients with severe liver disease. The remainder had in vitro immunoglobulin production comparable to controls. B cell abnormalities occur early in the course of HIV-1 infection. Liver disease and not clotting factor concentrate treatment cause B cell abnormalities in the absence of HIV-1 infection in haemophilia.


Assuntos
Linfócitos B/imunologia , Infecções por HIV/imunologia , HIV-1 , Hemofilia A/imunologia , Adolescente , Adulto , Fatores de Coagulação Sanguínea/uso terapêutico , Separação Celular , Células Cultivadas , Anticorpos Anti-HIV/análise , Infecções por HIV/etiologia , HIV-1/imunologia , Hemofilia A/complicações , Humanos , Imunoglobulinas/biossíntese , Hepatopatias/complicações , Ativação Linfocitária/imunologia , Masculino , Mitógenos de Phytolacca americana , Staphylococcus aureus , Subpopulações de Linfócitos T/imunologia , Reação Transfusional
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