RESUMO
Psoriasis (OMIM 177900) is a chronic inflammatory skin disorder of unknown pathogenesis affecting approximately 2% of the Western population. It occurs more frequently in individuals with human immunodeficiency virus, and 20-30% of individuals with psoriasis have psoriatic arthritis. Psoriasis is associated with HLA class I alleles, and previous linkage analysis by our group identified a second psoriasis locus at 17q24-q25 (PSORS2; ref. 7). Linkage to this locus was confirmed with independent family sets. Additional loci have also been proposed to be associated with psoriasis. Here we describe two peaks of strong association with psoriasis on chromosome 17q25 separated by 6 Mb. Associated single-nucleotide polymorphisms (SNPs) in the proximal peak lie in or near SLC9A3R1 (also called EBP50 and NHERF1) and NAT9, a new member of the N-acetyltransferase family. SLC9A3R1 is a PDZ domain-containing phosphoprotein that associates with members of the ezrin-radixin-moesin family and is implicated in diverse aspects of epithelial membrane biology and immune synapse formation in T cells. The distal peak of association is in RAPTOR (p150 target of rapamycin (TOR)-scaffold protein containing WD-repeats). Expression of SLC9A3R1 is highest in the uppermost stratum Malpighi of psoriatic and normal skin and in inactive versus active T cells. A disease-associated SNP lying between SLC9A3R1 and NAT9 leads to loss of RUNX1 binding. This is the second example of loss of a RUNX1 binding site associated with susceptibility to an autoimmune disease. It also suggests defective regulation of SLC9A3R1 or NAT9 by RUNX1 as a susceptibility factor for psoriasis.
Assuntos
Arilamina N-Acetiltransferase/genética , Proteínas de Transporte/genética , Proteínas de Ligação a DNA/genética , Fosfoproteínas/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas Proto-Oncogênicas , Psoríase/genética , Trocadores de Sódio-Hidrogênio , Fatores de Transcrição/genética , Sequência de Bases , Cromossomos Humanos Par 17/genética , Subunidade alfa 2 de Fator de Ligação ao Core , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Antígenos HLA-C/genética , Humanos , Células Jurkat , Luciferases , Masculino , Dados de Sequência Molecular , Regiões Promotoras Genéticas , Pele/metabolismo , Linfócitos T/metabolismoRESUMO
Psoriasis is a type I-deviated disease characterized by the presence of interferon (IFN)-gamma and multiple IFN-related inflammatory genes in lesions. Because interleukin (IL)-23 is now recognized to play a role in the recruitment of inflammatory cells in a T helper cell (Th)1-mediated disease, we examined psoriasis skin lesions for production of this newly described cytokine. IL-23 is composed of two subunits: a unique p19 subunit and a p40 subunit shared with IL-12. We found a reliable increase in p19 mRNA by quantitative reverse transcription polymerase chain reaction in lesional skin compared with nonlesional skin (22.3-fold increase; P = 0.001). The p40 subunit, shared by IL-12 and IL-23, increased by 11.6-fold compared with nonlesional skin (P = 0.003), but the IL-12 p35 subunit was not increased in lesional skin. IL-23 was expressed mainly by dermal cells and increased p40 immunoreactivity was visualized in large dermal cells in the lesions. Cell isolation experiments from psoriatic tissue showed strong expression of p19 mRNA in cells expressing monocyte (CD14+ CD11c+ CD83-) and mature dendritic cell (DC) markers (CD14- CD11c+ CD83+), whereas in culture, the mRNAs for p40 and p19 were strongly up-regulated in stimulated monocytes and monocyte-derived DCs, persisting in the latter for much longer periods than IL-12. Our data suggest that IL-23 is playing a more dominant role than IL-12 in psoriasis, a Th1 type of human inflammatory disease.
Assuntos
Regulação da Expressão Gênica/imunologia , Interleucinas/genética , Psoríase/genética , Psoríase/imunologia , Pele/imunologia , Adulto , Citometria de Fluxo , Humanos , Interleucina-12/genética , Interleucina-23 , Subunidade p19 da Interleucina-23 , Isoformas de Proteínas/genética , RNA Mensageiro/genética , Pele/patologia , Transcrição GênicaRESUMO
BACKGROUND: Alefacept (anti-CD2) biological therapy selectively targets effector memory T cells (Tem) in psoriasis vulgaris, a model Type 1 autoimmune disease. METHODS: Circulating leukocytes were phenotyped in patients receiving alefacept for moderate to severe psoriasis. RESULTS: In all patients, this treatment caused a preferential decrease in effector memory T cells (CCR7- CD45RA-) (mean 63% reduction) for both CD4+ and CD8+ Tem, while central memory T cells (Tcm) (CCR7+CD45RA-) were less affected, and naïve T cells (CCR7+CD45RA+) were relatively spared. Circulating CD8+ effector T cells and Type 1 T cells (IFN-gamma-producing) were also significantly reduced. CONCLUSION: Alefacept causes a selective reduction in circulating effector memory T cells (Tem) and relative preservation of central memory T cells (Tcm) in psoriasis.
Assuntos
Antígenos CD2/imunologia , Movimento Celular , Memória Imunológica , Psoríase/tratamento farmacológico , Psoríase/imunologia , Proteínas Recombinantes de Fusão/uso terapêutico , Linfócitos T/imunologia , Adulto , Idoso , Alefacept , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Movimento Celular/efeitos dos fármacos , Fármacos Dermatológicos/administração & dosagem , Fármacos Dermatológicos/uso terapêutico , Feminino , Humanos , Memória Imunológica/efeitos dos fármacos , Lectinas Tipo C , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Subpopulações de Linfócitos/efeitos dos fármacos , Subpopulações de Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Psoríase/patologia , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/farmacologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/patologiaRESUMO
BACKGROUND: Newer biological therapies for moderate-to-severe psoriasis are being used more frequently, but unexpected effects may occur. CASE PRESENTATIONS: We present a group of 15 patients who developed inflammatory papules while on efalizumab therapy (Raptiva, Genentech Inc, anti-CD11a). Immunohistochemistry showed that there were increased CD11b+, CD11c+ and iNOS+ cells (myeloid leukocytes) in the papules, with relatively few CD3+ T cells. While efalizumab caused a decreased expression of CD11a on T cells, other circulating leukocytes from patients receiving this therapy often showed increased CD11b and CD11c. In the setting of an additional stimulus such as skin trauma, this may predispose to increased trafficking into the skin using these alternative beta2 integrins. In addition, there may be impaired immune synapse formation, limiting the development of these lesions to small papules. There is little evidence for these papular lesions being "allergic" in nature as there are few eosinophils on biopsy, and they respond to minimal or no therapy even if efalizumab is continued. CONCLUSION: We hypothesize that these papules may represent a unique type of "mechanistic" inflammatory reaction, seen only in the context of drug-induced CD11a blockade, and not during the natural disease process.
Assuntos
Anticorpos Monoclonais/efeitos adversos , Toxidermias/etiologia , Psoríase/tratamento farmacológico , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Antígeno CD11a/imunologia , Antígeno CD11a/metabolismo , Antígeno CD11b/metabolismo , Antígeno CD11c/metabolismo , Complexo CD3/metabolismo , Células Dendríticas/enzimologia , Células Dendríticas/imunologia , Células Dendríticas/patologia , Toxidermias/enzimologia , Toxidermias/imunologia , Toxidermias/patologia , Humanos , Imuno-Histoquímica , Leucócitos/enzimologia , Leucócitos/imunologia , Óxido Nítrico Sintase Tipo II/metabolismo , Pele/enzimologia , Pele/imunologia , Pele/patologia , Linfócitos T/imunologia , Linfócitos T/patologiaRESUMO
We assessed expression of IL-20 and its receptors in psoriasis, given the recent implication of IL-20 in epidermal hyperplasia. Psoriatic lesional (LS) skin consistently expressed more IL-20 mRNA than nonlesional (NL) skin. Immunoreactivity to IL-20 protein was greater in LS tissue and mainly localized to infiltrating CD68+/CD11c+ (myeloid-derived) dermal leukocytes. Because this contrasted with earlier reports of a keratinocyte source, we assessed IL-20 mRNA expression in a variety of cells in vitro, and confirmed a myeloid-derived cellular source (monocytes). Plastic adhesion, activation of beta2 integrins, and incubation with tumor necrosis factor-alpha stimulated expression in these cells. IL-20 receptor (IL-20R)alpha and IL-20Rbeta mRNA was decreased in LS versus NL skin, which also contrasted with earlier findings. To investigate the relationship between IL-20 and disease activity, we examined psoriasis patients treated with the CD2-targeted agent alefacept. In therapeutic responders, lesional IL-20 mRNA decreased to NL levels, suggesting that CD2+ leukocytes may proximally regulate IL-20. Finally, to assess IL-20 function, we used microarrays to screen IL-20-treated keratinocytes, which demonstrated upregulation of disease-related and IFN-gamma-induced genes. Hence, IL-20 may influence inflammation through IFN-like effects. Together, these data indicate that IL-20 may be an important effector cytokine in psoriasis, and that its inhibition may represent a potential therapeutic target.
Assuntos
Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Antígeno CD11c/análise , Regulação da Expressão Gênica/fisiologia , Interleucinas/metabolismo , Leucócitos/imunologia , Leucócitos/metabolismo , Psoríase/genética , Psoríase/metabolismo , Adulto , Alefacept , Antígenos CD2/análise , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/imunologia , Cadeias beta de Integrinas/fisiologia , Interferon gama/fisiologia , Interleucinas/análise , Interleucinas/genética , Interleucinas/farmacologia , Queratinócitos/química , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Leucócitos/química , Leucócitos/efeitos dos fármacos , Monócitos/química , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Psoríase/tratamento farmacológico , Psoríase/fisiopatologia , RNA Mensageiro/análise , RNA Mensageiro/genética , Receptores de Interleucina/análise , Receptores de Interleucina/genética , Receptores de Interleucina/fisiologia , Proteínas Recombinantes de Fusão/farmacologia , Proteínas Recombinantes de Fusão/uso terapêutico , Pele/química , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Efalizumab (anti-CD11a) interferes with LFA-1/ICAM-1 binding and inhibits several key steps in psoriasis pathogenesis. This study characterizes the effects of efalizumab on T-cell activation responses and expression of surface markers on human circulating psoriatic T cells during a therapeutic trial. Our data suggest that efalizumab may induce a unique type of T-cell hyporesponsiveness, directly induced by LFA-1 binding, which is distinct from conventional anergy described in animal models. Direct activation of T cells through different activating receptors (CD2, CD3, CD3/28) is reduced, despite T cells being fully viable. This hyporesponsiveness was spontaneously reversible after withdrawal of the drug, and by IL-2 in vitro. In contrast to the state of anergy, Ca(+2) release is intact during efalizumab binding. Furthermore, lymphocyte function-associated antigen-1 (LFA-1) blockade resulted in an unexpected downregulation of a broad range of surface molecules, including the T-cell receptor complex, co-stimulatory molecules, and integrins unrelated to LFA-1, both in the peripheral circulation and in diseased skin tissue. These observations provide evidence for the mechanism of action of efalizumab. The nature of this T-cell hyporesponsiveness suggests that T-cell responses may be reduced during efalizumab therapy, but are reversible after ceasing efalizumab treatment.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Antígeno CD11a/imunologia , Psoríase/tratamento farmacológico , Psoríase/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Adulto , Idoso , Anticorpos Monoclonais Humanizados , Antígenos CD2/metabolismo , Antígenos CD28/metabolismo , Complexo CD3/metabolismo , Antígenos CD4/metabolismo , Antígenos CD8/metabolismo , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/imunologia , Feminino , Humanos , Integrina alfa4beta1/metabolismo , Interleucina-2/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Antígeno-1 Associado à Função Linfocitária/metabolismo , Masculino , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/metabolismoRESUMO
Alefacept is an LFA3-Ig fusion protein that binds to CD2 and is thought to inhibit T cell activation by antagonism of CD2 signaling or by lysis of CD2(+) cells. Alefacept is potential future therapeutic for organ transplant recipients or graft-vs-host disease and is an approved therapeutic for psoriasis vulgaris, which is a T cell-mediated inflammatory disease. However, alefacept improves psoriasis in only approximately 50% of patients treated for 12 wk. We studied the immunologic effects of alefacept in a group of psoriasis patients during treatment. We found that T cells, especially CD8(+) T cells, were rapidly decreased in the peripheral circulation. Decreases in circulating T cells were not associated with induced apoptosis. Unexpectedly, in addition to suppression of inflammatory genes, we found a marked induction of mRNAs for STAT1, IL-8, and monokine induced by IFN-gamma during the first day of treatment in PBMC. We confirmed the agonistic effects of alefacept in PBMC in vitro, which were similar to CD3/CD28 ligation on T cells. These data establish that alefacept activates gene expression programs in leukocytes and suggest that its therapeutic action may be as a mixed agonist/antagonist. Furthermore, responding patients to alefacept treatment show unique patterns of gene modulation. Whereas alefacept down-regulated TCRs CD3D and CD2 in responders, nonresponders reveal a higher expression of T cell activation genes such as CD69 in pretreatment PBMC. These finding suggest a potential basis for categorizing responders vs nonresponders at an early time point in treatment or before treatment of a broad range of proinflammatory diseases. This study 1) establishes alefacept as a novel CD2 agonist molecule for induction of leukocyte activation genes (prior work proposed its mechanism as a CD2 antagonist) and 2) that differential activation of genes may categorize clinical responders to this agent, critical for cost-effective use of this drug.
Assuntos
Regulação da Expressão Gênica/imunologia , Psoríase/imunologia , Psoríase/terapia , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/agonistas , Adulto , Idoso , Alefacept , Apoptose/genética , Apoptose/imunologia , Biomarcadores/sangue , Antígenos CD2/biossíntese , Antígenos CD2/genética , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Regulação para Baixo/genética , Regulação para Baixo/imunologia , Feminino , Humanos , Memória Imunológica/genética , Ativação Linfocitária/genética , Linfopenia/genética , Linfopenia/imunologia , Linfopenia/patologia , Masculino , Pessoa de Meia-Idade , Ligação Proteica/genética , Ligação Proteica/imunologia , Psoríase/genética , Psoríase/patologia , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes de Fusão/uso terapêutico , Fase de Repouso do Ciclo Celular/genética , Fase de Repouso do Ciclo Celular/imunologia , Pele/imunologia , Pele/metabolismo , Pele/patologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Regulação para Cima/genética , Regulação para Cima/imunologiaRESUMO
The mechanisms of action of marketed TNF-blocking drugs in lesional tissues are still incompletely understood. Because psoriasis plaques are accessible to repeat biopsy, the effect of TNF/lymphotoxin blockade with etanercept (soluble TNFR) was studied in ten psoriasis patients treated for 6 months. Histological response, inflammatory gene expression, and cellular infiltration in psoriasis plaques were evaluated. There was a rapid and complete reduction of IL-1 and IL-8 (immediate/early genes), followed by progressive reductions in many other inflammation-related genes, and finally somewhat slower reductions in infiltrating myeloid cells (CD11c+ cells) and T lymphocytes. The observed decreases in IL-8, IFN-gamma-inducible protein-10 (CXCL10), and MIP-3alpha (CCL20) mRNA expression may account for decreased infiltration of neutrophils, T cells, and dendritic cells (DCs), respectively. DCs may be less activated with therapy, as suggested by decreased IL-23 mRNA and inducible NO synthase mRNA and protein. Decreases in T cell-inflammatory gene expression (IFN-gamma, STAT-1, granzyme B) and T cell numbers may be due to a reduction in DC-mediated T cell activation. Thus, etanercept-induced TNF/lymphotoxin blockade may break the potentially self-sustaining cycle of DC activation and maturation, subsequent T cell activation, and cytokine, growth factor, and chemokine production by multiple cell types including lymphocytes, neutrophils, DCs, and keratinocytes. This results in reversal of the epidermal hyperplasia and cutaneous inflammation characteristic of psoriatic plaques.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Regulação para Baixo/imunologia , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/fisiologia , Psoríase/imunologia , Psoríase/patologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Anti-Inflamatórios não Esteroides/uso terapêutico , Contagem de Células , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/enzimologia , Células Dendríticas/patologia , Regulação para Baixo/efeitos dos fármacos , Etanercepte , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Humanos , Imunoglobulina G/administração & dosagem , Imunoglobulina G/uso terapêutico , Mediadores da Inflamação/metabolismo , Injeções Subcutâneas , Contagem de Linfócitos , Células Mieloides/efeitos dos fármacos , Células Mieloides/patologia , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Psoríase/tratamento farmacológico , Psoríase/genética , Receptores do Fator de Necrose Tumoral/administração & dosagem , Receptores do Fator de Necrose Tumoral/uso terapêutico , Linfócitos T/efeitos dos fármacos , Linfócitos T/patologia , Fator de Necrose Tumoral alfa/fisiologiaRESUMO
Psoriasis vulgaris, a skin disease that is considered to be the result of a type 1 autoimmune response, provides an opportunity for studying the changes that occur in a target-diseased tissue during innovative immunotherapies. To gain a more comprehensive picture of the response to an approved biological therapy, we studied alfacept, which is a CD2 binding fusion protein. We examined T cells, dendritic cells (DCs), and expression of a number of inflammatory genes. In 22 patients, 55% demonstrated a clear histological remission of the disease, with a 73% reduction in lesional lymphocytes and a 79% decrease in infiltrating CD8+ cells. Only histological responders showed marked reductions in the tissue expression of inflammatory genes IFN-gamma, signal transducer and activator of transcription 1, monokine induced by IFN-gamma, inducible NO synthase, IL-8, and IL-23 subunits. Parallel decreases in CD83+ and CD11c+ DCs also were measured by immunohistochemistry. Because we observed that alefacept binds primarily to T cells and not DCs, we suggest that T cells are the primary target for therapy, but that DCs and a spectrum of type 1 inflammatory genes are coordinately suppressed.
Assuntos
Células Dendríticas/imunologia , Inflamação/genética , Psoríase , Proteínas Recombinantes de Fusão/uso terapêutico , Linfócitos T/imunologia , Adulto , Idoso , Alefacept , Antígenos CD/imunologia , Biópsia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Ligação Proteica , Psoríase/tratamento farmacológico , Psoríase/genética , Psoríase/imunologia , Psoríase/patologia , Subpopulações de Linfócitos T/imunologiaRESUMO
We find that CD11c(+) cells with many markers of dendritic cells (DCs) are a major cell type in the skin lesions of psoriasis. These CD11c(+) cells, which are evident in both epidermis and dermis, are the sites for the expression of two mediators of inflammation, inducible nitric oxide synthase (iNOS) and TNF-alpha in diseased skin. These cells express HLA-DR, CD40, and CD86, lack the Langerin and CD14 markers of Langerhans cells and monocytes, respectively, and to a significant extent express the DC maturation markers DC-LAMP and CD83. Treatment of psoriasis with efalizumab (anti-CD11a, Raptiva) strongly reduces infiltration by these DCs in patients responding to this agent. Disease activity after therapy was more related to DC infiltrates and iNOS mRNA levels than T cell infiltrates, and CD11c(+) cells responded more quickly to therapy than epidermal keratinocytes. Our results suggest that a type of DC, which resembles murine "Tip-DCs" that can accumulate during infection, has proinflammatory effects in psoriasis through nitric oxide and TNF-alpha production, and can be an important target for suppressive therapies.
Assuntos
Anticorpos Monoclonais/farmacologia , Células Dendríticas/citologia , Óxido Nítrico Sintase Tipo II/fisiologia , Psoríase/patologia , Fator de Necrose Tumoral alfa/fisiologia , Anticorpos Monoclonais Humanizados , Antígenos CD/biossíntese , Antígeno B7-2/biossíntese , Antígeno CD11c/biossíntese , Antígenos CD40/biossíntese , Separação Celular , Células Dendríticas/metabolismo , Citometria de Fluxo , Antígenos HLA-DR/metabolismo , Humanos , Imunoglobulinas/biossíntese , Imuno-Histoquímica , Inflamação , Proteínas de Membrana Lisossomal/metabolismo , Glicoproteínas de Membrana/biossíntese , Microscopia de Fluorescência , Óxido Nítrico Sintase Tipo II/metabolismo , Psoríase/metabolismo , RNA Mensageiro/metabolismo , Fatores de Tempo , Antígeno CD83RESUMO
PURPOSE OF REVIEW: Discuss and update concepts and hypotheses for the pathogenesis of psoriasis based on new research reports (primarily from 2003 and early 2004). RECENT FINDINGS: Increases in newly defined dendritic cell subsets, cytokines, and chemokines have been identified in psoriasis lesions and have modified views of T-cell-mediated pathogenesis. In addition, the psoriasis transcriptome has been defined by large-scale genomic expression studies, and these data suggest distinct molecular mechanisms of type 1 T-cell-mediated inflammation. Somewhat surprisingly, therapeutic clinical trials suggest that tumor necrosis factor is a major pathogenic cytokine in psoriasis, whereas translational studies point to roles of other innate pathways mediated by heat shock proteins, glycolipids, natural killer T cells, or dendritic cells in disease pathogenesis. SUMMARY: An interactive network of inflammatory cytokines, chemokines, dendritic cells, and type 1 T cells or natural killer T cells potentially drives pathogenic inflammation in psoriasis vulgaris. Continued clinical studies with defined immune antagonists provide a critical means to dissect the contribution of different cell subsets and genomic pathways to the pathogenesis of psoriasis vulgaris.
Assuntos
Citocinas/imunologia , Células Dendríticas/imunologia , Psoríase/imunologia , Linfócitos T/imunologia , Humanos , Psoríase/genéticaRESUMO
In medical research, it is rare that a single variable is sufficient to represent all relevant aspects of epidemiological risk, genomic activity, adverse events, or clinical response. Since biological systems tend to be neither linear, nor hierarchical in nature, the assumptions of traditional multivariate statistical methods based on the linear model can often not be justified on theoretical grounds. Establishing concept validity through empirical validation is not only problematic, but also time consuming. This paper proposes the use of u-statistics for scoring multivariate ordinal data and a family of simple non-parametric tests for analysis. The scoring method is demonstrated to be applicable to scoring clinical response profiles in the treatment of psoriasis and then to identifying genomic pathways that best correlate with these profiles.
Assuntos
Ensaios Clínicos como Assunto/métodos , Estatística como Assunto/métodos , Adjuvantes Imunológicos/uso terapêutico , Citocinas/genética , Citocinas/imunologia , Interpretação Estatística de Dados , Humanos , Análise Multivariada , Psoríase/tratamento farmacológico , Psoríase/imunologia , RNA Mensageiro/química , RNA Mensageiro/genética , Projetos de Pesquisa , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estatísticas não ParamétricasRESUMO
Brain tumors carry a poor prognosis, and newer approaches to their therapy are urgently needed. Natural killer T (NKT) cells are distinct innate lymphocytes with antitumor potentials. Defects in NKT cell function have been observed in patients with other forms of cancer. Here we show that both the frequency and interferon-gamma-producing function of NKT cells are well preserved in adult patients with glioma (n=9) and comparable to findings in healthy controls (n=9). These cells can be readily expanded in culture using autologous mature dendritic cells loaded with the NKT ligand, alpha-galactosyl ceramide. The expanded NKT cells from glioma patients are functional and, importantly, kill glioma cells in a ligand- and CD1d-dependent manner. Expression of CD1d is detected both on primary glioma cells as well as endothelial cells in infiltrating new blood vessels by immunohistochemistry of glioma tissue sections. These data suggest that targeting NKT cells may provide a novel strategy for immunotherapy of glioma.
Assuntos
Neoplasias Encefálicas/imunologia , Células Dendríticas/imunologia , Glioma/imunologia , Células Matadoras Naturais/imunologia , Linfócitos T/imunologia , Adulto , Idoso , Antígenos CD1/metabolismo , Antígenos CD1d , Neoplasias Encefálicas/patologia , Citotoxicidade Imunológica , Endotélio Vascular/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Galactosilceramidas/imunologia , Galactosilceramidas/metabolismo , Glioma/patologia , Humanos , Interferon gama/biossíntese , Ligantes , Masculino , Pessoa de Meia-IdadeRESUMO
Therapeutic administration of efalizumab, a humanized antibody to CD11a, induces a marked but reversible increase of peripheral lymphocytes in psoriasis patients. In this study, 13 patients were treated with 12 weekly subcutaneous doses (2 mg/kg/week) of efalizumab, and all 13 patients had increases in leukocyte counts. This increased white blood cell count was mainly due to a 3- to 4-fold increase in the number of circulating CD3(+) lymphocytes during active treatment. Both naive and memory populations of CD4(+) and CD8(+) lymphocytes in the peripheral blood increased, with the largest increase observed in memory CD8(+) T cells. This CD8(+) memory T cell subset is a prominent T cell population found in psoriatic skin. An increase in Type 1 (IFN-gamma producing) T cells was also observed during treatment. Both components of LFA-1, CD11a and CD18, were downregulated during treatment, and surprisingly the integrins CD11b and beta 7 were similarly reduced. We conclude that efalizumab most likely blocks cutaneous entry of memory CD8(+) T cells, a highly disease-relevant cell population. The relatively smaller increase in naive peripheral blood T cells could be attributed to reduced trafficking of naive T cells.