RESUMO
OBJECTIVES: We aimed to identify transcriptional gene signatures predictive of clinical response, for pharmacodynamic evaluation, and to provide mechanistic insight into JNJ-55920839, a human IgG1κ neutralizing mAb targeting IFN-α/IFN-ω, in participants with systemic lupus erythematosus (SLE). METHODS: Blood samples were obtained from SLE participants at baseline and up to Day 130, who received six 10 mg/kg IV doses of JNJ-55920839/placebo every 2 weeks. Participants with mild-to-moderate SLE who achieved clinical responses using SLE Disease Activity Index 2000 Responder Index 4-point change were considered responders. Transcriptional signatures from longitudinally collected blood were generated by RNA-Seq; signatures were generated by microarray from baseline blood samples exposed in vitro to JNJ-55920839 versus untreated. RESULTS: Two gene signatures (IFN-I Signaling and Immunoglobulin Immune Response) exhibited pharmacodynamic changes among JNJ-55920839 responders. The Immunoglobulin signature, but not the IFN-I signature, was elevated at baseline in JNJ-55920839 responders. A gene cluster associated with neutrophil-mediated immunity was reduced at baseline in JNJ-55920839 responders, substantiated by lower neutrophil counts in responders. An IFN-I signature was suppressed by JNJ-55920839 in vitro treatment versus untreated blood to a greater extent in responders before in vivo dosing. CONCLUSIONS: These signatures may enable enrichment for treatment responders when using IFN-I-suppressing treatments in SLE.
Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Interferon-alfa/antagonistas & inibidores , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Administração Intravenosa , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Imunoglobulinas/genética , Imunoglobulinas/imunologia , Interferon Tipo I/efeitos dos fármacos , Interferon Tipo I/genética , Interferon-alfa/genética , Interferon-alfa/imunologia , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/genética , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Índice de Gravidade de Doença , Transcrição Gênica/genética , Transcriptoma/efeitos dos fármacos , Transcriptoma/genética , Ustekinumab/administração & dosagem , Ustekinumab/farmacologia , Ustekinumab/uso terapêuticoRESUMO
Gray leaf spot (GLS), caused by Cercospora zeae-maydis and Cercospora zeina, is one of the most important diseases of maize worldwide. The pathogen has a necrotrophic lifestyle and no major genes are known for GLS. Quantitative resistance, although poorly understood, is important for GLS management. We used genetic mapping to refine understanding of the genetic architecture of GLS resistance and to develop hypotheses regarding the mechanisms underlying quantitative disease resistance (QDR) loci. Nested association mapping (NAM) was used to identify 16 quantitative trait loci (QTL) for QDR to GLS, including seven novel QTL, each of which demonstrated allelic series with significant effects above and below the magnitude of the B73 reference allele. Alleles at three QTL, qGLS1.04, qGLS2.09, and qGLS4.05, conferred disease reductions of greater than 10%. Interactions between loci were detected for three pairs of loci, including an interaction between iqGLS4.05 and qGLS7.03. Near-isogenic lines (NILs) were developed to confirm and fine-map three of the 16 QTL, and to develop hypotheses regarding mechanisms of resistance. qGLS1.04 was fine-mapped from an interval of 27.0 Mb to two intervals of 6.5 Mb and 5.2 Mb, consistent with the hypothesis that multiple genes underlie highly significant QTL identified by NAM. qGLS2.09, which was also associated with maturity (days to anthesis) and with resistance to southern leaf blight, was narrowed to a 4-Mb interval. The distance between major leaf veins was strongly associated with resistance to GLS at qGLS4.05. NILs for qGLS1.04 were treated with the C. zeae-maydis toxin cercosporin to test the role of host-specific toxin in QDR. Cercosporin exposure increased expression of a putative flavin-monooxygenase (FMO) gene, a candidate detoxification-related gene underlying qGLS1.04. This integrated approach to confirming QTL and characterizing the potential underlying mechanisms advances the understanding of QDR and will facilitate the development of resistant varieties.
Assuntos
Ascomicetos/fisiologia , Doenças das Plantas/genética , Doenças das Plantas/imunologia , Zea mays/genética , Zea mays/imunologia , Pleiotropia Genética , Oxigenases/genética , Perileno/análogos & derivados , Perileno/farmacologia , Folhas de Planta/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Zea mays/classificaçãoRESUMO
Much remains unknown of molecular events controlling the plant hypersensitive defense response (HR), a rapid localized cell death that limits pathogen spread and is mediated by resistance (R-) genes. Genetic control of the HR is hard to quantify due to its microscopic and rapid nature. Natural modifiers of the ectopic HR phenotype induced by an aberrant auto-active R-gene (Rp1-D21), were mapped in a population of 3,381 recombinant inbred lines from the maize nested association mapping population. Joint linkage analysis was conducted to identify 32 additive but no epistatic quantitative trait loci (QTL) using a linkage map based on more than 7000 single nucleotide polymorphisms (SNPs). Genome-wide association (GWA) analysis of 26.5 million SNPs was conducted after adjusting for background QTL. GWA identified associated SNPs that colocalized with 44 candidate genes. Thirty-six of these genes colocalized within 23 of the 32 QTL identified by joint linkage analysis. The candidate genes included genes predicted to be in involved programmed cell death, defense response, ubiquitination, redox homeostasis, autophagy, calcium signalling, lignin biosynthesis and cell wall modification. Twelve of the candidate genes showed significant differential expression between isogenic lines differing for the presence of Rp1-D21. Low but significant correlations between HR-related traits and several previously-measured disease resistance traits suggested that the genetic control of these traits was substantially, though not entirely, independent. This study provides the first system-wide analysis of natural variation that modulates the HR response in plants.
Assuntos
Resistência à Doença/genética , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas/genética , Zea mays/genética , Mapeamento Cromossômico , Desequilíbrio de Ligação , Doenças das Plantas/genética , Proteínas de Plantas/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Psoriasis is an inflammatory disease with dynamic interactions between the immune system and the skin. The IL-23/Th17 axis plays an important role in the pathogenesis of psoriasis, although the exact contributions of IL-23 and IL-17 in vivo remain unclear. K5.Stat3C transgenic mice constitutively express activated Stat3 within keratinocytes, and these animals develop skin lesions with histological and cytokine profiles similar to those of human plaque psoriasis. In this study, we characterized the effects of anti-mouse IL-17A, anti-mouse IL-12/23p40, and anti-mouse IL-23p19 Abs on the development of psoriasis-like lesions in K5.Stat3C transgenic mice. Treatment with anti-IL-12/23p40 or anti-IL-23p19 Abs greatly inhibited 12-O-tetradecanoylphorbol-13-acetate-induced epidermal hyperplasia in the ears of K5.Stat3C mice, whereas the inhibitory effect of an anti-IL-17A Ab was relatively less prominent. Treatment with anti-IL-12/23p40 or anti-IL-23p19 Abs markedly lowered transcript levels of Th17 cytokines (e.g., IL-17 and IL-22), ß-defensins, and S100A family members in skin lesions. However, anti-IL-17A Ab treatment did not affect mRNA levels of Th17 cytokines. Crossing IL-17A-deficient mice with K5.Stat3C mice resulted in partial attenuation of 12-O-tetradecanoylphorbol-13-acetate-induced lesions, which were further attenuated by anti-IL-12/23p40 Ab treatment. FACS analysis of skin-draining lymph node cells from mice that were intradermally injected with IL-23 revealed an increase in both IL-22-producing T cells and NK-22 cells. Taken together, this system provides a useful mouse model for psoriasis and demonstrates distinct roles for IL-23 and IL-17.
Assuntos
Interleucina-17/fisiologia , Interleucina-23/fisiologia , Psoríase/imunologia , Psoríase/terapia , Animais , Células Cultivadas , Citocinas/biossíntese , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/imunologia , Humanos , Imunização Passiva , Imunofenotipagem , Interleucina-17/imunologia , Interleucina-23/imunologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Masculino , Camundongos , Camundongos Transgênicos , Células NIH 3T3 , Psoríase/patologia , Proteínas S100/biossíntese , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia , Acetato de Tetradecanoilforbol/análogos & derivados , Acetato de Tetradecanoilforbol/toxicidade , beta-Defensinas/biossínteseRESUMO
BACKGROUND: Retinoblastoma is a rare malignancy involving the retina, although, more common among children, with genetic inheritance explaining the incidence as well as acquired forms. The incidence varies among race and sex as well as mortality and survival. The current study aimed to assess retinoblastoma cumulative incidence (CMI), mortality, and survival by sex. METHODS: A retrospective cohort design was used to assess the CMI, mortality, and survival in this pediatric malignancy based on the Surveillance Epidemiology and End Results (SEER) data 2000-2017. The binomial regression model was used to examine sex differentials in mortality, as well as other study variables, while Cox proportional hazard model was used for the survival variability by sex. RESULTS: The CMI during this period was higher among males relative to females (males n = 249, 56.7%; females n = 190, 43.3%, χ2 = 2.90, df = 1, p = 0.089). There were sex differences in mortality, with excess mortality observed among males compared to females, risk ratio = 3.40, 95% CI [1.0-15.72]. The survival differences by sex indicated decreased survival among males relative to females, hazard ratio (HR) = 3.39, 95% CI [1.0-15.72]. After controlling for the potential confoundings, namely tumor grade, urbanity, and median income the survival disadvantage of males persisted. Compared to females', males were more than three times as likely to die, adjusted HR = 3.42, 99% CI [0.37-31.60]. CONCLUSION: In a representative sample of pediatric retinoblastoma, there was a sex differential in survival with excess risk of dying identified among males relative to females, which may be explained in part by male X-linkage.
Assuntos
Neoplasias da Retina , Retinoblastoma , Humanos , Masculino , Criança , Feminino , Estados Unidos/epidemiologia , Retinoblastoma/epidemiologia , Estudos Retrospectivos , Programa de SEER , Modelos de Riscos Proporcionais , Neoplasias da Retina/epidemiologia , IncidênciaRESUMO
Given the key role of the IL-23/Th17 axis in the pathogenesis of moderate-to-severe plaque psoriasis, several specific inhibitors of the p19 subunit of IL-23 have been approved to treat this chronic inflammatory disease. Clinical data indicate that guselkumab, one such selective IL-23 inhibitor, achieves greater clinical efficacy compared with ustekinumab, which inhibits both IL-12 and IL-23 via binding their shared p40 subunit. To understand mechanisms underlying the enhanced efficacy observed with the p19 subunit of IL-23-specific inhibition, we explored cellular and molecular changes in skin of psoriasis patients treated with ustekinumab or guselkumab and in ustekinumab inadequate responders (Investigator's Global Assessment of psoriasis score ≥ 2) subsequently treated with guselkumab (ustekinumabâguselkumab). Skin biopsies were collected pretreatment and posttreatment to assess histologic changes and molecular responses in ustekinumab- and guselkumab-treated patients. Serum cytokines and skin transcriptomics from the subset of ustekinumabâguselkumab-treated patients were also analyzed to characterize differential treatment effects. Ustekinumab and guselkumab demonstrated differential effects on secretion of pathogenic Th17-related cytokines induced by IL-23 in in vitro assays, which suggest guselkumab is a more potent therapeutic agent. Consistent with these findings, guselkumab elicited a significantly greater reduction in cellular and molecular psoriasis-related disease indicators than ustekinumab. In ustekinumabâguselkumab patients, suppression of serum IL-17A and IL-17F levels and neutralization of molecular scar and psoriasis-related gene markers in skin were significantly greater compared with patients continuing ustekinumab. This comparative study demonstrates that guselkumab inhibits psoriasis-associated pathology, suppresses Th17-related serum cytokines, and normalizes the psoriasis skin gene expression profile more effectively than ustekinumab.
Assuntos
Psoríase , Ustekinumab , Humanos , Ustekinumab/uso terapêutico , Transcriptoma , Anticorpos Monoclonais/farmacologia , Psoríase/metabolismo , Citocinas/metabolismo , Interleucina-23/metabolismo , Interleucina-23/uso terapêuticoRESUMO
Systemic lupus erythematosus (SLE) is an autoimmune disease with significant morbidity and mortality. Type I interferon (IFN) drives SLE pathology and plasmacytoid dendritic cells (pDCs) are potent producers of IFN; however, the specific effects of pDC depletion have not been demonstrated. We show CD123 was highly expressed on pDCs and the anti-CD123 antibody CSL362 potently depleted pDCs in vitro. CSL362 pre-treatment abrogated the induction of IFNα and IFN-induced gene transcription following stimulation with SLE patient-derived serum or immune complexes. RNA transcripts induced in pDCs by ex vivo stimulation with TLR ligands were reflected in gene expression profiles of SLE blood, and correlated with disease severity. TLR ligand-induced protein production by SLE patient peripheral mononuclear cells was abrogated by CSL362 pre-treatment including proteins over expressed in SLE patient serum. These findings implicate pDCs as key drivers in the cellular activation and production of soluble factors seen in SLE.
RESUMO
To capture diverse alleles at a set of loci associated with disease resistance in maize, heterogeneous inbred family (HIF) analysis was applied for targeted QTL mapping and near-isogenic line (NIL) development. Tropical maize lines CML52 and DK888 were chosen as donors of alleles based on their known resistance to multiple diseases. Chromosomal regions ("bins"; n = 39) associated with multiple disease resistance (MDR) were targeted based on a consensus map of disease QTLs in maize. We generated HIFs segregating for the targeted loci but isogenic at ~97% of the genome. To test the hypothesis that CML52 and DK888 alleles at MDR hotspots condition broad-spectrum resistance, HIFs and derived NILs were tested for resistance to northern leaf blight (NLB), southern leaf blight (SLB), gray leaf spot (GLS), anthracnose leaf blight (ALB), anthracnose stalk rot (ASR), common rust, common smut, and Stewart's wilt. Four NLB QTLs, two ASR QTLs, and one Stewart's wilt QTL were identified. In parallel, a population of 196 recombinant inbred lines (RILs) derived from B73 × CML52 was evaluated for resistance to NLB, GLS, SLB, and ASR. The QTLs mapped (four for NLB, five for SLB, two for GLS, and two for ASR) mostly corresponded to those found using the NILs. Combining HIF- and RIL-based analyses, we discovered two disease QTLs at which CML52 alleles were favorable for more than one disease. A QTL in bin 1.06-1.07 conferred resistance to NLB and Stewart's wilt, and a QTL in 6.05 conferred resistance to NLB and ASR.
Assuntos
Imunidade Inata/genética , Doenças das Plantas , Locos de Características Quantitativas , Zea mays , Alelos , Mapeamento Cromossômico , Genótipo , Fenótipo , Doenças das Plantas/genética , Doenças das Plantas/imunologia , Zea mays/genética , Zea mays/crescimento & desenvolvimento , Zea mays/imunologiaRESUMO
Helicobacter pylori (H. pylori) is a bacterial pathogen implicated in gastritis, gastric ulceration, and gastric carcinoma. This study aimed to synthesize literature in providing evidence on the causative role of H. pylori in gastric carcinoma development. This study is based on assessing public literature using an applied meta-analysis, namely, quantitative evidence synthesis (QES). The analytic procedure uses DerSimonian-Laird, including assessing heterogeneity. The QES also utilizes meta-regression and the environmental effect associated with H. pylori in gastric cancer development. Eighteen studies are included in the QES. There is increased prevalence of H. pylori exposure among the cases. The heterogeneity between the CES and individual effect sizes is also significant. Despite controlling for the confoundings, there is increased exposure to H. pylori among the gastric cancer cases, regardless of the differences in the geographic location. H. pylori in this synthesized literature illustrates the contributory role of this microbe in gastric carcinoma. Additionally, regardless of geographic locale, namely, South Korea or Spain, H. pylori is implicated in gastric cancer development.
RESUMO
BACKGROUND: Cancer is the leading cause of disease-related mortality among children, 0-14 years, and lymphoma, a malignant neoplasm of the lymphoid cells, mostly lymphatic B and T cells is common among children. The current study aimed to assess the cumulative incidence (CmI), mortality, and survival in pediatric lymphoma. MATERIALS AND METHODS: A retrospective cohort was utilized to examine children, 0-19 years with lymphoma for CmI, mortality and survival from the Surveillance, Epidemiology, and End Results (SEER) data. The variables assessed included social determinants of health, namely urbanity, median household income, and race. While chi square was used to characterize study variables by race, binomial regression was employed for mortality risk. The Cox proportional hazard model was used for survival modeling. RESULTS: The CmI was higher among white children (76.67%) relative to Black/African American (AA, 13.44%), American Indian/Alaskan Native (AI/AN, 0.67%), as well as Asian/Pacific Islander (A/PI, 7.53%). With respect to mortality, there was excess mortality among Black/AA children compared to white children, Risk Ratio (RR)â¯=â¯1.54, 95% CI, 1.33-1.79. Relative to whites, Blacks were 52% more likely to die, Hazard Ratio (HR)â¯=â¯1.52, 95% CI, 1.30-1.78. Survival disadvantage persisted among Blacks/AA after controlling for the other confoundings, adjusted hazard ratio (aHR)â¯=â¯1.54, 99% CI, 1.24-1.91. CONCLUSION: In a large cohort of children with lymphoma, Black/AA children relative to whites presented with survival disadvantage, which was explained by urbanity and median household income, suggestive of transforming the physical and social environments in narrowing the racial differences in pediatric lymphoma survival in the US.
Assuntos
Negro ou Afro-Americano , Linfoma , Criança , Humanos , Estudos Retrospectivos , Programa de SEER , Estados Unidos/epidemiologia , População BrancaRESUMO
BACKGROUND: Activation of the type I interferon (IFN) pathway is associated with systemic lupus erythematosus (SLE). We assessed the safety and tolerability of JNJ-55920839, a human monoclonal antibody that selectively neutralises most human IFNα subtypes and IFNω, in healthy participants and those with SLE. METHODS: This was a two-part, first-in-human, phase 1, randomised, double-blind, placebo-controlled, multicentre study of single-ascending intravenous doses of 0·3-15 mg/kg or a single subcutaneous dose of 1 mg/kg JNJ-55920839 administered to healthy participants (part A) and multiple intravenous doses of 10 mg/kg JNJ-55920839 administered to participants with SLE (part B). Healthy men and women (women had to be postmenopausal or surgically sterile) aged 18-55 years; bodyweight of 50-90 kg; and body-mass index (BMI) of 18-30 kg/m2 were eligible for inclusion in part A. Men and women with SLE were recruited to part B, fertile female participants were required to have a negative pregnancy test result before and during the study and be using two highly effective methods of birth control. The inclusion criteria for participants with SLE in part B matched part A, except for bodyweight (40-100 kg). In both parts, participants were randomly assigned (3:1) to receive JNJ-55920839 or placebo; a computer-generated randomisation schedule was used in part A, and randomisation was stratified by racial and ethnic subpopulation and elevated levels of serological disease activity in part B. The primary outcome was evaluation of safety and tolerability of the study regimen assessed using clinical and laboratory tests compared with placebo. This study is registered with ClinicalTrials.gov, NCT02609789. FINDINGS: Between Dec 11, 2015, and Sept 20, 2018, 48 healthy participants from a single site and 28 participants with mild-to-moderate SLE from 19 participating centres in seven countries were enrolled in the study. 12 healthy volunteers in part A and eight participants with SLE in part B received placebo. The most common treatment-emergent adverse events in both part A and B were in the system organ class of infections and infestations with a higher percentage of participants administered JNJ-55920839 with infections (ten [28%] of 36 in part A and nine [50%] of 18 in part B) than those exposed to placebo (two [17%] of 12 in part A and one [13%] of eight in part B). Particpants in part B were permitted to continue on defined ongoing standard of care medications. In two participants with SLE, locally disseminated herpes zoster of the skin was reported. No other clinically significant safety or tolerability issues were identified beyond the infections observed in participants treated with JNJ-55920839. INTERPRETATION: JNJ-55920839 was well tolerated and safe. Additional studies are warranted to determine optimal dosing of patients and further explore safety. FUNDING: Janssen.
RESUMO
The T-cell cytokine IL-17 is implicated in multiple inflammatory diseases through its induction of several pro-inflammatory cytokines and chemokines in a broad range of cell targets. Production of IL-17 defines the Th17 subset of helper T-cells associated with protection against microorganisms, a profile best characterized in the murine system. Multiple regulators of Th17 cell differentiation and IL-17 production are reported, but the impact of OX40L is not described. OX40 ligand (OX40L) is an early-stage activator of T-cells through its interaction with CD134 (OX40) that is up-regulated on antigen challenged T-cells. Here, we show that OX40L suppresses IL-17 production by PHA-stimulated human PBMC and purified CD4 and CD8 cells. In agreement with prior reports, OX40L signaling through CD134 increased IFNgamma and IL-4, both of which are reported to inhibit the production of IL-17. OX40L suppression of IL-17 was completely reversed by a neutralizing IFNgamma antibody while there was no effect with a neutralizing IL-4 antibody. Moreover, OX40L also suppressed IL-17 in the presence of IL-23, an established inducer of IL-17 and differentiation factor for Th17 cells. Presuming mediation by IFNgamma, we evaluated expression of this cytokine in the presence of OX40L and IL-23. Surprisingly, IL-23 also induced IFNgamma by PHA-stimulated T-cells and this effect was enhanced in the presence of OX40L. Addition of the IFNgamma antibody not only reversed the OX40L suppression of IL-17 in the presence of IL-23, it markedly enhanced the level of IL-17. These results further establish IFNgamma as a primary modulator of IL-17 production in the human cells, much as in the murine system.
Assuntos
Interleucina-17/imunologia , Ligante OX40/imunologia , Receptores OX40/imunologia , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Humanos , Interferon gama/imunologia , Interleucina-23/imunologia , Interleucina-4/imunologia , Interleucina-6/imunologia , Camundongos , Fito-Hemaglutininas/imunologiaRESUMO
The functional role of IL-12 and IL-23 in host defense and disease following viral infection of the CNS was determined. Instillation of mouse hepatitis virus (MHV, a positive-strand RNA virus) into the CNS of mice results in acute encephalitis followed by a chronic immune-mediated demyelinating disease. Antibody-mediated blocking of either IL-23 (anti-IL-23p19) or IL-12 and IL-23 (anti-IL-12/23p40) signaling did not mute T-cell trafficking into the CNS or antiviral effector responses and mice were able to control viral replication within the brain. Therapeutic administration of either anti-IL-23p19 or anti-IL-12/23p40 to mice with viral-induced demyelination did not attenuate T-cell or macrophage infiltration into the CNS nor improve clinical disease or diminish white matter damage. In contrast, treatment of mice with anti-IL-12/23p40 or anti-IL-23p19 resulted in inhibition of the autoimmune model of demyelination, experimental autoimmune encephalomyelitis (EAE). These data indicate that (1) IL-12 and IL-23 signaling are dispensable in generating a protective T-cell response following CNS infection with MHV, and (2) IL-12 and IL-23 do not contribute to demyelination in a model independent of autoimmune T-cell-mediated pathology. Therefore, therapeutic targeting of IL-12 and/or IL-23 for the treatment of autoimmune diseases may offer unique advantages by reducing disease severity without muting protective responses following viral infection.
Assuntos
Sistema Nervoso Central/imunologia , Infecções por Coronavirus/imunologia , Interleucina-12/imunologia , Interleucina-23/imunologia , Vírus da Hepatite Murina/imunologia , Linfócitos T/imunologia , Animais , Doenças Autoimunes , Sistema Nervoso Central/patologia , Infecções por Coronavirus/patologia , Doenças Desmielinizantes/imunologia , Encefalomielite/imunologia , Feminino , CamundongosRESUMO
PURPOSE: Although many previous studies have indicated that the acute inflammatory response following traumatic brain injury (TBI) is detrimental, inflammation may also positively influence outcome in the more chronic post-injury recovery period. We evaluated the effects of monoclonal antibodies (mAB), neutralizing either IL-6 (IL-6 mAB) or TNF-alpha (TNF mAB), administered intracerebroventricularly (i.c.v) on acute neurobehavioral outcome following TBI. METHODS: Male Sprague-Dawley rats (n = 173) were anesthetized (sodium pentobarbital, 60 mg/kg) and subjected to lateral fluid percussion (FP) brain injury of moderate severity (n = 123) or sham injury (n = 50). Beginning 1 h post-injury, TNF mAB (n = 41, of which 25 were brain-injured) or IL-6 mAB (n = 42, of which 25 were brain-injured) at a concentration of 2 mg/mL was infused i.c.v ipsilateral to the injury for 48 hours. Vehicle-treated animals (control IgG; n = 43, of which 26 were brain-injured) served as controls. In Study 1, cognitive function was evaluated in the Morris Water Maze (MWM) followed by evaluation of regional cerebral edema at 48 h post-injury. In Study 2, animals were evaluated for neurological motor function and post-injury learning in the MWM at one week post-injury. RESULTS: FP brain injury caused significant cognitive (p < 0.05) and neurological motor (p < 0.05) deficits and increased regional brain water content in the injured hemisphere. Treatment with either TNF- or IL-6-mAB had no effect on neurological motor, cognitive function or brain edema during the first post-injury week. CONCLUSIONS: Evaluation of anti-inflammatory mABs on more chronic behavioral deficits appears warranted.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Lesões Encefálicas/tratamento farmacológico , Transtornos Cognitivos/prevenção & controle , Mediadores da Inflamação/antagonistas & inibidores , Interleucina-6/antagonistas & inibidores , Interleucina-6/imunologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Edema Encefálico/tratamento farmacológico , Edema Encefálico/fisiopatologia , Lesões Encefálicas/metabolismo , Lesões Encefálicas/mortalidade , Lesões Encefálicas/fisiopatologia , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/fisiopatologia , Mediadores da Inflamação/imunologia , Aprendizagem/efeitos dos fármacos , Aprendizagem/fisiologia , Masculino , Destreza Motora/efeitos dos fármacos , Destreza Motora/fisiologia , Ratos , Ratos Sprague-DawleyRESUMO
The oral administration of neuroantigens can suppress as well as treat autoimmune disease. Using EAE as a model system, we examined the antigen-presenting cell in oral tolerance. Expansion of dendritic cells (DCs) prior to or after disease is established facilitated oral tolerance. Transfer of oral antigen-loaded DCs resulted in protection from EAE by induction of IL-4 and IL-5 in recipient animals. LPS treatment of donors abrogated the ability of DCs to transfer protection from EAE, emphasizing the importance of the DC activation state. T cells exposed to orally administered antigen were monitored in TCR transgenic mice and found to undergo activation followed by deletion. The thymus plays a critical role in oral tolerance since thymectomized mice could not be tolerized. The thymus is postulated to be a site for deletion of autoreactive T cells or a site for generation of regulatory T cells.
Assuntos
Autoantígenos/imunologia , Imunidade nas Mucosas , Linfócitos T/imunologia , Administração Oral , Animais , Células Apresentadoras de Antígenos/imunologia , Antígenos/imunologia , Encefalomielite Autoimune Experimental/imunologia , Humanos , Modelos ImunológicosRESUMO
Since the original publication of the article "Development of the IL-12/23 antagonist ustekinumab in psoriasis: Past, present and future perspectives" in March 2011 (see Appendix),(1) there have been several new publications and developments of note. A number of new reports from the ustekinumab psoriasis clinical development program have been published. The analysis of efficacy and safety in the PHOENIX 1 long-term extension demonstrated that continuous stable maintenance dosing of ustekinumab was generally well tolerated and sustained durable efficacy through up to three years of treatment.(2) Pooled safety data from the phase 2 and phase 3 global trials showed that the safety profile of long-term continuous ustekinumab treatment through up to three years(3,4) and four years(5) of follow-up was favorable and comparable to what has been reported previously in the shorter-term ustekinumab psoriasis studies.(6-8) This represents the greatest exposure and longest follow-up of psoriasis patients treated with a biologic published to date. Additional phase 3 trials in Asian populations demonstrated similar high levels of efficacy and favorable safety profiles in Japanese,(9,10) Korean,(11,12) and Taiwanese(11,12) patients as those observed in trials conducted in mostly White populations in North America and Europe.(6-8) These data support the positive benefit:risk profile and consistency of response to ustekinumab over years of usage, and in multiple ethnic groups. Results from up to five years of treatment with ustekinumab in the long-term extensions of the phase 3 trials, and the efficacy, safety, and effect on quality of life in Chinese patients will be available in 2012. In addition to clinical trials of ustekinumab for the treatment of psoriasis, 24-week data from one phase 3 study of ustekinumab for the treatment of psoriatic arthritis has recently been presented(13) and another study is ongoing. A Phase 2b trial in Crohn's disease has also been presented,(14) and three phase 3 studies in Crohn's disease are currently in progress.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Descoberta de Drogas/tendências , Interleucina-12/antagonistas & inibidores , Interleucina-23/antagonistas & inibidores , Psoríase/tratamento farmacológico , Animais , Anticorpos Monoclonais Humanizados , Descoberta de Drogas/métodos , Previsões , Humanos , Psoríase/imunologia , Transdução de Sinais/imunologia , Resultado do Tratamento , UstekinumabRESUMO
Monoclonal antibody (mAb) therapy was first established upon the approval of a mouse antibody for treatment of human acute organ rejection. However, the high incidence of immune response against the mouse mAb restricted therapeutic utility. Development of chimeric, "humanized" and human mAbs broadened therapeutic application to immune-mediated diseases requiring long-term treatment. Indeed, mAb therapeutics targeting soluble cytokines are highly effective in numerous immune-mediated disorders. A recent example is ustekinumab, a first-in-class therapeutic human immunoglobulin G1 kappa mAb that binds to the interleukins (IL)-12 and IL-23, cytokines that modulate lymphocyte function, including T-helper (Th) 1 and Th17 cell subsets. Ustekinumab was generated via recombinant human IL-12 immunization of human immunoglobulin (hu-Ig) transgenic mice. Ustekinumab binds to the p40 subunit common to IL-12 and IL-23 and prevents their interaction with the IL-12 receptor ß1 subunit of the IL-12 and IL-23 receptor complexes. Ustekinumab is approved for treatment of moderate-to-severe plaque psoriasis and has demonstrated efficacy in Crohn disease and psoriatic arthritis. The clinical characterization of ustekinumab continues to clarify our understanding of human immune pathologies and may offer a novel therapeutic option for certain immune-mediated diseases.
Assuntos
Anticorpos Monoclonais/imunologia , Interleucina-12/imunologia , Interleucina-23/imunologia , Psoríase/terapia , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Humanos , Camundongos , Psoríase/imunologia , Resultado do Tratamento , UstekinumabRESUMO
Preclinical and clinical studies conducted in the mid-1990s reported strong association and causality between the T-cell helper (T(H)) 1 inductor cytokine interleukin (IL)-12 and numerous immune-mediated disorders, which spurred the development of therapeutic agents targeting IL-12 function. One of the first to enter the clinic, ustekinumab, is a human monoclonal antibody (mAb) that binds to the p40 subunit of IL-12. Subsequent to the generation of ustekinumab, it was discovered that IL-23 also contains the p40 subunit. Thus, although ustekinumab was designed to target IL-12, it also modulates IL-23, a cytokine important to the development and/or maintenance of T(H)17 cells. Clinical observations established that IL-12/23p40 is integral to the pathologies of psoriasis, psoriatic arthritis and Crohn's disease. The molecular and cellular evaluations conducted in ustekinumab clinical programs have provided numerous insights into the pathologic processes of these disorders, illustrating how a novel molecular entity can contribute to our understanding of disease. The individual contributions of these cytokines to specific pathologies require investigation and clinical evaluation of the role of IL-12- and IL-23-specific inhibitors.
Assuntos
Anticorpos Monoclonais/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Interleucina-12/antagonistas & inibidores , Interleucina-23/antagonistas & inibidores , Transdução de Sinais/fisiologia , Animais , Anticorpos Monoclonais Humanizados , Humanos , Transdução de Sinais/efeitos dos fármacos , UstekinumabRESUMO
The development of ustekinumab as a first-in-class anti-interleukin (IL) 12/23p40 therapeutic agent for psoriasis represents an important example of modern and rational drug design and development. Psoriasis is a chronic, systemic, immune-mediated skin disorder with considerable clinical, psychosocial, and economic burden. Ustekinumab is a human monoclonal antibody (mAb) that binds the p40 subunit common to IL-12 and IL-23, key cytokines in psoriasis pathogenesis. The therapeutic mAb was developed using human gamma-1 immunoglobulin (IgG)-expressing transgenic mice, which created a molecule with endogenous IgG(1) biologic properties and low immunogenicity. Ustekinumab was well tolerated in clinical studies and yielded rapid, significant, and sustained efficacy plus improved quality of life/work performance and reduced depression/anxiety. Its pharmacologic properties afford the most convenient dosing regimen among approved biologics, representing a significant advancement in the treatment of moderate to severe psoriasis. Ustekinumab also holds promise for other immune-mediated disorders with significant unmet need.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Desenho de Fármacos , Interleucina-12/antagonistas & inibidores , Interleucina-23/antagonistas & inibidores , Psoríase/tratamento farmacológico , Animais , Anticorpos Monoclonais/biossíntese , Anticorpos Monoclonais Humanizados , Descoberta de Drogas/tendências , Previsões , Humanos , Fatores Imunológicos/uso terapêutico , Interleucina-12/imunologia , Interleucina-23/imunologia , Camundongos , Modelos Biológicos , UstekinumabRESUMO
Interleukin (IL)-12 and IL-23 are heterodimeric proinflammatory cytokines that share a common p40 subunit, paired with p35 and p19 subunits, respectively. They represent an attractive class of therapeutic targets for the treatment of psoriasis and other immune-mediated diseases. Ustekinumab is a fully human monoclonal antibody (mAb) that binds specifically to IL-12/IL-23p40 and neutralizes human IL-12 and IL-23 bioactivity. The crystal structure of ustekinumab Fab (antigen binding fragment of mAb), in complex with human IL-12, has been determined by X-ray crystallography at 3.0 Å resolution. Ustekinumab Fab binds the D1 domain of the p40 subunit in a 1:1 ratio in the crystal, consistent with a 2 cytokines:1 mAb stoichiometry, as measured by isothermal titration calorimetry. The structure indicates that ustekinumab binds to the same epitope on p40 in both IL-12 and IL-23 with identical interactions. Mutational analyses confirm that several residues identified in the IL-12/IL-23p40 epitope provide important molecular binding interactions with ustekinumab. The electrostatic complementarity between the mAb antigen binding site and the p40 D1 domain epitope appears to play a key role in antibody/antigen recognition specificity. Interestingly, this structure also reveals significant structural differences in the p35 subunit and p35/p40 interface, compared with the published crystal structure of human IL-12, suggesting unusual and potentially functionally relevant structural flexibility of p35, as well as p40/p35 recognition. Collectively, these data describe unique observations about IL-12p35 and ustekinumab interactions with p40 that account for its dual binding and neutralization of IL-12 and IL-23.