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BACKGROUND: In most CKDs, lysyl oxidase oxidation of collagen forms allysine side chains, which then form stable crosslinks. We hypothesized that MRI with the allysine-targeted probe Gd-oxyamine (OA) could be used to measure this process and noninvasively detect renal fibrosis. METHODS: Two mouse models were used: hereditary nephritis in Col4a3-deficient mice (Alport model) and a glomerulonephritis model, nephrotoxic nephritis (NTN). MRI measured the difference in kidney relaxation rate, ΔR1, after intravenous Gd-OA administration. Renal tissue was collected for biochemical and histological analysis. RESULTS: ΔR1 was increased in the renal cortex of NTN mice and in both the cortex and the medulla of Alport mice. Ex vivo tissue analyses showed increased collagen and Gd-OA levels in fibrotic renal tissues and a high correlation between tissue collagen and ΔR1. CONCLUSIONS: Magnetic resonance imaging using Gd-OA is potentially a valuable tool for detecting and staging renal fibrogenesis.
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Riñón , Nefritis Hereditaria , Ratones , Animales , Riñón/diagnóstico por imagen , Riñón/patología , Nefritis Hereditaria/patología , Fibrosis , Imagen por Resonancia Magnética/métodos , Modelos Animales de EnfermedadRESUMEN
Background Liver biopsy is the reference standard to diagnose nonalcoholic steatohepatitis (NASH) but is invasive with potential complications. Purpose To evaluate molecular MRI with type 1 collagen-specific probe EP-3533 and allysine-targeted fibrogenesis probe Gd-Hyd, MR elastography, and native T1 to characterize fibrosis and to assess treatment response in a rat model of NASH. Materials and Methods MRI was performed prospectively (June-November 2018) in six groups of male Wistar rats (a) age- and (b) weight-matched animals received standard chow (n = 12 per group); (c) received choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD) for 6 weeks or (d) 9 weeks (n = 8 per group); (e) were fed 6 weeks of CDAHFD and switched to standard chow for 3 weeks (n = 12); (f) were fed CDAHFD for 9 weeks with daily treatment of elafibranor beginning at week 6 (n = 14). Differences in imaging measurements and tissue analyses among groups were tested with one-way analysis of variance. The ability of each imaging measurement to stage fibrosis was quantified by using area under the receiver operating characteristic curve (AUC) with quantitative digital pathology (collagen proportionate area [CPA]) as reference standard. Optimal cutoff values for distinguishing advanced fibrosis were used to assess treatment response. Results AUC for distinguishing fibrotic (CPA >4.8%) from nonfibrotic (CPA ≤4.8%) livers was 0.95 (95% confidence interval [CI]: 0.91, 1.00) for EP-3533, followed by native T1, Gd-Hyd, and MR elastography with AUCs of 0.90 (95% CI: 0.83, 0.98), 0.84 (95% CI: 0.74, 0.95), and 0.65 (95% CI: 0.51, 0.79), respectively. AUCs for discriminating advanced fibrosis (CPA >10.3%) were 0.86 (95% CI: 0.76, 0.97), 0.96 (95% CI: 0.90, 1.01), 0.84 (95% CI: 0.70, 0.98), and 0.74 (95% CI: 0.63, 0.86) for EP-3533, Gd-Hyd, MR elastography, and native T1, respectively. Gd-Hyd MRI had the highest accuracy (24 of 26, 92%; 95% CI: 75%, 99%) in identifying responders and nonresponders in the treated groups compared with MR elastography (23 of 26, 88%; 95% CI: 70%, 98%), EP-3533 (20 of 26, 77%; 95% CI: 56%, 91%), and native T1 (14 of 26, 54%; 95% CI: 33%, 73%). Conclusion Collagen-targeted molecular MRI most accurately detected early onset of fibrosis, whereas the fibrogenesis probe Gd-Hyd proved most accurate for detecting treatment response. © RSNA, 2020 Online supplemental material is available for this article.
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Cirrosis Hepática/diagnóstico por imagen , Cirrosis Hepática/terapia , Imagen por Resonancia Magnética/métodos , Enfermedad del Hígado Graso no Alcohólico/diagnóstico por imagen , Enfermedad del Hígado Graso no Alcohólico/terapia , Animales , Chalconas/uso terapéutico , Dieta/métodos , Modelos Animales de Enfermedad , Hígado/diagnóstico por imagen , Cirrosis Hepática/etiología , Masculino , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Propionatos/uso terapéutico , Estudios Prospectivos , Ratas , Ratas WistarRESUMEN
Macrophage-mediated renal injury promotes the development of diabetic nephropathy. Blockade of chemokine (C-C motif) receptor 2 (CCR2) inhibits kidney macrophage accumulation and early glomerular damage in diabetic animals. This study tested early and late interventions with a CCR2 antagonist (CCR2A) in a model of progressive diabetic glomerulosclerosis and determined whether CCR2A provides added benefit over conventional treatment with an angiotensin-converting enzyme inhibitor (ACEi). Diabetes was induced in hypertensive endothelial nitric oxide synthase (Nos3)-deficient mice by administration of five low-dose streptozotocin (STZ) injections daily. Groups of diabetic Nos3-/- mice received a CCR2A (30 mg·kg-1·day-1 PF-04634817 in chow) as an early intervention (weeks 2-15 after STZ). The late intervention (weeks 8-15 after STZ) involved PF-04634817 alone, ACEi (captopril in water 10 mg·kg-1·day-1) alone, or combined ACEi + CCR2A. Control diabetic and nondiabetic Nos3-/- mice received normal chow and water. Early intervention with a CCR2A inhibited kidney inflammation and glomerulosclerosis, albuminuria, podocyte loss, and renal function impairment but not hypertension in diabetic Nos3-/- mice. Late intervention with a CCR2A also inhibited kidney inflammation, glomerulosclerosis, and renal dysfunction but did not affect albuminuria. ACEi alone suppressed hypertension and albuminuria and partially reduced podocyte loss and glomerulosclerosis but did not affect renal dysfunction. Compared with ACEi alone, the combined late intervention with ACEi + CCR2A provided better protection against kidney damage (inflammation, glomerulosclerosis, and renal function impairment) but not albuminuria. In conclusion, this study demonstrates that combining CCR2A and ACEi provides broader and superior renal protection than ACEi alone in a model of established diabetic glomerulosclerosis with hypertension.
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Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Nefropatías Diabéticas/prevención & control , Óxido Nítrico Sintasa de Tipo III/genética , Receptores CCR2/antagonistas & inhibidores , Albuminuria/prevención & control , Animales , Compuestos de Azabiciclo/uso terapéutico , Captopril/uso terapéutico , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Nefropatías Diabéticas/patología , Progresión de la Enfermedad , Hipertensión Renal/etiología , Hipertensión Renal/prevención & control , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Óxido Nítrico Sintasa de Tipo III/deficiencia , Podocitos/patología , Pirimidinas/uso terapéuticoRESUMEN
Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease, encompasses steatosis and metabolic dysfunction-associated steatohepatitis (MASH), leading to cirrhosis and hepatocellular carcinoma. Preclinical MASLD research is mainly performed in rodents; however, the model that best recapitulates human disease is yet to be defined. We conducted a wide-ranging retrospective review (metabolic phenotype, liver histopathology, transcriptome benchmarked against humans) of murine models (mostly male) and ranked them using an unbiased MASLD 'human proximity score' to define their metabolic relevance and ability to induce MASH-fibrosis. Here, we show that Western diets align closely with human MASH; high cholesterol content, extended study duration and/or genetic manipulation of disease-promoting pathways are required to intensify liver damage and accelerate significant (F2+) fibrosis development. Choline-deficient models rapidly induce MASH-fibrosis while showing relatively poor translatability. Our ranking of commonly used MASLD models, based on their proximity to human MASLD, helps with the selection of appropriate in vivo models to accelerate preclinical research.
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Modelos Animales de Enfermedad , Enfermedad del Hígado Graso no Alcohólico , Animales , Humanos , Ratones , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/patología , Masculino , Hígado/metabolismo , Hígado/patología , Enfermedades Metabólicas/metabolismo , Enfermedades Metabólicas/etiología , Dieta Occidental/efectos adversos , Estudios Retrospectivos , Cirrosis Hepática/metabolismo , Cirrosis Hepática/etiologíaRESUMEN
Type 2 diabetes (T2D) and its complications can have debilitating, sometimes fatal consequences for afflicted individuals. The disease can be difficult to control, and therapeutic strategies to prevent T2D-induced tissue and organ damage are needed. Here we describe the results of administering a potent and selective inhibitor of Protein Kinase C (PKC) family members PKCα and PKCß, Cmpd 1, in the ZSF1 obese rat model of hyperphagia-induced, obesity-driven T2D. Although our initial intent was to evaluate the effect of PKCα/ß inhibition on renal damage in this model setting, Cmpd 1 unexpectedly caused a marked reduction in the hyperphagic response of ZSF1 obese animals. This halted renal function decline but did so indirectly and indistinguishably from a pair feeding comparator group. However, above and beyond this food intake effect, Cmpd 1 lowered overall animal body weights, reduced liver vacuolation, and reduced inguinal adipose tissue (iWAT) mass, inflammation, and adipocyte size. Taken together, Cmpd 1 had strong effects on multiple disease parameters in this obesity-driven rodent model of T2D. Further evaluation for potential translation of PKCα/ß inhibition to T2D and obesity in humans is warranted.
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Adiposidad , Diabetes Mellitus Tipo 2 , Humanos , Ratas , Animales , Adiposidad/fisiología , Proteína Quinasa C-alfa , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Obesidad/complicaciones , Obesidad/tratamiento farmacológico , Hiperfagia/complicaciones , Hiperfagia/tratamiento farmacológico , Riñón/fisiologíaRESUMEN
Macrophages are central orchestrators of the tissue response to injury, with distinct macrophage activation states playing key roles in fibrosis progression and resolution. Identifying key macrophage populations found in human fibrotic tissues could lead to new treatments for fibrosis. Here, we used human liver and lung single-cell RNA sequencing datasets to identify a subset of CD9+TREM2+ macrophages that express SPP1, GPNMB, FABP5, and CD63. In both human and murine hepatic and pulmonary fibrosis, these macrophages were enriched at the outside edges of scarring and adjacent to activated mesenchymal cells. Neutrophils expressing MMP9, which participates in the activation of TGF-ß1, and the type 3 cytokines GM-CSF and IL-17A coclustered with these macrophages. In vitro, GM-CSF, IL-17A, and TGF-ß1 drive the differentiation of human monocytes into macrophages expressing scar-associated markers. Such differentiated cells could degrade collagen IV but not collagen I and promote TGF-ß1-induced collagen I deposition by activated mesenchymal cells. In murine models blocking GM-CSF, IL-17A or TGF-ß1 reduced scar-associated macrophage expansion and hepatic or pulmonary fibrosis. Our work identifies a highly specific macrophage population to which we assign a profibrotic role across species and tissues. It further provides a strategy for unbiased discovery, triage, and preclinical validation of therapeutic targets based on this fibrogenic macrophage population.
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Factor Estimulante de Colonias de Granulocitos y Macrófagos , Fibrosis Pulmonar , Humanos , Ratones , Animales , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Interleucina-17/metabolismo , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/patología , Cicatriz , Macrófagos/patología , Inflamación/patología , Proteínas de Unión a Ácidos Grasos/metabolismo , Glicoproteínas de Membrana , Receptores InmunológicosRESUMEN
A diaryl ketone series was identified as vanin-1 inhibitors from a high-throughput screening campaign. While this novel scaffold provided valuable probe 2 that was used to build target confidence, concerns over the ketone moiety led to the replacement of this group. The successful replacement of this moiety was achieved with pyrimidine carboxamides derived from cyclic secondary amines that were extensively characterized using biophysical and crystallographic methods as competitive inhibitors of vanin-1. Through optimization of potency and physicochemical and ADME properties, and guided by co-crystal structures with vanin-1, 3 was identified with a suitable profile for advancement into preclinical development.
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Amidohidrolasas/antagonistas & inhibidores , Piridinas/síntesis química , Piridinas/farmacología , Animales , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Cristalografía por Rayos X , Sulfato de Dextran , Perros , Descubrimiento de Drogas , Femenino , Proteínas Ligadas a GPI/antagonistas & inhibidores , Ensayos Analíticos de Alto Rendimiento , Cetonas/química , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Piridinas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
Non-alcoholic steatohepatitis (NASH) is an increasing cause of chronic liver disease characterized by steatosis, inflammation, and fibrosis which can lead to cirrhosis, hepatocellular carcinoma, and mortality. Quantitative, noninvasive methods for characterizing the pathophysiology of NASH at both the preclinical and clinical level are sorely needed. We report here a multiparametric magnetic resonance imaging (MRI) protocol with the fibrogenesis probe Gd-Hyd to characterize fibrotic disease activity and steatosis in a common mouse model of NASH. Mice were fed a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) to induce NASH with advanced fibrosis. Mice fed normal chow and CDAHFD underwent MRI after 2, 6, 10 and 14 weeks to measure liver T1, T2*, fat fraction, and dynamic T1-weighted Gd-Hyd enhanced imaging of the liver. Steatosis, inflammation, and fibrosis were then quantified by histology. NASH and fibrosis developed quickly in CDAHFD fed mice with strong correlation between morphometric steatosis quantification and liver fat estimated by MRI (r = 0.90). Sirius red histology and collagen quantification confirmed increasing fibrosis over time (r = 0.82). Though baseline T1 and T2* measurements did not correlate with fibrosis, Gd-Hyd signal enhancement provided a measure of the extent of active fibrotic disease progression and correlated strongly with lysyl oxidase expression. Gd-Hyd MRI accurately detects fibrogenesis in a mouse model of NASH with advanced fibrosis and can be combined with other MR measures, like fat imaging, to more accurately assess disease burden.
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Medios de Contraste/farmacología , Complejos de Coordinación/farmacología , Gadolinio/farmacología , Hígado/diagnóstico por imagen , Imagen por Resonancia Magnética , Enfermedad del Hígado Graso no Alcohólico/diagnóstico por imagen , Animales , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Masculino , Ratones , Enfermedad del Hígado Graso no Alcohólico/inducido químicamenteRESUMEN
Non-alcoholic fatty liver disease (NAFLD) is a progressive liver disease characterized by dysregulated lipid metabolism and chronic inflammation ultimately resulting in fibrosis. Untreated, NAFLD may progress to non-alcoholic steatohepatitis (NASH), cirrhosis and death. However, currently there are no FDA approved therapies that treat NAFLD/NASH. Thrombospondin-I (TSP-1) is a large glycoprotein in the extracellular matrix that regulates numerous cellular pathways including transforming growth factor beta 1 (TGF-ß1) activation, angiogenesis, inflammation and cellular adhesion. Increased expression of TSP-1 has been reported in various liver diseases; however, its role in NAFLD/NASH is not well understood. We first examined TSP-1 modulation in hepatic stellate cell activation, a critical initiating step in hepatic fibrosis. Knockdown or inhibition of TSP-1 attenuated HSC activation measured by alpha smooth muscle actin (α-SMA) and Collagen I expression. To investigate the impact of TSP-1 modulation in context of NAFLD/NASH, we examined the effect of TSP-1 deficiency in the choline deficient L-amino acid defined high fat diet (CDAHFD) model of NASH in mice by assessing total body and liver weight, serum liver enzyme levels, serum lipid levels, liver steatosis, liver fibrosis and liver gene expression in wild type (WT) and TSP-1 null mice. CDAHFD fed mice, regardless of genotype, developed phenotypes of NASH, including significant increase in liver weight and liver enzymes, steatosis and fibrosis. However, in comparison to WT, CDAHFD-fed TSP-1 deficient mice were protected against numerous NASH phenotypes. TSP-1 null mice exhibited a decrease in serum lipid levels, inflammation markers and hepatic fibrosis. RNA-seq based transcriptomic profiles from the liver of CDAHFD fed mice determined that both WT and TSP-1 null mice exhibited similar gene expression signatures following CDAHFD, similar to biophysical and histological assessment comparison. Comparison of transcriptomic profiles based on genotype suggested that peroxisome proliferator activated receptor alpha (PPARα) pathway and amino acid metabolism pathways are differentially expressed in TSP-1 null mice. Activation of PPARα pathway was supported by observed decrease in serum lipid levels. Our findings provide important insights into the role of TSP-1 in context of NAFLD/NASH and TSP-1 may be a target of interest to develop anti-fibrotic therapeutics for NAFLD/NASH.
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Metabolismo de los Lípidos , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Trombospondina 1/fisiología , Animales , Biomarcadores/metabolismo , Células Cultivadas , Deficiencia de Colina , Modelos Animales de Enfermedad , Células Estrelladas Hepáticas , Humanos , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/inducido químicamente , Trombospondina 1/genéticaRESUMEN
Interleukin (IL)-13 is a key cytokine driving allergic and asthmatic responses and contributes to airway inflammation in cynomolgus monkeys after segmental challenge with Ascaris suum antigen. IL-13 bioactivity is mediated by a heterodimeric receptor (IL-13Ralpha1/IL-4Ralpha) and can be inhibited in vitro by targeting IL-13 interaction with either chain. However, in cytokine systems, in vitro neutralization activity may not always predict inhibitory function in vivo. To address the efficacy of two different IL-13 neutralization mechanisms in a primate model of atopic disease, two humanized monoclonal antibodies to IL-13 were generated, with highly homologous properties, differing in epitope recognition. Ab01 blocks IL-13 interaction with IL-4Ralpha, and Ab02 blocks IL-13 interaction with IL-13Ralpha1. In a cynomolgus monkey model of IgE responses to A. suum antigen, both Ab01 and Ab02 effectively reduced serum titers of Ascaris-specific IgE and diminished ex vivo Ascaris-triggered basophil histamine release, assayed 8 weeks after a single administration of antibody. The two antibodies also produced comparable reductions in pulmonary inflammation after lung segmental challenge with Ascaris antigen. Increased serum levels of IL-13, lacking demonstrable biological activity, were seen postchallenge in animals given either anti-IL-13 antibody but not in control animals given human IgG of irrelevant specificity. These findings demonstrate a potent effect of IL-13 neutralization on IgE-mediated atopic responses in a primate system and show that IL-13 can be efficiently neutralized by targeting either the IL-4Ralpha-binding epitope or the IL-13Ralpha1-binding epitope.
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Antígenos Helmínticos/inmunología , Ascaris/inmunología , Inmunoglobulina E/sangre , Inmunoglobulina G/inmunología , Inflamación/inmunología , Interleucina-13/inmunología , Pulmón/inmunología , Receptores de Interleucina-13/inmunología , Animales , Anticuerpos Antihelmínticos/inmunología , Basófilos/inmunología , Líquido del Lavado Bronquioalveolar/inmunología , Epítopos/inmunología , Liberación de Histamina/inmunología , Humanos , Macaca fascicularis , MasculinoRESUMEN
ZSF1 rats exhibit spontaneous nephropathy secondary to obesity, hypertension, and diabetes, and have gained interest as a model system with potentially high translational value to progressive human disease. To thoroughly characterize this model, and to better understand how closely it recapitulates human disease, we performed a high resolution longitudinal analysis of renal disease progression in ZSF1 rats spanning from early disease to end stage renal disease. Analyses included metabolic endpoints, renal histology and ultrastructure, evaluation of a urinary biomarker of fibrosis, and transcriptome analysis of glomerular-enriched tissue over the course of disease. Our findings support the translational value of the ZSF1 rat model, and are provided here to assist researchers in the determination of the model's suitability for testing a particular mechanism of interest, the design of therapeutic intervention studies, and the identification of new targets and biomarkers for type 2 diabetic nephropathy.
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Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/genética , Fallo Renal Crónico/complicaciones , Riñón/metabolismo , Animales , Análisis por Conglomerados , Colágeno/genética , Colágeno/metabolismo , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Perfilación de la Expresión Génica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Inmunohistoquímica , Riñón/patología , Riñón/ultraestructura , Fallo Renal Crónico/patología , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Glomérulos Renales/ultraestructura , Masculino , Microscopía Electrónica de Transmisión , Obesidad/complicaciones , Ratas , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Matrix metalloprotease 12 plays a significant role in airway inflammation and remodeling. Increased expression and production of MMP-12 have been found in the lung of human COPD patients. MMP408 (14), a potent and selective MMP-12 inhibitor, was derived from a potent matrix metalloprotease 2 and 13 inhibitor via lead optimization and has good physical properties and bioavailability. The compound blocks rhMMP-12-induced lung inflammation in a mouse model and was advanced for further development for the treatment of COPD.
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Benzofuranos/síntesis química , Inhibidores de la Metaloproteinasa de la Matriz , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Sulfonamidas/síntesis química , Animales , Benzofuranos/farmacocinética , Benzofuranos/farmacología , Disponibilidad Biológica , Haplorrinos , Humanos , Técnicas In Vitro , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Neumonía/inducido químicamente , Neumonía/tratamiento farmacológico , Ratas , Proteínas Recombinantes , Ovinos , Especificidad de la Especie , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologíaRESUMEN
BACKGROUND: Airway inflammation is a hallmark feature of asthma and a driver of airway hyperresponsiveness. IL-13 is a key inducer of airway inflammation in rodent models of respiratory disease, but a role for IL-13 has not been demonstrated in primates. OBJECTIVE: We sought to test the efficacy of a neutralizing antibody to human IL-13 in a cynomolgus monkey model of lung inflammation. METHODS: Using cynomolgus monkeys (Macaca fascicularis) that are sensitized to Ascaris suum through natural exposure, we developed a reproducible model of acute airway inflammation after segmental A suum antigen challenge. This model was used to test the in vivo efficacy of mAb13.2, a mouse mAb directed against human IL-13, and IMA-638, the humanized counterpart of mAb13.2. Bronchoalveolar lavage (BAL) cells and BAL fluid were collected before and after antigen challenge and assayed for cellular content by means of differential count. RESULTS: Total BAL cell count, eosinophil number, and neutrophil number were all reduced in animals treated with mAb13.2 or IMA-638 compared with values in control animals that were untreated, given saline, or treated with human IgG of irrelevant specificity. In addition, levels of eotaxin and RANTES in BAL fluid were reduced in anti-IL-13-treated animals compared with levels seen in control animals. CONCLUSION: These findings support a role for IL-13 in maintaining lung inflammation in response to allergen challenge in nonhuman primates. CLINICAL IMPLICATIONS: IL-13 neutralization with a specific antibody could be a useful therapeutic strategy for asthma.