RESUMO
T cell engaging therapies, like CAR-T cells and T cell engagers, redirect T cells toward tumor cells, facilitating the formation of a cytotoxic synapse and resulting in subsequent tumor cell killing. T cell receptor or CAR-T downstream signaling triggers a release of pro-inflammatory cytokines, which can induce a Cytokine Release Syndrome (CRS). The incidence of CRS is still hardly predictable among individuals and remains one of the major dose-limiting safety liabilities associated with on-target activity of T cell engaging therapies. This emphasizes the need to elaborate mitigation strategies, which reduce cytokine release while retaining efficacy. Here, we review pre-clinical and clinical approaches applied for the management of CRS symptoms in the context of T cell engaging therapies, highlighting the use of tyrosine kinase inhibitors as an emerging mitigation strategy. In particular, we focus on the effects of Bruton's tyrosine kinase (BTK), Src family including Lck, mammalian target of rapamycin (mTOR) and Janus tyrosine kinase (JAK) inhibitors on T cell functionality and cytokine release, to provide a rationale for their use as mitigation strategies against CRS in the context of T cell engaging therapies.
Assuntos
Síndrome da Liberação de Citocina , Receptores de Antígenos de Linfócitos T , Síndrome da Liberação de Citocina/etiologia , Citocinas , Humanos , Linfócitos TRESUMO
Alzheimer's disease (AD) is a progressive neurodegenerative condition in which aggregated tau and amyloid proteins accumulate in the brain causing neuronal dysfunction which eventually leads to cognitive decline. Hyperphosphorylated tau aggregates in the neuron are believed to cause most of the pathology associated with AD. These aggregates are assumed to be released into the extracellular compartment and taken up by adjacent healthy neurons where they induce further tau aggregation. This "prion-like" spreading can be interrupted by antibodies capable of binding and "neutralizing" extracellular tau aggregates as shown in preclinical mouse models of AD. One of the proposed mechanisms by which therapeutic antibodies reduce pathology is antibody-mediated uptake and clearance of pathological aggregated forms of tau by microglia. Here, we describe a quantitative cell-based assay to assess tau uptake by microglia. This assay uses the mouse microglial cell line BV-2, allows for high specificity, low variability and medium throughput. Data generated with this assay can contribute to a better characterization of anti-tau antibody effector functions.
Assuntos
Doença de Alzheimer/patologia , Microglia/metabolismo , Proteínas tau/metabolismo , Humanos , Microglia/citologiaRESUMO
Misfolding and aggregation of tau protein are closely associated with the onset and progression of Alzheimer's Disease (AD). By interrogating IgG+ memory B cells from asymptomatic donors with tau peptides, we have identified two somatically mutated VH5-51/VL4-1 antibodies. One of these, CBTAU-27.1, binds to the aggregation motif in the R3 repeat domain and blocks the aggregation of tau into paired helical filaments (PHFs) by sequestering monomeric tau. The other, CBTAU-28.1, binds to the N-terminal insert region and inhibits the spreading of tau seeds and mediates the uptake of tau aggregates into microglia by binding PHFs. Crystal structures revealed that the combination of VH5-51 and VL4-1 recognizes a common Pro-Xn-Lys motif driven by germline-encoded hotspot interactions while the specificity and thereby functionality of the antibodies are defined by the CDR3 regions. Affinity improvement led to improvement in functionality, identifying their epitopes as new targets for therapy and prevention of AD.
Assuntos
Linfócitos B/metabolismo , Imunoglobulina G/farmacologia , Cadeias Pesadas de Imunoglobulinas/metabolismo , Cadeias Leves de Imunoglobulina/metabolismo , Proteínas tau/imunologia , Proteínas tau/metabolismo , Adolescente , Adulto , Idoso , Especificidade de Anticorpos , Linfócitos B/efeitos dos fármacos , Cristalização , Relação Dose-Resposta a Droga , Feminino , Humanos , Epitopos Imunodominantes/metabolismo , Masculino , Microglia/metabolismo , Microscopia de Força Atômica , Pessoa de Meia-Idade , Modelos Moleculares , Dados de Sequência Molecular , Agregados Proteicos , Adulto JovemRESUMO
Influenza viruses are among the most important human pathogens and are responsible for annual epidemics and sporadic, potentially devastating pandemics. The humoral immune response plays an important role in the defense against these viruses, providing protection mainly by producing antibodies directed against the hemagglutinin (HA) glycoprotein. However, their high genetic variability allows the virus to evade the host immune response and the potential protection offered by seasonal vaccines. The emergence of resistance to antiviral drugs in recent years further limits the options available for the control of influenza. The development of alternative strategies for influenza prophylaxis and therapy is therefore urgently needed. In this study, we describe a human monoclonal antibody (PN-SIA49) that recognizes a highly conserved epitope located on the stem region of the HA and able to neutralize a broad spectrum of influenza viruses belonging to different subtypes (H1, H2 and H5). Furthermore, we describe its protective activity in mice after lethal challenge with H1N1 and H5N1 viruses suggesting a potential application in the treatment of influenza virus infections.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Hemaglutininas/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Virus da Influenza A Subtipo H5N1/imunologia , Vacinas contra Influenza/uso terapêutico , Infecções por Orthomyxoviridae/prevenção & controle , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Antivirais/imunologia , Epitopos/genética , Epitopos/imunologia , Feminino , Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Hemaglutininas/genética , Hemaglutininas/metabolismo , Humanos , Vírus da Influenza A Subtipo H1N1/genética , Virus da Influenza A Subtipo H5N1/genética , Vacinas contra Influenza/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Mutagênese , Mutação/genética , Testes de Neutralização , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Conformação Proteica , Homologia de Sequência de AminoácidosRESUMO
The interest in broad-range anti-influenza A monoclonal antibodies (mAbs) has recently been strengthened by the identification of anti-hemagglutinin (HA) mAbs endowed with heterosubtypic neutralizing activity to be used in the design of "universal" prophylactic or therapeutic tools. However, the majority of the single mAbs described to date do not bind and neutralize viral isolates belonging to highly divergent subtypes clustering into the two different HA-based influenza phylogenetic groups: the group 1 including, among others, subtypes H1, H2, H5 and H9 and the group 2 including, among others, H3 subtype. Here, we describe a human mAb, named PN-SIA28, capable of binding and neutralizing all tested isolates belonging to phylogenetic group 1, including H1N1, H2N2, H5N1 and H9N2 subtypes and several isolates belonging to group 2, including H3N2 isolates from the first period of the 1968 pandemic. Therefore, PN-SIA28 is capable of neutralizing isolates belonging to subtypes responsible of all the reported pandemics, as well as other subtypes with pandemic potential. The region recognized by PN-SIA28 has been identified on the stem region of HA and includes residues highly conserved among the different influenza subtypes. A deep characterization of PN-SIA28 features may represent a useful help in the improvement of available anti-influenza therapeutic strategies and can provide new tools for the development of universal vaccinal strategies.
Assuntos
Anticorpos Monoclonais/química , Vacinas contra Influenza/uso terapêutico , Influenza Humana/metabolismo , Orthomyxoviridae/genética , Orthomyxoviridae/imunologia , Alanina/genética , Animais , Anticorpos Neutralizantes/química , Linhagem Celular , Análise por Conglomerados , Cães , Glicoproteínas/química , Hemaglutininas Virais/química , Humanos , Influenza Humana/prevenção & controle , Modelos Moleculares , Conformação Molecular , Mutagênese Sítio-Dirigida , Testes de Neutralização , Filogenia , Ligação ProteicaRESUMO
The role of humoral response in the effective control of infection by influenza viruses is well known, but the protection is usually limited to the infecting or vaccinating isolate and to few related strains. Recent studies have evidenced the existence of B-cell epitopes broadly conserved among different influenza subtypes recognized by monoclonal antibodies endowed with unprecedented broad activity. In this review, all major monoclonal antibodies directed against different influenza virus proteins are reported and their potential in the design of new anti-influenza prophylactic or therapeutic strategies is discussed.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Vírus da Influenza A/efeitos dos fármacos , Influenza Humana/tratamento farmacológico , Influenza Humana/prevenção & controle , Animais , Anticorpos Monoclonais/imunologia , Humanos , Vírus da Influenza A/genética , Vírus da Influenza A/imunologia , Vacinas contra Influenza/imunologia , Vacinas contra Influenza/uso terapêutico , Influenza Humana/imunologia , Influenza Humana/virologia , Proteínas Virais/genética , Proteínas Virais/imunologiaRESUMO
The new H1N1 swine-origin influenza virus (S-OIV) strain is a global health problem. The elucidation of the virus-host relationship is crucial for the control of the new infection. Two human monoclonal antibody Fab fragments (HMab) neutralizing the novel H1N1 influenza strain at very low concentrations were cloned before the emergence of S-OIV from a patient who had a broad-range H1N1 serum neutralizing activity. The two HMabs neutralized all tested H1N1 strains, including S-OIV and a swine strain with IC(50) ranging from 2 to 7 microg/ml. Data demonstrate that infection with previously circulating H1N1 strains can elicit antibodies neutralizing S-OIV. Finally, the human genes coding for the neutralizing HMabs could be used for generating full human monoclonal IgGs that can be safely administered being potentially useful in the prophylaxis and the treatment of this human infection.
Assuntos
Anticorpos Monoclonais/imunologia , Linfócitos B/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A/imunologia , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/genética , Sequência de Bases , Galinhas/virologia , Relação Dose-Resposta Imunológica , Imunofluorescência , Humanos , Fragmentos Fab das Imunoglobulinas/imunologia , Vírus da Influenza A Subtipo H1N1/isolamento & purificação , Vírus da Influenza A/isolamento & purificação , Influenza Humana/imunologia , Influenza Humana/virologia , Pessoa de Meia-Idade , Testes de Neutralização , Infecções por Orthomyxoviridae/virologia , Alinhamento de Sequência , Suínos/virologia , Ensaio de Placa ViralRESUMO
Recent data indicated that adaptive immunity is involved in the process of atherogenesis. Oligoclonal recruitment of T lymphocytes has been described in coronary plaques of patients with acute coronary syndrome. However, the nature of immune response remains to be determined. In the present study, we examined the Ab response in six coronary plaques obtained by endoluminal directional atherectomy. The IgG1/kappa-coding gene repertoires of B lymphocytes present in circulating blood and in coronary plaques were cloned and analyzed. In all of the six plaques, we observed 1) a skewed usage of heavy and light IgG1/kappa Ab-coding genes, 2) an oligoclonal distribution of V(K), J(K), and V(H), D(H), and J(H) genes with overrepresentation of some rarely used IgG genes, and 3) the unequivocal signs of Ag-driven clonal expansion and evolution of B cells. The data document for the first time the presence of a local Ag-driven clonal evolution of B cells in human atherosclerotic plaques.
Assuntos
Antígenos de Bactérias/fisiologia , Autoantígenos/fisiologia , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/patologia , Doença da Artéria Coronariana/imunologia , Evolução Molecular , Imunoglobulina G/biossíntese , Cadeias kappa de Imunoglobulina/biossíntese , Adulto , Idoso , Subpopulações de Linfócitos B/microbiologia , Proliferação de Células , Células Clonais , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/patologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/genética , Cadeias kappa de Imunoglobulina/sangue , Cadeias kappa de Imunoglobulina/genética , Masculino , Pessoa de Meia-Idade , Família Multigênica/imunologiaRESUMO
The pandemic caused by the new H1N1 swine-origin influenza virus (S-OIV) strain is a worldwide health emergency and alternative therapeutic and prophylactic options are greatly needed. Two human monoclonal antibody Fab fragments (HMab) neutralizing the novel H1N1 influenza strain at very low concentrations were cloned from a patient who had a broad-range anti-H1N1 serum neutralizing activity. The two HMabs neutralized S-OIV with an IC50 of 2.8 and 4 microg/mL. The genes coding for the neutralizing HMabs could be used for generating full human monoclonal IgGs that can be safely administered with the potentially of representing a novel drug to be used in the prophylaxis and the treatment of this human infection. This is the first report of molecular cloning of human monoclonal antibodies against the new pandemic swine-origin influenza virus.
Assuntos
Anticorpos Monoclonais , Anticorpos Neutralizantes , Anticorpos Antivirais , Clonagem Molecular/métodos , Vírus da Influenza A Subtipo H1N1/imunologia , Animais , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/genética , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/genética , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/uso terapêutico , Linhagem Celular , Surtos de Doenças , Humanos , Fragmentos Fab das Imunoglobulinas/genética , Fragmentos Fab das Imunoglobulinas/imunologia , Imunoglobulina G/genética , Imunoglobulina G/imunologia , Imunoglobulina G/uso terapêutico , Influenza Humana/imunologia , Influenza Humana/prevenção & controle , Influenza Humana/virologia , Pessoa de Meia-Idade , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Infecções por Orthomyxoviridae/virologia , Suínos , Doenças dos Suínos/imunologia , Doenças dos Suínos/prevenção & controle , Doenças dos Suínos/virologiaRESUMO
Childhood obesity is associated with an increased carotid intima-media thickness (IMT) and stiffness. Increased carotid wall thickening and rigidity are considered markers of subclinical atherosclerosis. The aim of the present study was to test the effect of two hypocaloric diets of varying glycemic index on weight loss and markers of subclinical atherosclerosis in obese children. Seventy consecutive obese children attending the Outpatient Weight Clinic of the Department of Pediatrics were invited to participate in an intensive dietary protocol. Twenty-six accepted and were randomly assigned to two different groups: the first group followed a hypocaloric low-glycemic index diet and the second a hypocaloric high-glycemic index diet. Anthropometric measures and biochemical tests were performed in all children. Quantitative B-mode ultrasound scans were used to measure intima-media thickness (IMT) and diameters of the common carotid artery. Considering both groups together, at 6 months, body mass index decreased from 28.3 +/- 3.1 to 25.8 +/- 3.3 kg/m(2), systolic blood pressure from 119 +/- 12 to 110 +/- 11 mmHg (P< 0.001), diastolic blood pressure from 78 +/- 8 to 74 +/- 7 mmHg (P< 0.001), IMT from 0.48 +/- 0.05 to 0.43 +/- 0.07 mm (P< 0.001), stiffness from 3.57 +/- 1.04 to 2.98 +/- 0.94 mm (P = 0.002), and high-sensitivity C-reactive protein from 1.5 +/- 0.9 (values log transformed) to 0.4 +/- 1.1 (P < 0.001). No differences were detectable in fasting serum triglycerides, total cholesterol, and high-density lipoprotein cholesterol. Insulin resistance (calculated by the HOmeostatic Model Assessment index [HOMA] score) significantly reduced only in the low-glycemic-index diet group (P < 0.04). In conclusion, this study confirms a benefit of hypocaloric diets on carotid IMT and stiffness in obese children and demonstrates, for the first time, an amelioration of insulin sensitivity in obese children after a low-glycemic index diet. These results justify the advice to obese children to follow a low-glycemic index diet in order to improve their cardiometabolic profile.
Assuntos
Doenças das Artérias Carótidas/dietoterapia , Artéria Carótida Primitiva/fisiopatologia , Dieta Redutora , Índice Glicêmico , Obesidade/dietoterapia , Adolescente , Biomarcadores/sangue , Pressão Sanguínea , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , Doenças das Artérias Carótidas/etiologia , Doenças das Artérias Carótidas/metabolismo , Doenças das Artérias Carótidas/fisiopatologia , Artéria Carótida Primitiva/diagnóstico por imagem , Criança , Elasticidade , Feminino , Humanos , Resistência à Insulina , Lipídeos/sangue , Masculino , Obesidade/complicações , Obesidade/metabolismo , Obesidade/fisiopatologia , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento , Ultrassonografia , Circunferência da CinturaRESUMO
Antibodies against conserved epitopes on HIV-1 envelope glycoproteins (Env), such as the gp120 CD4-binding site (CD4bs), could contribute to protection against HIV-1. Env-based immunogens inducing such a response could be a major component of future anti-HIV-1 strategies. In this proof-of-concept study we describe the generation of two anti-idiotype (AI) murine antibodies mimicking the CD4bs epitope. Sera were collected from long-term non-progressor patients to obtain CD4bs-directed IgG, through sequential purification steps. The purified IgG were then used as Fab fragments to immunize mice for hybridoma generation. Two hybridomas (P1 and P2), reacting only against the CD4bs-directed IgG, were identified and characterized. The P1 and P2 antibodies were shown to recognize the idiotype of the broadly neutralizing anti-CD4bs human mAb b12. Both P1 and P2 Fabs were able to induce a strong anti-gp120 response in rabbits. Moreover, the rabbits' sera were shown to neutralize two sensitive tier 1 strains of HIV-1 in an Env-pseudotype neutralization assay. In particular, 3/5 rabbits in the P1 group and 1/5 in the P2 group showed greater than 80% neutralizing activity against the HXB2 pseudovirus. Two rabbits also neutralized the pseudovirus HIV-MN. Overall, these data describe the first anti-idiotypic vaccine approach performed to generate antibodies to the CD4bs of the HIV-1 gp120. Although future studies will be necessary to improve strength and breadth of the elicited neutralizing response, this proof-of-concept study documents that immunogens designed on the idiotype of broadly neutralizing Abs are feasible and could help in the design of future anti-HIV strategies.
Assuntos
Anticorpos Anti-Idiotípicos/imunologia , Formação de Anticorpos , Antígenos CD4/imunologia , Proteína gp120 do Envelope de HIV/imunologia , Vacinas contra a AIDS , Animais , Anticorpos Anti-Idiotípicos/administração & dosagem , Anticorpos Antivirais/sangue , Formação de Anticorpos/efeitos dos fármacos , Epitopos , Humanos , Camundongos , Mimetismo Molecular/imunologia , CoelhosRESUMO
Hepatitis C virus (HCV) infection has been closely related to mixed cryoglobulinemia (MC). During HCV infection, cryoglobulins derive from the restricted expression of few germline genes as VH1-69, a subfamily highly represented in anti-HCV humoral response. Little is known about the self-reacting IgM component of the cryoprecipitate. In the present study, the IgM/K repertoire of an HCV-infected cryoglobulinemic patient was dissected by phage-display on well-characterized anti-HCV/E2 VH1-69-derived monoclonal IgG1/Kappa Fab fragments cloned from the same patient. All selected IgM clones were shown to react with the anti-HCV/E2 antibodies belonging to VH1-69 subfamily. More than 60% of selected clones showed a bias in VH gene usage, restricted to two VH subfamilies frequently described in autoimmune manifestations (VH3-23; VH3-21). Moreover, all selected clones showed an high similarity (>98.5%) to germline genes evidencing their natural origin. A possible hypothesis is that clones belonging to some subfamilies are naturally prone to react against other VH gene subfamilies, as VH 1-69. An antigen-driven stimulation of these subfamilies, and their overexpression as in HCV infection, could lead to a breaking of humoral homeostatic balance exposing the patients to the risk of developing autoimmune disorders.
Assuntos
Autoanticorpos/imunologia , Crioglobulinemia/imunologia , Crioglobulinemia/virologia , Hepatite C/imunologia , Imunoglobulina M/imunologia , Autoanticorpos/genética , Clonagem Molecular , Crioglobulinemia/genética , Hepacivirus/imunologia , Hepatite C/genética , Humanos , Fragmentos Fab das Imunoglobulinas/genética , Fragmentos Fab das Imunoglobulinas/imunologia , Imunoglobulina M/genética , Análise de Sequência de DNA , Proteínas do Envelope Viral/imunologiaRESUMO
The rapid diagnosis of an infectious cause in the course of fever of unknown origin plays a pivotal role in the correct management of neutropenic patients. In this study, blood samples from febrile oncohaematological patients were tested using a novel commercial real-time PCR assay (LightCycler SeptiFast; Roche Molecular Systems) and blood culture (BacT/Alert 3D; bioMérieux). Twenty-one (20.4 %) and 34 (33 %) of the 103 samples under study tested positive by blood culture and PCR, respectively. The analysis of concordance evidenced a low correlation between the two approaches (83 %), mainly due to samples that tested negative by culture but positive using the molecular approach. Among 14 discordant cases negative by culture but positive by PCR, 12 were observed in sequential samples of patients with initial concordant results on samples drawn before the administration of a specific antimicrobial therapy. Moreover, DNA of a fastidious organism, Aspergillus fumigatus, not easily detectable by the cultural approach was rapidly detected in the two remaining discordant cases. Overall, the characteristics featured by the molecular method could be of interest in the development of new algorithms for the diagnosis of sepsis in critical patients.
Assuntos
Neoplasias Hematológicas/complicações , Neutropenia/complicações , Sepse/complicações , Sepse/diagnóstico , Adulto , Idoso , Técnicas Bacteriológicas , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Sepse/sangueRESUMO
The increasing incidence of severe fungal infections highlights the need for rapid and precise identification methods in clinical mycology. The aim of this study was to develop and validate a culture-indipendent molecular approach that could allow the detection of fungal pathogens in clinical samples, with particular attention to the identification of drug-resistant Candida and Aspergillus species. A real-time multiplex PCR assay was developed using TaqMan probes specific for highly discriminating ITS sequences. In its multiplex format the assay showed a high specificity, clearly discriminating among different species, as well as a high sensitivity (20 CFU/1 mL sample), making it a potentially useful starting point for the development of a more complete molecular diagnostic assay.
Assuntos
Fungos/isolamento & purificação , Micoses/diagnóstico , Reação em Cadeia da Polimerase/métodos , Antifúngicos , Aspergillus/efeitos dos fármacos , Candida/efeitos dos fármacos , Sondas de DNA , DNA Fúngico/genética , DNA Intergênico , DNA Ribossômico/genética , DNA Espaçador Ribossômico/genética , Farmacorresistência Fúngica , Fungos/genética , Humanos , Micoses/microbiologia , Sensibilidade e Especificidade , Taq PolimeraseRESUMO
Obesity in childhood has been associated with the development of early cardiovascular abnormalities. The aim of the present study was to investigate whether preclinical functional changes are detectable in the abdominal aorta of obese children. One hundred consecutively seen obese children and 50 healthy controls were studied. The groups were matched in terms of age and gender. The pulsatile wall-motion of the abdominal aorta was determined using a B-mode ultrasound technique. The following mechanical property parameters were measured or computed: lumen diastolic and systolic diameters, relative aortic strain, elastic modulus, and stiffness. Compared to controls, obese children had higher blood pressure values and higher concentrations of total cholesterol, triglycerides, insulin, and C-reactive protein. Homeostasis model assessment (HOMA) score, a parameter of insulin resistance, was significantly higher in obese children than in controls (3.2 +/- 1.9 v 1.4 +/- 0.5, P <.001). Aortic mechanical parameters were significantly different in obese children as compared to controls: stiffness was higher (3.00 +/- 1.45 v 2.22 +/- 0.87, P <.001) as was elastic modulus (0.38 +/- 0.18 v 0.24 +/- 0.10 N/m(2), P <.001). Obese girls with insulin resistance (ie, in the highest tertile of HOMA, >3.7) had increased aortic stiffness (3.79 +/- 2.25) compared to obese girls in the lowest tertiles of HOMA (2.67 +/- 1.09, P =.045), even after adjustment for traditional cardiovascular risk factors (P =.031). The present findings suggest that preclinical changes in the aortic elastic properties are detectable in obese children. Insulin resistance seems to play an important role in the increased rigidity of the aortic wall in obese girls.