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1.
Diagn Microbiol Infect Dis ; 109(3): 116344, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38735147

RESUMO

Combinations of the ß-lactam/ß-lactamase inhibitor sulbactam-durlobactam and seventeen antimicrobial agents were tested against strains of Acinetobacter baumannii in checkerboard assays. Most combinations resulted in indifference with no instances of antagonism. These results suggest sulbactam-durlobactam antibacterial activity against A. baumannii is unlikely to be affected if co-dosed with other antimicrobial agents.


Assuntos
Acinetobacter baumannii , Antibacterianos , Compostos Azabicíclicos , Testes de Sensibilidade Microbiana , Sulbactam , Sulbactam/farmacologia , Acinetobacter baumannii/efeitos dos fármacos , Compostos Azabicíclicos/farmacologia , Antibacterianos/farmacologia , Humanos , Acinetobacter calcoaceticus/efeitos dos fármacos , Inibidores de beta-Lactamases/farmacologia , Infecções por Acinetobacter/microbiologia , Infecções por Acinetobacter/tratamento farmacológico , Combinação de Medicamentos
2.
J Clin Microbiol ; 62(1): e0122823, 2024 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-38095417

RESUMO

Sulbactam-durlobactam is a ß-lactam/ß-lactamase inhibitor combination developed to treat hospital-acquired and ventilator-associated bacterial pneumonia caused by Acinetobacter baumannii-calcoaceticus complex (ABC). Durlobactam is a diazabicyclooctane ß-lactamase inhibitor with potent activity against Ambler classes A, C, and D serine ß-lactamases and restores sulbactam activity against multidrug-resistant ABC. Studies were conducted to establish sulbactam-durlobactam antimicrobial susceptibility testing methods for both broth microdilution minimal inhibitory concentration (MIC) and disk diffusion tests as well as quality control (QC) ranges. To establish the MIC test method, combinations of sulbactam and durlobactam were evaluated using a panel of genetically characterized A. baumannii isolates which were categorized as predicted to be susceptible or resistant based on the spectrum of ß-lactamase inhibition by durlobactam. MIC testing with doubling dilutions of sulbactam with a fixed concentration of 4 µg/mL of durlobactam resulted in the greatest discrimination of the pre-defined susceptible and resistant strains. Similarly, the sulbactam/durlobactam 10/10 µg disk concentration showed the best discrimination as well as correlation with the MIC test. A. baumannii NCTC 13304 was selected for QC purposes because it assesses the activity of both sulbactam and durlobactam with clear endpoints. Multi-laboratory QC studies were conducted according to CLSI M23 Tier 2 criteria. A sulbactam-durlobactam broth MIC QC range of 0.5/4-2/4 µg/mL and a zone diameter QC range of 24-30 mm were determined for A. baumannii NCTC 13304 and have been approved by CLSI. These studies will enable clinical laboratories to perform susceptibility tests with accurate and reproducible methods.


Assuntos
Acinetobacter baumannii , Compostos Azabicíclicos , Sulbactam , Humanos , Sulbactam/farmacologia , Sulbactam/uso terapêutico , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Inibidores de beta-Lactamases/farmacologia , Inibidores de beta-Lactamases/uso terapêutico , Testes de Sensibilidade Microbiana , Controle de Qualidade , Combinação de Medicamentos
3.
Antimicrob Agents Chemother ; 67(11): e0066523, 2023 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-37843305

RESUMO

Acinetobacter baumannii-calcoaceticus complex (ABC) causes severe infections that are difficult to treat due to pre-existing antibiotic resistance. Sulbactam-durlobactam (SUL-DUR) is a targeted ß-lactam/ß-lactamase inhibitor combination antibiotic designed to treat serious infections caused by Acinetobacter, including multidrug- and carbapenem-resistant strains. In a recent global surveillance study of 5,032 ABC clinical isolates collected from 2016 to 2021, less than 2% of ABC isolates had SUL-DUR MIC values >4 µg/mL. Molecular characterization of these isolates confirmed the primary drivers of resistance are metallo-ß-lactamases or penicillin-binding protein 3 (PBP3) mutations, as previously described. In addition, this study shows that certain common PBP3 variants, such as A515V, are insufficient to confer sulbactam resistance and that the efflux of durlobactam by AdeIJK is likely to play a role in a subset of strains.


Assuntos
Acinetobacter baumannii , Sulbactam , Sulbactam/farmacologia , Sulbactam/uso terapêutico , Antibacterianos/uso terapêutico , Compostos Azabicíclicos/farmacologia , Inibidores de beta-Lactamases/farmacologia , Inibidores de beta-Lactamases/uso terapêutico , Monobactamas , Testes de Sensibilidade Microbiana
4.
Adv Biol Regul ; 84: 100890, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35255409

RESUMO

Regulatory T cells (Tregs) are a critical subset of CD4 T cells that modulate the immune response to prevent autoimmunity and chronic inflammation. CARD11, a signaling hub and scaffold protein that links antigen receptor engagement to activation of NF-κB and other downstream signaling pathways, is essential for the development and function of thymic Tregs. Mouse models with deficiencies in CARD11 and CARD11-associated signaling components generally have Treg defects, but some mouse models develop overt autoimmunity and inflammatory disease whereas others do not. Inhibition of CARD11 signaling in Tregs within the tumor microenvironment can potentially promote anti-tumor immunity. In this review, we summarize evidence for the involvement of CARD11 signaling in Treg development and function and discuss key unanswered questions and future research opportunities.


Assuntos
Proteínas Adaptadoras de Sinalização CARD , Linfócitos T Reguladores , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Proteína 10 de Linfoma CCL de Células B/metabolismo , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Guanilato Ciclase/metabolismo , Humanos , Camundongos , NF-kappa B/metabolismo , Transdução de Sinais/fisiologia
5.
Nature ; 597(7878): 698-702, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34526714

RESUMO

The development of new antibiotics to treat infections caused by drug-resistant Gram-negative pathogens is of paramount importance as antibiotic resistance continues to increase worldwide1. Here we describe a strategy for the rational design of diazabicyclooctane inhibitors of penicillin-binding proteins from Gram-negative bacteria to overcome multiple mechanisms of resistance, including ß-lactamase enzymes, stringent response and outer membrane permeation. Diazabicyclooctane inhibitors retain activity in the presence of ß-lactamases, the primary resistance mechanism associated with ß-lactam therapy in Gram-negative bacteria2,3. Although the target spectrum of an initial lead was successfully re-engineered to gain in vivo efficacy, its ability to permeate across bacterial outer membranes was insufficient for further development. Notably, the features that enhanced target potency were found to preclude compound uptake. An improved optimization strategy leveraged porin permeation properties concomitant with biochemical potency in the lead-optimization stage. This resulted in ETX0462, which has potent in vitro and in vivo activity against Pseudomonas aeruginosa plus all other Gram-negative ESKAPE pathogens, Stenotrophomonas maltophilia and biothreat pathogens. These attributes, along with a favourable preclinical safety profile, hold promise for the successful clinical development of the first novel Gram-negative chemotype to treat life-threatening antibiotic-resistant infections in more than 25 years.


Assuntos
Antibacterianos/farmacologia , Desenho de Fármacos , Farmacorresistência Bacteriana Múltipla , Bactérias Gram-Negativas/efeitos dos fármacos , Animais , Antibacterianos/química , Compostos Aza/química , Compostos Aza/farmacologia , Ciclo-Octanos/química , Ciclo-Octanos/farmacologia , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Proteínas de Ligação às Penicilinas/antagonistas & inibidores , Pseudomonas aeruginosa/efeitos dos fármacos , beta-Lactamases
6.
J Clin Invest ; 131(11)2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34060488

RESUMO

Calcineurin inhibitors (CNIs) such as cyclosporin A and FK506 are widely administered immunosuppressive drugs. Calcineurin relieves inhibitory phosphorylation from nuclear factor of activated T cells (NFAT) transcription factors downstream of T cell receptor engagement, resulting in their nuclear translocation and the production of cytokines, including IL-2, IFN-γ, and TNF-α. It was previously believed that CNIs downregulate immunity by reducing NFAT activation. However, work from Otsuka et al. in this issue of the JCI revealed a second mechanism by which CNIs suppress T cell function. The authors previously reported that calcineurin removes an inhibitory phosphate from the tyrosine kinase Lck at Ser59 (Lck-S59) and that this dephosphorylation positively regulates T cell activation. In the present work, the authors showed that inhibition of Lck-S59 dephosphorylation was essential for the CNI-mediated suppression of acute graft-versus-host disease (aGVHD). These findings have important implications for future approaches to the management of aGVHD, organ transplant rejection, and autoimmune disease.


Assuntos
Inibidores de Calcineurina , Doença Enxerto-Hospedeiro , Calcineurina , Inibidores de Calcineurina/farmacologia , Ciclosporina , Humanos , Imunossupressores/farmacologia , Fatores de Transcrição NFATC/genética , Tacrolimo
7.
ACS Infect Dis ; 7(1): 79-87, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33291867

RESUMO

Mutations in KPC-2 and KPC-3 ß-lactamase can confer resistance to the ß-lactam/ß-lactamase inhibitor antibacterial intravenous drug combination ceftazidime-avibactam, introduced in 2015. Avibactam was the first of the diazabicyclooctane class of non-ß-lactam ß-lactamase inhibitors to be approved for clinical use. The orally bioavailable prodrug ETX0282 of the diazabicyclooctane ß-lactamase inhibitor ETX1317 is in clinical development in combination with the oral ß-lactam prodrug cefpodoxime proxetil for use against complicated urinary tract infections. We investigated the effects of 3 ceftazidime-avibactam resistance mutations in KPC-3 (V240G, D179Y, and D179Y/T243M) on the ability of ETX1317 to overcome KPC-3-induced cefpodoxime resistance. Isogenic Escherichia coli strains, each expressing the wild-type or a mutant KPC-3 at similar levels, retained susceptibility to cefpodoxime-ETX1317 (1:2) with essentially identical minimal inhibitory concentrations of 0.125-0.25 µg/mL cefpodoxime. The KPC-3 mutations had little or no effect on the kinact/Ki values for inhibition by each of 3 diazabicyclooctanes: avibactam, durlobactam (ETX2514), and ETX1317. The KM values for hydrolysis of cefpodoxime were similar for all 4 variants, but the kcat values of the D179Y and D179Y/T243M variants were much lower than those of the wild-type and V240G mutant enzymes. All 4 KPC-3 variants formed stable, reversibly covalent complexes with ETX1317, but dissociation of ETX1317 was much slower from the D179Y and D179Y/T243M mutants than from the wild-type and V240G mutant enzymes. Thus, the KPC-3 variants examined here that cause resistance to ceftazidime-avibactam do not cause resistance to cefpodoxime-ETX1317.


Assuntos
Compostos Azabicíclicos , beta-Lactamases , Compostos Azabicíclicos/farmacologia , Ceftazidima , Ceftizoxima/análogos & derivados , Combinação de Medicamentos , Mutação , beta-Lactamases/genética , Cefpodoxima
8.
Bioorg Med Chem ; 28(24): 115826, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33160146

RESUMO

UDP-3-O-(R-3-hydroxyacyl)-N-acetylglucosamine deacetylase (LpxC), the zinc metalloenzyme catalyzing the first committed step of lipid A biosynthesis in Gram-negative bacteria, has been a target for antibacterial drug discovery for many years. All inhibitor chemotypes reaching an advanced preclinical stage and clinical phase 1 have contained terminal hydroxamic acid, and none have been successfully advanced due, in part, to safety concerns, including hemodynamic effects. We hypothesized that the safety of LpxC inhibitors could be improved by replacing the terminal hydroxamic acid with a different zinc-binding group. After choosing an N-hydroxyformamide zinc-binding group, we investigated the structure-activity relationship of each part of the inhibitor scaffold with respect to Pseudomonas aeruginosa and Escherichia coli LpxC binding affinity, in vitro antibacterial potency and pharmacological properties. We identified a novel, potency-enhancing hydrophobic binding interaction for an LpxC inhibitor. We demonstrated in vivo efficacy of one compound in a neutropenic mouse E. coli infection model. Another compound was tested in a rat hemodynamic assay and was found to have a hypotensive effect. This result demonstrated that replacing the terminal hydroxamic acid with a different zinc-binding group was insufficient to avoid this previously recognized safety issue with LpxC inhibitors.


Assuntos
Amidoidrolases/antagonistas & inibidores , Antibacterianos/farmacologia , Inibidores Enzimáticos/química , Formamidas/química , Hemodinâmica/efeitos dos fármacos , Amidoidrolases/metabolismo , Animais , Antibacterianos/química , Antibacterianos/metabolismo , Antibacterianos/uso terapêutico , Sítios de Ligação , Cristalografia por Raios X , Modelos Animais de Doenças , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Escherichia coli/efeitos dos fármacos , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/patologia , Feminino , Formamidas/metabolismo , Formamidas/farmacologia , Formamidas/uso terapêutico , Meia-Vida , Masculino , Camundongos , Simulação de Dinâmica Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
9.
J Med Chem ; 63(21): 12511-12525, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-32658473

RESUMO

Multidrug resistant Gram-negative bacterial infections are an increasing public health threat due to rapidly rising resistance toward ß-lactam antibiotics. The hydrolytic enzymes called ß-lactamases are responsible for a large proportion of the resistance phenotype. ß-Lactamase inhibitors (BLIs) can be administered in combination with ß-lactam antibiotics to negate the action of the ß-lactamases, thereby restoring activity of the ß-lactam. Newly developed BLIs offer some advantage over older BLIs in terms of enzymatic spectrum but are limited to the intravenous route of administration. Reported here is a novel, orally bioavailable diazabicyclooctane (DBO) ß-lactamase inhibitor. This new DBO, ETX1317, contains an endocyclic carbon-carbon double bond and a fluoroacetate activating group and exhibits broad spectrum activity against class A, C, and D serine ß-lactamases. The ester prodrug of ETX1317, ETX0282, is orally bioavailable and, in combination with cefpodoxime proxetil, is currently in development as an oral therapy for multidrug resistant and carbapenem-resistant Enterobacterales infections.


Assuntos
Antibacterianos/química , Compostos Azabicíclicos/química , Inibidores de beta-Lactamases/química , beta-Lactamases/química , Administração Oral , Animais , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Compostos Azabicíclicos/metabolismo , Compostos Azabicíclicos/farmacologia , Compostos Azabicíclicos/uso terapêutico , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Meia-Vida , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Proteínas de Ligação às Penicilinas/química , Proteínas de Ligação às Penicilinas/metabolismo , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Ligação Proteica , Ratos , Dermatopatias/tratamento farmacológico , Dermatopatias/patologia , Dermatopatias/veterinária , Relação Estrutura-Atividade , Inibidores de beta-Lactamases/metabolismo , Inibidores de beta-Lactamases/farmacologia , Inibidores de beta-Lactamases/uso terapêutico , beta-Lactamases/metabolismo
10.
ACS Infect Dis ; 6(6): 1389-1397, 2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32255609

RESUMO

Multi-drug-resistant Enterobacteriales expressing a wide array of ß-lactamases are emerging as a global health threat in both hospitals and communities. Although several intravenous drugs have recently been approved to address this need, there are no oral Gram-negative agents that are both safe and broadly effective against such pathogens. The lack of an effective oral agent is of concern for common infections which could otherwise be treated in the community but, due to antibiotic resistance, require hospitalization to allow for intravenous therapy. ETX1317 is a novel, broad spectrum, serine ß-lactamase inhibitor of the diazabicyclooctane class that restores the antibacterial activity of multiple ß-lactams against multiple species of multi-drug-resistant Enterobacteriales, including carbapenem-resistant strains. A combination of its oral prodrug, ETX0282, and the oral prodrug of a third-generation cephalosporin, cefpodoxime proxetil, is currently in clinical development. This report describes the biochemical and microbiological properties of ETX1317, which is more potent and demonstrates a greater breadth of inhibition than avibactam, the parenteral prototype of this class of ß-lactamase inhibitors.


Assuntos
Preparações Farmacêuticas , Inibidores de beta-Lactamases , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Carbapenêmicos , Inibidores de beta-Lactamases/farmacologia , beta-Lactamas
11.
Front Immunol ; 9: 2105, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30283447

RESUMO

CARD11 functions as a key signaling scaffold that controls antigen-induced lymphocyte activation during the adaptive immune response. Somatic mutations in CARD11 are frequently found in Non-Hodgkin lymphoma, and at least three classes of germline CARD11 mutations have been described as the basis for primary immunodeficiency. In this review, we summarize our current understanding of how CARD11 signals, how its activity is regulated, and how mutations bypass normal regulation to cause disease.


Assuntos
Imunidade Adaptativa/genética , Proteínas Adaptadoras de Sinalização CARD/genética , Regulação da Expressão Gênica , Predisposição Genética para Doença/genética , Guanilato Ciclase/genética , Mutação , Transdução de Sinais/genética , Proteína 10 de Linfoma CCL de Células B/genética , Humanos , Ativação Linfocitária/genética , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/genética
12.
Sci Rep ; 7(1): 16025, 2017 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-29167511

RESUMO

Transcription factor NF-κB plays a central role in immunity from fruit flies to humans, and NF-κB activity is altered in many human diseases. To investigate a role for NF-κB in immunity and disease on a broader evolutionary scale we have characterized NF-κB in a sea anemone (Exaiptasia pallida; called Aiptasia herein) model for cnidarian symbiosis and dysbiosis (i.e., "bleaching"). We show that the DNA-binding site specificity of Aiptasia NF-κB is similar to NF-κB proteins from a broad expanse of organisms. Analyses of NF-κB and IκB kinase proteins from Aiptasia suggest that non-canonical NF-κB processing is an evolutionarily ancient pathway, which can be reconstituted in human cells. In Aiptasia, NF-κB protein levels, DNA-binding activity, and tissue expression increase when loss of the algal symbiont Symbiodinium is induced by heat or chemical treatment. Kinetic analysis of NF-κB levels following loss of symbiosis show that NF-κB levels increase only after Symbiodinium is cleared. Moreover, introduction of Symbiodinium into naïve Aiptasia larvae results in a decrease in NF-κB expression. Our results suggest that Symbiodinium suppresses NF-κB in order to enable establishment of symbiosis in Aiptasia. These results are the first to demonstrate a link between changes in the conserved immune regulatory protein NF-κB and cnidarian symbiotic status.


Assuntos
NF-kappa B/metabolismo , Anêmonas-do-Mar/metabolismo , Animais , DNA/metabolismo , Humanos , Simbiose/fisiologia
13.
ACS Infect Dis ; 3(11): 833-844, 2017 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-28835096

RESUMO

ETX2514 is a non-ß-lactam serine ß-lactamase inhibitor in clinical development that has greater potency and broader spectrum of ß-lactamase inhibition than the related diazabicyclooctanone avibactam. Despite opening of its cyclic urea ring upon acylation, avibactam can recyclize and dissociate intact from certain ß-lactamases. We investigated reversibility of ETX2514 acylation of 10 serine ß-lactamases representing Ambler classes A, C, and D. Dissociation rate constants varied widely between enzymes and were lowest for class D. For most enzymes, the covalent adduct mass was that of ETX2514 (277 Da). OXA-10 was acylated with 277 and 197 Da adducts, consistent with loss of the sulfate moiety. KPC-2 showed only the 197 Da adduct. ETX2514 recyclized and dissociated intact from AmpC, CTX-M-15, P99, SHV-5 and TEM-1 but not from KPC-2, OXA-10, OXA-23, OXA-24, or OXA-48. Inactivation partition ratios were 1 for all enzymes except KPC-2, for which it increased to 3.0 after 2 h. This result and mass spectrometry showed that KPC-2 very slowly degraded ETX2514. Nevertheless, ETX2514 restored ß-lactam activity to equal potency against isogenic Pseudomonas aeruginosa strains each overexpressing one of the 10 ß-lactamases.


Assuntos
Pseudomonas aeruginosa/genética , Sulfonas/química , Inibidores de beta-Lactamases/farmacologia , Antibacterianos/química , Compostos Azabicíclicos/química , Compostos Azabicíclicos/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/enzimologia , Inibidores de beta-Lactamases/química , beta-Lactamases/metabolismo
14.
Nat Microbiol ; 2: 17104, 2017 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-28665414

RESUMO

Multidrug-resistant (MDR) bacterial infections are a serious threat to public health. Among the most alarming resistance trends is the rapid rise in the number and diversity of ß-lactamases, enzymes that inactivate ß-lactams, a class of antibiotics that has been a therapeutic mainstay for decades. Although several new ß-lactamase inhibitors have been approved or are in clinical trials, their spectra of activity do not address MDR pathogens such as Acinetobacter baumannii. This report describes the rational design and characterization of expanded-spectrum serine ß-lactamase inhibitors that potently inhibit clinically relevant class A, C and D ß-lactamases and penicillin-binding proteins, resulting in intrinsic antibacterial activity against Enterobacteriaceae and restoration of ß-lactam activity in a broad range of MDR Gram-negative pathogens. One of the most promising combinations is sulbactam-ETX2514, whose potent antibacterial activity, in vivo efficacy against MDR A. baumannii infections and promising preclinical safety demonstrate its potential to address this significant unmet medical need.


Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Compostos Azabicíclicos/química , Compostos Azabicíclicos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Inibidores de beta-Lactamases/química , Inibidores de beta-Lactamases/farmacologia , Infecções por Acinetobacter/tratamento farmacológico , Infecções por Acinetobacter/microbiologia , Animais , Compostos Azabicíclicos/uso terapêutico , Compostos Azabicíclicos/toxicidade , Carbapenêmicos/farmacologia , Cães , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Farmacorresistência Bacteriana Múltipla , Enterobacteriaceae/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Humanos , Camundongos , Modelos Moleculares , Proteínas de Ligação às Penicilinas/antagonistas & inibidores , Ratos , Sulbactam/química , Sulbactam/farmacologia , Inibidores de beta-Lactamases/uso terapêutico , Inibidores de beta-Lactamases/toxicidade , beta-Lactamases/metabolismo , beta-Lactamas/farmacologia
15.
Blood ; 119(19): 4441-50, 2012 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-22310911

RESUMO

Immune responses to foreign and self-Ags can be controlled by regulatory T cells (Tregs) expressing CD4 and IL-2Rα chain (CD25). Defects in Tregs lead to autoimmunity, whereas induction of Ag-specific CD4+CD25+ Tregs restores tolerance. Ag-specific CD4+CD25+ FOXP3+Tregs activated by the T helper type 2 (Th2) cytokine, IL-4, and specific alloantigen promote allograft tolerance. These Tregs expressed the specific IL-5Rα and in the presence of IL-5 proliferate to specific but not third-party Ag. These findings suggest that recombinant IL-5 (rIL-5) therapy may promote Ag-specific Tregs to mediate tolerance. This study showed normal CD4+CD25+ Tregs cultured with IL-4 and an autoantigen expressed Il-5rα. Treatment of experimental autoimmune neuritis with rIL-5 markedly reduced clinical paralysis, weight loss, demyelination, and infiltration of CD4+ (Th1 and Th17) CD8+ T cells and macrophages in nerves. Clinical improvement was associated with expansion of CD4+CD25+FOXP3+ Tregs that expressed Il-5rα and proliferated only to specific autoantigen that was enhanced by rIL-5. Depletion of CD25+ Tregs or blocking of IL-4 abolished the benefits of rIL-5. Thus, rIL-5 promoted Ag-specific Tregs, activated by autoantigen and IL-4, to control autoimmunity. These findings may explain how Th2 responses, especially to parasitic infestation, induce immune tolerance. rIL-5 therapy may be able to induce Ag-specific tolerance in autoimmunity.


Assuntos
Autoimunidade/efeitos dos fármacos , Antígenos CD4/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Interleucina-5/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Antígenos de Diferenciação de Linfócitos T/metabolismo , Autoimunidade/imunologia , Células CHO , Cricetinae , Cricetulus , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/imunologia , Avaliação Pré-Clínica de Medicamentos , Feminino , Tolerância Imunológica/efeitos dos fármacos , Ratos , Ratos Endogâmicos Lew , Proteínas Recombinantes/farmacologia , Especificidade do Receptor de Antígeno de Linfócitos T/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/fisiologia
16.
J Neuroimmunol ; 229(1-2): 98-106, 2010 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-20850187

RESUMO

Antibody deposition and complement activation, especially membrane attack complex (MAC) formation are considered central for immune mediated demyelination. To examine the role of MAC in immune mediated demyelination, we studied experimental allergic neuritis (EAN) in Lewis rats deficient in complement component 6 (C6) that cannot form MAC. A C6 deficient Lewis (Lewis/C6-) strain of rats was bred by backcrossing the defective C6 gene, from PVG/C6- rats, onto the Lewis background. Lewis/C6- rats had the same C6 gene deletion as PVG/C6- rats and their sera did not support immune mediated haemolysis unless C6 was added. Active EAN was induced in Lewis and Lewis/C6- rats by immunization with bovine peripheral nerve myelin in complete Freund's adjuvant (CFA), and Lewis/C6- rats had delayed clinical EAN compared to the Lewis rats. Peripheral nerve demyelination in Lewis/C6- was also delayed but was similar in extent at the peak of disease. Compared to Lewis, Lewis/C6- nerves had no MAC deposition, reduced macrophage infiltrate and IL-17A, but similar T cell infiltrate and Th1 cytokine mRNA expression. ICAM-1 and P-selectin mRNA expression and immunostaining on vascular endothelium were delayed in Lewis C6- compared to Lewis rats' nerves. This study found that MAC was not required for immune mediated demyelination; but that MAC enhanced early symptoms and early demyelination in EAN, either by direct lysis or by sub-lytic induction of vascular endothelial expression of ICAM-1 and P-selectin.


Assuntos
Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Doenças Desmielinizantes/imunologia , Doenças Desmielinizantes/metabolismo , Neurite Autoimune Experimental/imunologia , Neurite Autoimune Experimental/metabolismo , Animais , Animais Geneticamente Modificados , Bovinos , Complemento C6/deficiência , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática/métodos , Adjuvante de Freund/imunologia , Humanos , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-17/metabolismo , Macrófagos/metabolismo , Microscopia Eletrônica de Transmissão/métodos , Bainha de Mielina/imunologia , Neurite Autoimune Experimental/patologia , Neurite Autoimune Experimental/fisiopatologia , Selectina-P/genética , Selectina-P/metabolismo , Nervos Periféricos/metabolismo , Nervos Periféricos/patologia , Nervos Periféricos/ultraestrutura , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos Lew , Fatores de Tempo
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