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1.
Immunotherapy ; 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38695680

RESUMO

WHAT IS THIS SUMMARY ABOUT?: Atopic dermatitis (AD) is a chronic (long-lasting) skin disease that leads to dry, itchy, and swollen red spots, which can also be painful and flare up at any time. Some people with AD have a high number of eosinophils, a type of white blood cell, which are associated with worse disease. Medicated creams and lotions, prescribed by health care providers, are meant to reduce the symptoms of AD. For some people, these creams and lotions do not work. Benralizumab injection is a medication that reduces and removes eosinophils. A clinical trial called HILLER tested benralizumab to see if there was a difference in symptoms of AD after reducing or removing eosinophils. This article explains how benralizumab reduced eosinophils and the effect it had on AD symptoms in the HILLIER study. WHAT WERE THE MAIN CONCLUSIONS REPORTED BY THE RESEARCHERS?: Benralizumab reduced blood eosinophil numbers. However, benralizumab showed no evidence of treatment benefit on signs, symptoms, or severity of AD, as measured by three skin assessments compared with placebo. Benralizumab was well tolerated and had a safety profile that was consistent with previous studies. The five most commonly reported side effects were COVID-19 infection, upper respiratory tract infection, headache, swelling of the lymph nodes, and pink eye (conjunctivitis) in patients who received either benralizumab or placebo. WHAT ARE THE KEY TAKEAWAYS?: Benralizumab lowered the number of blood eosinophils without improving AD symptoms and was well tolerated.

2.
J Med Chem ; 64(18): 13807-13829, 2021 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-34464130

RESUMO

Inverse agonists of the nuclear receptor RORC2 have been widely pursued as a potential treatment for a variety of autoimmune diseases. We have discovered a novel series of isoindoline-based inverse agonists of the nuclear receptor RORC2, derived from our recently disclosed RORC2 inverse agonist 2. Extensive structure-activity relationship (SAR) studies resulted in AZD0284 (20), which combined potent inhibition of IL-17A secretion from primary human TH17 cells with excellent metabolic stability and good PK in preclinical species. In two preclinical in vivo studies, compound 20 reduced thymocyte numbers in mice and showed dose-dependent reduction of IL-17A containing γδ-T cells and of IL-17A and IL-22 RNA in the imiquimod induced inflammation model. Based on these data and a favorable safety profile, 20 was progressed to phase 1 clinical studies.


Assuntos
Anti-Inflamatórios/uso terapêutico , Inflamação/tratamento farmacológico , Isoindóis/uso terapêutico , Receptores Nucleares Órfãos/agonistas , Sulfonas/uso terapêutico , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacocinética , Cães , Agonismo Inverso de Drogas , Feminino , Humanos , Imiquimode , Inflamação/induzido quimicamente , Isoindóis/líquido cefalorraquidiano , Isoindóis/síntese química , Isoindóis/farmacocinética , Masculino , Camundongos Endogâmicos C57BL , Estrutura Molecular , Ratos Wistar , Relação Estrutura-Atividade , Sulfonas/líquido cefalorraquidiano , Sulfonas/síntese química , Sulfonas/farmacocinética , Células Th17 , Timócitos/efeitos dos fármacos
3.
J Med Chem ; 61(17): 7796-7813, 2018 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-30095900

RESUMO

Retinoic acid receptor related orphan receptor γt (RORγt), has been identified as the master regulator of TH17-cell function and development, making it an attractive target for the treatment of autoimmune diseases by a small-molecule approach. Herein, we describe our investigations on a series of 4-aryl-thienyl acetamides, which were guided by insights from X-ray cocrystal structures. Efforts in targeting the cofactor-recruitment site from the 4-aryl group on the thiophene led to a series of potent binders with nanomolar activity in a primary human-TH17-cell assay. The observation of a DMSO molecule binding in a subpocket outside the LBD inspired the introduction of an acetamide into the benzylic position of these compounds. Hereby, a hydrogen-bond interaction of the introduced acetamide oxygen with the backbone amide of Glu379 was established. This greatly enhanced the cellular activity of previously weakly cell-active compounds. The best compounds combined potent inhibition of IL-17 release with favorable PK in rodents, with compound 32 representing a promising starting point for future investigations.


Assuntos
Acetamidas/farmacologia , Desenho de Fármacos , Agonismo Inverso de Drogas , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Conformação Proteica , Células Th17/efeitos dos fármacos , Células Th17/metabolismo , Acetamidas/administração & dosagem , Acetamidas/química , Acetamidas/farmacocinética , Administração Oral , Animais , Sítios de Ligação , Disponibilidade Biológica , Células Cultivadas , Cristalografia por Raios X , Humanos , Interleucina-17/metabolismo , Modelos Moleculares , Estrutura Molecular , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/química , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Ligação Proteica , Roedores , Relação Estrutura-Atividade , Células Th17/imunologia , Distribuição Tecidual
4.
ChemMedChem ; 11(2): 207-16, 2016 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-26553345

RESUMO

RORγt, an isoform of the retinoic acid-related orphan receptor gamma (RORc, RORγ), has been identified as the master regulator of T-helper 17 (TH 17) cell function and development, making it an attractive target for the treatment of autoimmune diseases. Validation for this target comes from antibodies targeting interleukin-17 (IL-17), the signature cytokine produced by TH 17 cells, which have shown impressive results in clinical trials. Through focused screening of our compound collection, we identified a series of N-sulfonylated benzoxazepines, which displayed micromolar affinity for the RORγ ligand-binding domain (LBD) in a radioligand binding assay. Optimization of these initial hits resulted in potent binders, which dose-dependently decreased the ability of the RORγ-LBD to interact with a peptide derived from steroid receptor coactivator 1, and inhibited the release of IL-17 secretion from isolated and cultured human TH 17 cells with nanomolar potency. A cocrystal structure of inverse agonist 15 (2-chloro-6-fluoro-N-(4-{[3-(trifluoromethyl)phenyl]sulfonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzamide) bound to the RORγ-LBD illustrated that both hydrophobic interactions, leading to an induced fit around the substituted benzamide moiety of 15, as well as a hydrogen bond from the amide NH to His479 seemed to be important for the mechanism of action. This structure is compared with the structure of agonist 25 (N-(2-fluorophenyl)-4-[(4-fluorophenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-6-amine ) and structures of other known RORγ modulators.


Assuntos
Interleucina-17/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Oxazepinas/farmacologia , Células Th17/efeitos dos fármacos , Células Th17/metabolismo , Sítios de Ligação/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Interleucina-17/imunologia , Modelos Moleculares , Estrutura Molecular , Oxazepinas/síntese química , Oxazepinas/química , Ligação Proteica/efeitos dos fármacos , Relação Estrutura-Atividade , Células Th17/imunologia
5.
J Immunol ; 183(7): 4360-70, 2009 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-19734224

RESUMO

Migration of CD4+CD25+FOXP3+ regulatory T cells (Treg) is important for suppressing immune responses in different tissues. Previous studies show that the majority of Treg at birth express gut homing receptor alpha(4)beta(7) and that only few express CCR4, while the reverse pattern is found in adults. The age at which homing receptor switch occurs in vivo is not known. In this study, we show, in a prospective study of human infants from birth to 3 years of age, that homing receptor switch from alpha(4)beta(7) to CCR4 commences between 1 1/2 and 3 years of age and that Treg at that age also had started their switch to a memory phenotype. The majority of naive Treg express alpha(4)beta(7) in infants but not in adults, while the majority of memory Treg express CCR4 both infants and adults. The homing receptor expression on Treg corresponds to their actual migration properties, because Treg from cord blood migrate foremost toward the gut-associated chemokine CCL25. CD4+FOXP3+ T cell numbers increase rapidly in the circulation during the first days of life indicating conversion to suppressive Treg from CD25(high) Treg precursors. These findings suggest that the gut is the primary site of Treg stimulation to exogenous Ags during the first 18 mo of life and that homing receptor switch toward a more extra-intestinal phenotype occurs thereafter.


Assuntos
Diferenciação Celular/imunologia , Memória Imunológica , Subunidade alfa de Receptor de Interleucina-2/biossíntese , Receptores de Retorno de Linfócitos/biossíntese , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Adulto , Fatores Etários , Pré-Escolar , Sangue Fetal/citologia , Sangue Fetal/imunologia , Sangue Fetal/metabolismo , Fatores de Transcrição Forkhead/biossíntese , Fatores de Transcrição Forkhead/sangue , Humanos , Lactente , Recém-Nascido , Integrinas/biossíntese , Integrinas/sangue , Subunidade alfa de Receptor de Interleucina-2/sangue , Contagem de Linfócitos , Pessoa de Meia-Idade , Estudos Prospectivos , Receptores CCR4/biossíntese , Receptores CCR4/sangue , Receptores de Retorno de Linfócitos/sangue
6.
J Clin Immunol ; 29(6): 752-60, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19543958

RESUMO

INTRODUCTION: The aim of this study was to investigate the suppressive capacity of CD25(+) regulatory T cells on birch allergen-induced T-cell responses during the first birch pollen season after initiation of specific immunotherapy (SIT). METHODS: CD25(pos) and CD25(neg) T cells were purified from blood of birch-allergic SIT patients and birch-allergic controls, stimulated with birch pollen extract, and analyzed for T-cell proliferation and production of interferon gamma (IFN-gamma), interleukin (IL)-5 and IL-10. RESULTS: We show that allergen-induced proliferation and IFN-gamma production were suppressed equally well by CD25(pos) T cells from SIT patients and controls, while the IL-5 production was not suppressed by either of the groups. IL-10 levels were higher in SIT patients relative to controls only when CD25(neg) and CD25(pos) were cultured together. Furthermore, neither FOXP3 levels nor proportions of CD25(high) T cells were enhanced in SIT patients compared to allergic controls. DISCUSSION: These results suggest that the Th2-suppressive capacity of allergen-stimulated CD25(pos) Treg in vitro is not improved by SIT in spite of increased IL-10 production from T cells.


Assuntos
Betula/imunologia , Hipersensibilidade/terapia , Imunoterapia/métodos , Linfócitos T Reguladores/imunologia , Células Th2/citologia , Adolescente , Adulto , Alérgenos , Proliferação de Células , Células Cultivadas , Feminino , Humanos , Hipersensibilidade/imunologia , Interferon gama/análise , Interleucina-10/análise , Interleucina-5/análise , Masculino , Pessoa de Meia-Idade , Extratos Vegetais/administração & dosagem , Extratos Vegetais/uso terapêutico , Pólen/imunologia , Células Th2/imunologia , Adulto Jovem
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