RESUMO
BACKGROUNDLimited information is available on the impact of immunosuppressants on COVID-19 vaccination in patients with immune-mediated inflammatory diseases (IMID).METHODSThis observational cohort study examined the immunogenicity of SARS-CoV-2 mRNA vaccines in adult patients with inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, or psoriatic disease, with or without maintenance immunosuppressive therapies. Ab and T cell responses to SARS-CoV-2, including neutralization against SARS-CoV-2 variants, were determined before and after 1 and 2 vaccine doses.RESULTSWe prospectively followed 150 subjects, 26 healthy controls, 9 patients with IMID on no treatment, 44 on anti-TNF, 16 on anti-TNF with methotrexate/azathioprine (MTX/AZA), 10 on anti-IL-23, 28 on anti-IL-12/23, 9 on anti-IL-17, and 8 on MTX/AZA. Ab and T cell responses to SARS-CoV-2 were detected in all participants, increasing from dose 1 to dose 2 and declining 3 months later, with greater attrition in patients with IMID compared with healthy controls. Ab levels and neutralization efficacy against variants of concern were substantially lower in anti-TNF-treated patients than in healthy controls and were undetectable against Omicron by 3 months after dose 2.CONCLUSIONSOur findings support the need for a third dose of the mRNA vaccine and for continued monitoring of immunity in these patient groups.FUNDINGFunded by a donation from Juan and Stefania Speck and by Canadian Institutes of Health (CIHR)/COVID-Immunity Task Force (CITF) grants VR-1 172711 and VS1-175545 (to THW and ACG), CIHR FDN-143250 (to THW), GA2-177716 (to VC, ACG, and THW), and GA1-177703 (to ACG) and the CIHR rapid response network to SARS-CoV-2 variants, CoVaRR-Net (to ACG).
Assuntos
Vacinas contra COVID-19 , COVID-19 , Anticorpos Antivirais , Vacina BNT162 , COVID-19/prevenção & controle , Canadá , Humanos , SARS-CoV-2 , Inibidores do Fator de Necrose Tumoral , Vacinas Sintéticas , Vacinas de mRNARESUMO
CD4+ T cells play critical roles during chronic viral infections, but the factors that regulate these responses remain incompletely defined. During chronic infection of mice with lymphocytic choriomeningitis virus clone 13 (LCMV13), the TNFR family member GITR plays a critical CD4+ T cell-intrinsic role in allowing T cell accumulation and viral control. Previously, RNA sequencing of GITR+/+ and GITR-/- T cells sorted from the spleen of mice at day 3 of LCMV13 infection identified the chemokine receptor CX3CR1 as increased by GITR signaling in CD4+ T cells. In this study, we evaluated the role of CX3CR1 on CD4+ T cells during LCMV13 infection. CX3CR1 expression is induced on Ag-specific CD4+ T cells upon Ag stimulation, and GITR signaling further increases the level of CX3CR1 expression. CX3CR1 marks the most differentiated T-bethi, Th1 effector population. Adoptively transferred CX3CR1-/- SMARTA cells had slightly reduced expression of T-bet and IFN-γ per cell compared with their CX3CR1+/+ counterparts but showed no deficit in accumulation in the spleen, lung, or liver. In mixed-radiation chimeras reconstituted with CX3CR1+/+ and CX3CR1-/- bone marrow, CX3CR1+/+ CD4+ T cells showed a marginal deficit in tissue-resident memory T cell numbers compared with the CX3CR1-/- T cells. CX3CR1 may limit acquisition of the tissue-resident memory T cell phenotype because of its effects on increasing T-bet expression, albeit these small effects are unlikely to be of major biological significance. Taken together, these studies show that CX3CR1 marks the most highly differentiated CD4+ Th1 effector population but is largely dispensable for CD4+ T cell responses during chronic viral infection.
Assuntos
Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/fisiologia , Receptor 1 de Quimiocina CX3C/genética , Proteína Relacionada a TNFR Induzida por Glucocorticoide/fisiologia , Viroses/imunologia , Transferência Adotiva , Animais , Diferenciação Celular/genética , Doença Crônica , Feminino , Memória Imunológica , Coriomeningite Linfocítica/genética , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Viroses/genéticaRESUMO
Tissue resident memory T cells (Trm) are critical for local protection against reinfection. The accumulation of T cells in the tissues requires a post-priming signal from TNFR superfamily members, referred to as signal 4. Glucocorticoid-induced TNFR-related protein (GITR; TNFRSF18) signaling is important for this post-priming signal and for Trm formation during respiratory infection with influenza virus. As GITR signaling impacts both effector T cell accumulation and Trm formation, we asked if GITR differentially affects subsets of effector cells with different memory potential. Effector CD4+ T cells can be subdivided into 2 populations based on expression of lymphocyte antigen 6C (Ly6C), whereas effector CD8+ cells can be divided into 3 populations based on Ly6C and CX3CR1. The Ly6Chi and CX3CR1hi T cell populations represent the most differentiated effector T cells. Upon transfer, the Ly6Clo CD4+ effector T cells preferentially enter the lung parenchyma, compared to the Ly6Chi CD4+ T cells. We show that GITR had a similar effect on the accumulation of both the Ly6Chi and Ly6Clo CD4+ T cell subsets. In contrast, whereas GITR increased the accumulation of all three CD8+ T cell subsets defined by CX3CR1 and Ly6C expression, it had a more substantial effect on the least differentiated Ly6Clo CX3CR1lo subset. Moreover, GITR selectively up-regulated CXCR6 on the less differentiated CX3CR1lo CD8+ T cell subsets and induced a small but significant increase in CD127 selectively on the Ly6Clo CD4+ T cell subset. Thus, GITR contributes to accumulation of both differentiated effector cells as well as memory precursors, but with some differences between subsets.
Assuntos
Antígenos Ly/genética , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Proteína Relacionada a TNFR Induzida por Glucocorticoide/genética , Vírus da Influenza A/imunologia , Infecções por Orthomyxoviridae/imunologia , Animais , Antígenos Ly/imunologia , Linfócitos T CD4-Positivos/classificação , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/classificação , Linfócitos T CD8-Positivos/patologia , Linfócitos T CD8-Positivos/virologia , Receptor 1 de Quimiocina CX3C/genética , Receptor 1 de Quimiocina CX3C/imunologia , Diferenciação Celular , Movimento Celular , Feminino , Regulação da Expressão Gênica , Proteína Relacionada a TNFR Induzida por Glucocorticoide/deficiência , Proteína Relacionada a TNFR Induzida por Glucocorticoide/imunologia , Memória Imunológica , Imunofenotipagem , Vírus da Influenza A/crescimento & desenvolvimento , Subunidade alfa de Receptor de Interleucina-7/genética , Subunidade alfa de Receptor de Interleucina-7/imunologia , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Contagem de Linfócitos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infecções por Orthomyxoviridae/genética , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/virologia , Transdução de Sinais , Baço/imunologia , Baço/patologia , Baço/virologiaRESUMO
This study investigates the participation of PI3Kγ in the development of joint inflammation and dysfunction in an experimental model of acute gout in mice. Acute gout was induced by injection of monosodium urate (MSU) crystals into the tibiofemoral joint of mice. The involvement of PI3Kγ was evaluated using a selective inhibitor and mice deficient for PI3Kγ (PI3Kγ-/- ) or with loss of kinase activity. Neutrophils recovered from the inflamed joint were quantified and stained for phosphorylated Akt (pAkt) and production of reactive oxygen species (ROS). The adherence of leukocytes to the joint microvasculature was assessed by intravital microscopy and cleaved caspase-1 by Western blot. Injection of MSU crystals induced massive accumulation of neutrophils expressing phosphorylated Akt. In the absence of PI3Kγ, there was reduction of pAkt expression, chemokine production, and neutrophil recruitment. Genetic or pharmacological inhibition of PI3Kγ reduced the adherence of leukocytes to the joint microvasculature, even in joints with established inflammation. Neutrophils from PI3Kγ-/- mice produced less ROS than wild-type neutrophils. There was decreased joint damage and dysfunction in the absence of PI3Kγ. In addition, in the absence of PI3Kγ activity, there was reduction of cleaved caspase-1 and IL-1ß production in synovial tissue after injection of MSU crystals and leukotriene B4 . Our studies suggest that PI3Kγ is crucial for MSU crystal-induced acute joint inflammation. It is necessary for regulating caspase-1 activation and for mediating neutrophil migration and activation. Drugs that impair PI3Kγ function may be useful to control acute gout inflammation.
Assuntos
Artrite Gotosa/enzimologia , Artrite Gotosa/imunologia , Caspase 1/metabolismo , Classe Ib de Fosfatidilinositol 3-Quinase/metabolismo , Infiltração de Neutrófilos , Doença Aguda , Animais , Adesão Celular , Movimento Celular , Classe Ib de Fosfatidilinositol 3-Quinase/deficiência , Citoplasma/metabolismo , Ativação Enzimática , Inflamassomos/metabolismo , Inflamação/patologia , Interleucina-1beta/metabolismo , Articulações/patologia , Leucotrieno B4/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Microvasos/patologia , Neutrófilos/metabolismo , Nociceptividade , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Membrana Sinovial/irrigação sanguínea , Ácido ÚricoRESUMO
The TNFR superfamily member 4-1BB is important in the establishment of tissue-resident memory T cells (Trm) in the lung tissue following influenza infection. Moreover, supraphysiological boosting of 4-1BB in the airways during the boost phase of a prime-boost immunization regimen increases the long-lived Trm population, correlating with increased protection against heterotypic challenge. However, little is known about how 4-1BB contributes to the establishment of the lung Trm population. In this study, we show that effects of 4-1BB on lung Trm accumulation are already apparent at the effector stage, suggesting that the major role of 4-1BB in Trm formation is to allow persistence of CD8 T effector cells in the lung as they transition to Trm. Using supraphysiological stimulation of 4-1BB in the boost phase of a prime-boost immunization, we show that the effect of 4-1BB on Trm generation requires local delivery of both Ag and costimulation, is inhibited by rapamycin treatment during secondary CD8 effector T cell expansion, and is dependent on the signaling adaptor TRAF1. The decrease in lung Trm following early rapamycin treatment is accompanied by increased circulating memory T cells, as well as fewer effectors, suggesting a role for mammalian target of rapamycin (mTOR) in the formation of Trm through effects on the accumulation of effector precursors. Taken together, these data point to an important role for 4-1BB, TRAF1, and mTOR in the persistence of CD8 effector T cells in the lung parenchyma, thereby allowing the transition to Trm.
Assuntos
Ligante 4-1BB/imunologia , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Vírus da Influenza A/imunologia , Pneumopatias/imunologia , Pulmão/imunologia , Infecções por Orthomyxoviridae/imunologia , Fator 1 Associado a Receptor de TNF/imunologia , Serina-Treonina Quinases TOR/imunologia , Ligante 4-1BB/genética , Animais , Linfócitos T CD8-Positivos/patologia , Pulmão/patologia , Pulmão/virologia , Pneumopatias/genética , Pneumopatias/patologia , Pneumopatias/virologia , Camundongos , Camundongos Knockout , Infecções por Orthomyxoviridae/genética , Infecções por Orthomyxoviridae/patologia , Fator 1 Associado a Receptor de TNF/genética , Serina-Treonina Quinases TOR/genéticaRESUMO
T-cell responses in the lung are critical for protection against respiratory pathogens. TNFR superfamily members play important roles in providing survival signals to T cells during respiratory infections. However, whether these signals take place mainly during priming in the secondary lymphoid organs and/or in the peripheral tissues remains unknown. Here we show that under conditions of competition, GITR provides a T-cell intrinsic advantage to both CD4 and CD8 effector T cells in the lung tissue, as well as for the formation of CD4 and CD8 tissue-resident memory T cells during respiratory influenza infection in mice. In contrast, under non-competitive conditions, GITR has a preferential effect on CD8 over CD4 T cells. The nucleoprotein-specific CD8 T-cell response partially compensated for GITR deficiency by expansion of higher affinity T cells; whereas, the polymerase-specific response was less flexible and more GITR dependent. Following influenza infection, GITR is expressed on lung T cells and GITRL is preferentially expressed on lung monocyte-derived inflammatory antigen presenting cells. Accordingly, we show that GITR+/+ T cells in the lung parenchyma express more phosphorylated-ribosomal protein S6 than their GITR-/- counterparts. Thus, GITR signaling within the lung tissue critically regulates effector and tissue-resident memory T-cell accumulation.
Assuntos
Células Apresentadoras de Antígenos/imunologia , Proteína Relacionada a TNFR Induzida por Glucocorticoide/metabolismo , Vírus da Influenza A/imunologia , Pulmão/imunologia , Infecções por Orthomyxoviridae/imunologia , Linfócitos T/imunologia , Fatores de Necrose Tumoral/metabolismo , Animais , Diferenciação Celular , Movimento Celular , Células Cultivadas , Proteína Relacionada a TNFR Induzida por Glucocorticoide/genética , Memória Imunológica , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Proteínas Quinases S6 Ribossômicas/metabolismo , Fatores de Necrose Tumoral/genéticaRESUMO
There is currently much interest in how different APC subsets shape the immune response. We recently described a division of labor between classical dendritic cells (cDC) and inflammatory monocyte-derived APC in provision of costimulatory ligands to T cells early during chronic lymphocytic choriomeningitis clone 13 (LCMV 13) infection in mice. At day 2 of LCMV 13 infection, cDC preferentially express CD80 and CD86, whereas TNF superfamily ligands GITRL, 4-1BBL, CD70, and OX40L are preferentially induced by type I IFN on inflammatory monocyte-derived APC, with minimal expression on cDC. In this study, we further investigate the expression of TNF and B7 family ligands on APC over the course of LCMV 13 infection. OX40L and 4-1BBL remain above baseline through the chronic stage of infection, with predominant expression on inflammatory APC compared with cDC in the spleen, partially blocked by anti-IFN-γR Ab pretreatment. Conversely, CD70, like GITRL, returns to baseline on the APC within a few days postinfection. In the lung, TNF family ligands were also preferentially expressed on inflammatory monocyte-derived APC. CD86 was generally higher on cDC than inflammatory APC in the spleen, but in the lung CD86 was highest on inflammatory APC. Moreover, in the spleen, CD80 levels on different APC subsets fluctuated over the course of the infection. We also show that LPS induction of TNF superfamily ligands is largely mediated through type I IFN. This study highlights the importance of IFNs and monocyte-derived APC in TNF superfamily ligand expression in both secondary lymphoid organs and tissues during chronic viral infection.
Assuntos
Células Apresentadoras de Antígenos/imunologia , Infecções por Arenaviridae/imunologia , Interferon Tipo I/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Fator de Necrose Tumoral alfa/imunologia , Ligante 4-1BB/imunologia , Animais , Antígeno B7-1/imunologia , Antígeno B7-2/imunologia , Antígeno B7-H1/imunologia , Ligante CD27/imunologia , Técnicas de Cultura de Células , Feminino , Antígenos de Histocompatibilidade Classe II/imunologia , Ligantes , Macrófagos/imunologia , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/imunologia , Ligante OX40 , Baço/imunologia , Linfócitos T/imunologia , Fatores de Necrose Tumoral/imunologiaRESUMO
Metabolic alterations are associated with arthritis apart from obesity. However, it is still unclear which is the underlying process behind these metabolic changes. Here, we investigate the role of tumor necrosis factor (TNF) in this process in an acute model of antigen-induced arthritis (AIA). Immunized male BALB/c mice received an intra-articular injection of PBS (control) or methylated bovine serum albumin (mBSA) into their knees, and were also pre-treated with different drugs: Etanercept, an anti-TNF drug, DF2156A, a CXCR1/2 receptor antagonist, or a monoclonal antibody RB6-8C5 to deplete neutrophils. Local challenge with mBSA evoked an acute neutrophil influx into the knee joint, and enhanced the joint nociception, along with a transient systemic metabolic alteration (higher levels of glucose and lipids, and altered adipocytokines). Pre-treatment with the conventional biological Etanercept, an inhibitor of TNF action, ameliorated the nociception and the acute joint inflammation dominated by neutrophils, and markedly improved many of the altered systemic metabolites (glucose and lipids), adipocytokines and PTX3. However, the lessening of metabolic changes was not due to diminished accumulation of neutrophils in the joint by Etanercept. Reduction of neutrophil recruitment by pre-treating AIA mice with DF2156A, or even the depletion of these cells by using RB6-8C5 reduced all of the inflammatory parameters and hypernociception developed after AIA challenge, but could not prevent the metabolic changes. Therefore, the induction of joint inflammation provoked acute metabolic alterations which were involved with TNF. We suggest that the role of TNF in arthritis-associated metabolic changes is not due to local neutrophils, which are the major cells present in this model, but rather due to cytokines.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/tratamento farmacológico , Cartilagem Articular/efeitos dos fármacos , Etanercepte/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adipocinas/genética , Adipocinas/metabolismo , Animais , Anticorpos Monoclonais/farmacologia , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Proteína C-Reativa/genética , Proteína C-Reativa/metabolismo , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Bovinos , Expressão Gênica , Glucose/metabolismo , Injeções Intra-Articulares , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Neutrófilos/patologia , Receptores de Interleucina-8A/antagonistas & inibidores , Receptores de Interleucina-8A/genética , Receptores de Interleucina-8A/metabolismo , Receptores de Interleucina-8B/antagonistas & inibidores , Receptores de Interleucina-8B/genética , Receptores de Interleucina-8B/metabolismo , Soroalbumina Bovina , Sulfonamidas/farmacologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Tributyrin (TBT) is a TAG composed of three butyric acids that has beneficial effects on ulcerative colitis due to its trophic, anti-inflammatory, pro-apoptotic and anti-carcinogenic properties. The goal of the present study was to evaluate the efficacy and mechanisms of action of TBT supplementation in the prevention of mucosal damage in experimental colitis. Mice received either a control diet or a TBT-supplemented diet for 15 d. Colitis was induced by dextran sodium sulphate administration during the last 7 d. Mucosal damage and the activation of immune cells and cytokines were determined by histological score, flow cytometry and ELISA. Leucocyte rolling and adhesion were assessed by intravital microscopy. Oxidative stress was determined by monitoring hydroperoxide concentration and evaluating superoxide dismutase (SOD) and catalase activities. Intestinal permeability was analysed using diethylenetriaminepentaacetate acid (99mTcDTPA). Compared with the colitis group, the animals in the colitis+TBT group had reduced mucosal damage and neutrophil and eosinophil mucosal infiltration, which were associated with a higher percentage of regulatory T cells (Treg) and higher levels of transforming growth factor ß and IL-10 in the lamina propria. The level of in vivo leucocyte adhesion in the colon microvasculature was reduced after TBT supplementation. A lower level of hydroperoxide and higher levels of SOD and catalase activities were associated with TBT supplementation. TBT-supplemented mice showed reduced intestinal permeability to the levels intermediate between the control and colitis groups. In conclusion, the present results show that TBT has positive effects on colonic restructuring in experimental colitis. Additionally, TBT supplementation changes the immune response by controlling inflammation and regulating the expression of anti-inflammatory cytokines and Treg.