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1.
Genes Immun ; 2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33223527

RESUMO

T-cell activation is a critical driver of immune responses. The CD28 costimulation is an essential regulator of CD4 T-cell responses, however, its relative importance in naive and memory T cells is not fully understood. Using different model systems, we observe that human memory T cells are more sensitive to CD28 costimulation than naive T cells. To deconvolute how the T-cell receptor (TCR) and CD28 orchestrate activation of human T cells, we stimulate cells using varying intensities of TCR and CD28 and profiled gene expression. We show that genes involved in cell cycle progression and division are CD28-driven in memory cells, but under TCR control in naive cells. We further demonstrate that T-helper differentiation and cytokine expression are controlled by CD28. Using chromatin accessibility profiling, we observe that AP1 transcriptional regulation is enriched when both TCR and CD28 are engaged, whereas open chromatin near CD28-sensitive genes is enriched for NF-kB motifs. Lastly, we show that CD28-sensitive genes are enriched in GWAS regions associated with immune diseases, implicating a role for CD28 in disease development. Our study provides important insights into the differential role of costimulation in naive and memory T-cell responses and disease susceptibility.

3.
Nature ; 583(7814): 90-95, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32499645

RESUMO

Primary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges. Although the most severe forms of PID are identified in early childhood, most patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent and up to 10% develop lymphoid malignancies1-3. Consequently, in sporadic (or non-familial) PID genetic diagnosis is difficult and the role of genetics is not well defined. Here we address these challenges by performing whole-genome sequencing in a large PID cohort of 1,318 participants. An analysis of the coding regions of the genome in 886 index cases of PID found that disease-causing mutations in known genes that are implicated in monogenic PID occurred in 10.3% of these patients, and a Bayesian approach (BeviMed4) identified multiple new candidate PID-associated genes, including IVNS1ABP. We also examined the noncoding genome, and found deletions in regulatory regions that contribute to disease causation. In addition, we used a genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization of-and interplay between-novel high-penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to the variable penetrance and phenotypic complexity that are observed in PID. Thus, using a cohort-based whole-genome-sequencing approach in the diagnosis of PID can increase diagnostic yield and further our understanding of the key pathways that influence immune responsiveness in humans.


Assuntos
Doenças da Imunodeficiência Primária/genética , Sequenciamento Completo do Genoma , Complexo 2-3 de Proteínas Relacionadas à Actina/genética , Teorema de Bayes , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Doenças da Imunodeficiência Primária/diagnóstico , Doenças da Imunodeficiência Primária/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 2/genética , Proteínas de Ligação a RNA/genética , Sequências Reguladoras de Ácido Nucleico/genética , Proteína 1 Supressora da Sinalização de Citocina/genética , Fatores de Transcrição/genética
5.
Nat Commun ; 10(1): 3106, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31308374

RESUMO

Immune responses need to be controlled tightly to prevent autoimmune diseases, yet underlying molecular mechanisms remain partially understood. Here, we identify biallelic mutations in three patients from two unrelated families in differentially expressed in FDCP6 homolog (DEF6) as the molecular cause of an inborn error of immunity with systemic autoimmunity. Patient T cells exhibit impaired regulation of CTLA-4 surface trafficking associated with reduced functional CTLA-4 availability, which is replicated in DEF6-knockout Jurkat cells. Mechanistically, we identify the small GTPase RAB11 as an interactor of the guanine nucleotide exchange factor DEF6, and find disrupted binding of mutant DEF6 to RAB11 as well as reduced RAB11+CTLA-4+ vesicles in DEF6-mutated cells. One of the patients has been treated with CTLA-4-Ig and achieved sustained remission. Collectively, we uncover DEF6 as player in immune homeostasis ensuring availability of the checkpoint protein CTLA-4 at T-cell surface, identifying a potential target for autoimmune and/or cancer therapy.


Assuntos
Antígeno CTLA-4/metabolismo , Proteínas de Ligação a DNA/deficiência , Fatores de Troca do Nucleotídeo Guanina/deficiência , Doenças da Imunodeficiência Primária/genética , Antígeno B7-1/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Técnicas de Inativação de Genes , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/imunologia , Homeostase , Humanos , Células Jurkat , Linfócitos T/metabolismo , Linfócitos T/fisiologia , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismo
6.
Sci Immunol ; 4(35)2019 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-31152091

RESUMO

CTLA-4 is a critical negative regulator of the immune system and a major target for immunotherapy. However, precisely how it functions in vivo to maintain immune homeostasis is not clear. As a highly endocytic molecule, CTLA-4 can capture costimulatory ligands from opposing cells by a process of transendocytosis (TE). By restricting costimulatory ligand expression in this manner, CTLA-4 controls the CD28-dependent activation of T cells. Regulatory T cells (Tregs) constitutively express CTLA-4 at high levels and, in its absence, show defects in TE and suppressive function. Activated conventional T cells (Tconv) are also capable of CTLA-4-dependent TE; however, the relative use of this mechanism by Tregs and Tconv in vivo remains unclear. Here, we set out to characterize both the perpetrators and cellular targets of CTLA-4 TE in vivo. We found that Tregs showed constitutive cell surface recruitment of CTLA-4 ex vivo and performed TE rapidly after TCR stimulation. Tregs outperformed activated Tconv at TE in vivo, and expression of ICOS marked Tregs with this capability. Using TCR transgenic Tregs that recognize a protein expressed in the pancreas, we showed that the presentation of tissue-derived self-antigen could trigger Tregs to capture costimulatory ligands in vivo. Last, we identified migratory dendritic cells (DCs) as the major target for Treg-based CTLA-4-dependent regulation in the steady state. These data support a model in which CTLA-4 expressed on Tregs dynamically regulates the phenotype of DCs trafficking to lymph nodes from peripheral tissues in an antigen-dependent manner.


Assuntos
Antígeno CTLA-4/metabolismo , Movimento Celular/imunologia , Células Dendríticas/imunologia , Linfócitos T Reguladores/imunologia , Transcitose/imunologia , Animais , Apresentação do Antígeno/imunologia , Autoantígenos/imunologia , Antígeno B7-1/metabolismo , Antígeno B7-2/metabolismo , Antígeno CTLA-4/genética , Feminino , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Fenótipo , Receptores de Antígenos de Linfócitos T/metabolismo
7.
Methods Mol Biol ; 1899: 87-101, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30649767

RESUMO

Regulatory T cells (Treg) have a central role in controlling the activation of self-reactive T cells and maintaining peripheral tolerance in our body. Many effector mechanisms for Treg function have been described including a role for the protein CTLA-4 which is constitutively expressed by these cells. Despite its importance, there is currently little consensus in the methods and protocols for studying CTLA-4 function, which is partially due to debate over CTLA-4 function itself. In this chapter, we outline protocols used in our lab to study CTLA-4 function, which have been generated based on the observation that CTLA-4 acts to physically remove and degrade its ligands expressed by antigen presenting cells. Accordingly, we provide protocols for isolation of human monocytes and their differentiation into dendritic cells (DC), purification of conventional and regulatory T-cell populations, and the assembly of CTLA-4-dependent Treg suppression assays. We hope that this will offer a reliable platform for dissecting the biology of CTLA-4 on Treg and for testing reagents aimed at modulating CTLA-4 function. Such assays are increasingly vital for the study of immune function in both healthy individuals and patients with a variety of autoimmune and immune dysregulation syndromes.


Assuntos
Antígeno CTLA-4/genética , Separação Celular/métodos , Monócitos/citologia , Linfócitos T Reguladores/citologia , Células Apresentadoras de Antígenos/imunologia , Antígeno CTLA-4/metabolismo , Diferenciação Celular/genética , Células Dendríticas/citologia , Humanos , Ligantes , Linfócitos T Reguladores/imunologia
8.
Immunity ; 51(6): 972-974, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31951541

RESUMO

Targeting the CTLA-4 and PD-1 "checkpoints" is an effective treatment for a number of cancers. In this issue of Immunity, Hui et al. reveal that interaction between a CTLA-4 ligand, CD80, and its counterpart in the PD-1 pathway, PD-L1, affects both PD-1 and CTLA-4 function, raising new questions about the biological effects of using checkpoint inhibitors alone and in combination.


Assuntos
Antígeno B7-H1 , Antígenos CD28 , Antígeno B7-1 , Antígeno CTLA-4 , Receptor de Morte Celular Programada 1
9.
Biophys J ; 115(7): 1330-1343, 2018 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-30219287

RESUMO

CTLA4 is an essential negative regulator of T-cell immune responses and a key checkpoint regulating autoimmunity and antitumor responses. Genetic mutations resulting in quantitative defects in the CTLA4 pathway are also associated with the development of immune dysregulation syndromes in humans. It has been proposed that CTLA4 functions to remove its ligands CD80 and CD86 from opposing cells by a process known as transendocytosis. A quantitative characterization of CTLA4 synthesis, endocytosis, degradation, and recycling and how these affect its function is currently lacking. In a combined in vitro and in silico study, we developed a mathematical model and identified these trafficking parameters. Our model predicts optimal ligand removal in an intermediate affinity range. The intracellular CTLA4 pool as well as fast internalization, recovery of free CTLA4 from internalized complexes, and recycling is critical for sustained functionality. CD80-CTLA4 interactions are predicted to dominate over CD86-CTLA4. Implications of these findings in the context of control of antigen-presenting cells by regulatory T cells and of pathologic genetic deficiencies are discussed. The presented mathematical model can be reused in the community beyond these questions to better understand other trafficking receptors and study the impact of CTLA4 targeting drugs.


Assuntos
Antígeno CTLA-4/metabolismo , Animais , Antígeno B7-1/metabolismo , Antígeno B7-2/metabolismo , Células CHO , Cricetulus , Regulação da Expressão Gênica , Cinética , Ligantes , Modelos Biológicos , Ligação Proteica
10.
J Allergy Clin Immunol ; 142(6): 1932-1946, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29729943

RESUMO

BACKGROUND: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative immune regulator. Heterozygous CTLA4 germline mutations can cause a complex immune dysregulation syndrome in human subjects. OBJECTIVE: We sought to characterize the penetrance, clinical features, and best treatment options in 133 CTLA4 mutation carriers. METHODS: Genetics, clinical features, laboratory values, and outcomes of treatment options were assessed in a worldwide cohort of CTLA4 mutation carriers. RESULTS: We identified 133 subjects from 54 unrelated families carrying 45 different heterozygous CTLA4 mutations, including 28 previously undescribed mutations. Ninety mutation carriers were considered affected, suggesting a clinical penetrance of at least 67%; median age of onset was 11 years, and the mortality rate within affected mutation carriers was 16% (n = 15). Main clinical manifestations included hypogammaglobulinemia (84%), lymphoproliferation (73%), autoimmune cytopenia (62%), and respiratory (68%), gastrointestinal (59%), or neurological features (29%). Eight affected mutation carriers had lymphoma, and 3 had gastric cancer. An EBV association was found in 6 patients with malignancies. CTLA4 mutations were associated with lymphopenia and decreased T-, B-, and natural killer (NK) cell counts. Successful targeted therapies included application of CTLA-4 fusion proteins, mechanistic target of rapamycin inhibitors, and hematopoietic stem cell transplantation. EBV reactivation occurred in 2 affected mutation carriers after immunosuppression. CONCLUSIONS: Affected mutation carriers with CTLA-4 insufficiency can present in any medical specialty. Family members should be counseled because disease manifestation can occur as late as 50 years of age. EBV- and cytomegalovirus-associated complications must be closely monitored. Treatment interventions should be coordinated in clinical trials.


Assuntos
Antígeno CTLA-4/genética , Síndromes de Imunodeficiência/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Humanos , Síndromes de Imunodeficiência/diagnóstico por imagem , Síndromes de Imunodeficiência/terapia , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Adulto Jovem
11.
Clin Immunol ; 188: 94-102, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29305966

RESUMO

The CTLA-4 checkpoint regulates the activation of T cells. Individuals with heterozygous mutations in CTLA-4 have a complex phenotype typically characterized by antibody deficiency alongside variable autoimmunity. Despite severe disease in some individuals, others remain largely unaffected with reasons for this variation unknown. We studied a large family carrying a single point mutation in CTLA-4 leading to an amino acid change R75W and compared both unaffected with affected individuals. We measured a variety of features pertaining to T cell and CTLA-4 biology and observed that at the cellular level there was complete penetrance of CTLA-4 mutations. Accordingly, unaffected individuals were indistinguishable from those with disease in terms of level of CTLA-4 expression, percentage of Treg, upregulation of CTLA-4 upon stimulation and proliferation of CD4 T cells. We conclude that the wide variation in disease phenotype is influenced by immune variation outside of CTLA-4 biology.


Assuntos
Antígenos CD28/imunologia , Antígeno CTLA-4/imunologia , Ativação Linfocitária/imunologia , Linfócitos T/imunologia , Antígenos CD28/metabolismo , Antígeno CTLA-4/deficiência , Antígeno CTLA-4/genética , Diarreia/genética , Diarreia/imunologia , Diarreia/metabolismo , Saúde da Família , Feminino , Humanos , Enteropatias/genética , Enteropatias/imunologia , Enteropatias/metabolismo , Ativação Linfocitária/genética , Masculino , Mutação de Sentido Incorreto , Linhagem , Índice de Gravidade de Doença , Transdução de Sinais/imunologia , Linfócitos T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
12.
J Autoimmun ; 88: 50-60, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29066221

RESUMO

1,25-dihydroxyvitaminD3 (1,25(OH)2D3), has potent anti-inflammatory effects, including suppression of IL-17 + and IFNγ+ T cells implicated in rheumatoid arthritis (RA), but efficacy at the site of active disease is unclear. To investigate this, T cells from synovial fluid (SF) and paired blood of patients with active RA were studied. 1,25(OH)2D3 had significantly less suppressive effect on Th17 cells (IL-17+IFNγ-) and Th17.1 cells (IL-17+IFNγ+) from SF compared to those from blood, and had no effect on SF CD4+ or CD8+ IFNγ+ T cell frequencies. Memory T cells (CD45RO+) predominate in SF, and 1,25(OH)2D3 had less effect on memory T cells relative to naïve (CD45RA+) T cells. RT-PCR and flow cytometry showed that this was not due to decreased expression of the vitamin D receptor or its transcription partners in memory T cells. Further studies using stimulated CD4+ T cells sorted according to IL-17 and IFNγ expression confirmed the ability of 1,25(OH)2D3 to suppress pre-existing cytokines. However, 1,25(OH)2D3 was most effective at suppressing de novo IL-17 and IFNγ induction. Correspondingly, T cell responses to 1,25(OH)2D3 correlated directly with capacity for phenotype change, which was lower in cells from SF compared to blood. These findings indicate that anti-inflammatory effects of 1,25(OH)2D3 in active RA are impaired because of reduced effects on phenotype-committed, inflammatory memory T cells that are enriched in SF. Restoration of 1,25(OH)2D3 responses in memory T cells may provide a new strategy for treatment of inflammatory diseases such as RA.


Assuntos
Artrite Reumatoide/imunologia , Calcitriol/farmacologia , Imunossupressores/farmacologia , Articulações/imunologia , Células Th17/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Cultivadas , Feminino , Humanos , Memória Imunológica , Interferon gama/metabolismo , Interleucina-17/metabolismo , Masculino , Pessoa de Meia-Idade , Líquido Sinovial/imunologia
13.
Blood ; 131(1): 58-67, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29118008

RESUMO

CD28 and CTLA-4 are members of a family of immunoglobulin-related receptors that are responsible for various aspects of T-cell immune regulation. The family includes CD28, CTLA-4, and ICOS as well as other proteins, including PD-1, BTLA, and TIGIT. These receptors have both stimulatory (CD28, ICOS) and inhibitory roles (CTLA-4, PD-1, BTLA, and TIGIT) in T-cell function. Increasingly, these pathways are targeted as part of immune modulatory strategies to treat cancers, referred to generically as immune checkpoint blockade, and conversely to treat autoimmunity and CTLA-4 deficiency. Here, we focus on the biology of the CD28/CTLA-4 pathway as a framework for understanding the impacts of therapeutic manipulation of this pathway.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígeno CTLA-4/antagonistas & inibidores , Imunoterapia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Animais , Antígeno CTLA-4/imunologia , Humanos
15.
J Allergy Clin Immunol ; 140(6): 1660-1670.e16, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28400115

RESUMO

BACKGROUND: Thymus transplantation is a promising strategy for the treatment of athymic complete DiGeorge syndrome (cDGS). METHODS: Twelve patients with cDGS underwent transplantation with allogeneic cultured thymus. OBJECTIVE: We sought to confirm and extend the results previously obtained in a single center. RESULTS: Two patients died of pre-existing viral infections without having thymopoiesis, and 1 late death occurred from autoimmune thrombocytopenia. One infant had septic shock shortly after transplantation, resulting in graft loss and the need for a second transplant. Evidence of thymopoiesis developed from 5 to 6 months after transplantation in 10 patients. Median circulating naive CD4 counts were 44 × 106/L (range, 11-440 × 106/L) and 200 × 106/L (range, 5-310 × 106/L) at 12 and 24 months after transplantation and T-cell receptor excision circles were 2,238/106 T cells (range, 320-8,807/106 T cells) and 4,184/106 T cells (range, 1,582-24,596/106 T cells). Counts did not usually reach normal levels for age, but patients were able to clear pre-existing infections and those acquired later. At a median of 49 months (range, 22-80 months), 8 have ceased prophylactic antimicrobials, and 5 have ceased immunoglobulin replacement. Histologic confirmation of thymopoiesis was seen in 7 of 11 patients undergoing biopsy of transplanted tissue, including 5 showing full maturation through to the terminal stage of Hassall body formation. Autoimmune regulator expression was also demonstrated. Autoimmune complications were seen in 7 of 12 patients. In 2 patients early transient autoimmune hemolysis settled after treatment and did not recur. The other 5 experienced ongoing autoimmune problems, including thyroiditis (3), hemolysis (1), thrombocytopenia (4), and neutropenia (1). CONCLUSIONS: This study confirms the previous reports that thymus transplantation can reconstitute T cells in patients with cDGS but with frequent autoimmune complications in survivors.


Assuntos
Doenças Autoimunes/imunologia , Síndrome de DiGeorge/terapia , Transplante de Órgãos , Complicações Pós-Operatórias/imunologia , Linfócitos T/imunologia , Timo/transplante , Doenças Autoimunes/etiologia , Células Cultivadas , Criança , Pré-Escolar , Síndrome de DiGeorge/imunologia , Europa (Continente) , Feminino , Humanos , Reconstituição Imune , Lactente , Masculino , Técnicas de Cultura de Órgãos , Transplante Homólogo , Resultado do Tratamento
16.
Blood ; 129(11): 1458-1468, 2017 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-28159733

RESUMO

Heterozygous CTLA-4 deficiency has been reported as a monogenic cause of common variable immune deficiency with features of immune dysregulation. Direct mutation in CTLA-4 leads to defective regulatory T-cell (Treg) function associated with impaired ability to control levels of the CTLA-4 ligands, CD80 and CD86. However, additional mutations affecting the CTLA-4 pathway, such as those recently reported for LRBA, indirectly affect CTLA-4 expression, resulting in clinically similar disorders. Robust phenotyping approaches sensitive to defects in the CTLA-4 pathway are therefore required to inform understanding of such immune dysregulation syndromes. Here, we describe assays capable of distinguishing a variety of defects in the CTLA-4 pathway. Assessing total CTLA-4 expression levels was found to be optimal when restricting analysis to the CD45RA-Foxp3+ fraction. CTLA-4 induction following stimulation, and the use of lysosomal-blocking compounds, distinguished CTLA-4 from LRBA mutations. Short-term T-cell stimulation improved the capacity for discriminating the Foxp3+ Treg compartment, clearly revealing Treg expansions in these disorders. Finally, we developed a functionally orientated assay to measure ligand uptake by CTLA-4, which is sensitive to ligand-binding or -trafficking mutations, that would otherwise be difficult to detect and that is appropriate for testing novel mutations in CTLA-4 pathway genes. These approaches are likely to be of value in interpreting the functional significance of mutations in the CTLA-4 pathway identified by gene-sequencing approaches.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Antígeno CTLA-4/genética , Mutação , Antígeno CTLA-4/metabolismo , Linhagem Celular , Imunodeficiência de Variável Comum/genética , Fatores de Transcrição Forkhead/análise , Humanos , Fenômenos do Sistema Imunológico/genética , Ligantes , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia
18.
J Immunol ; 198(1): 528-537, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-27881707

RESUMO

Affinity- and stability-engineered variants of CTLA4-Ig fusion molecules with enhanced pharmacokinetic profiles could yield improved therapies with the potential of higher efficacy and greater convenience to patients. In this study, to our knowledge, we have, for the first time, used in vitro evolution to simultaneously optimize CTLA4 affinity and stability. We selected for improved binding to both ligands, CD80 and CD86, and screened as dimeric Fc fusions directly in functional assays to identify variants with stronger suppression of in vitro T cell activation. The majority of CTLA4 molecules showing the largest potency gains in primary in vitro and ex vivo human cell assays, using PBMCs from type 1 diabetes patients, had significant improvements in CD80, but only modest gains in CD86 binding. We furthermore observed different potency rankings between our lead molecule MEDI5265, abatacept, and belatacept, depending on which type of APC was used, with MEDI5265 consistently being the most potent. We then created fusions of both stability- and potency-optimized CTLA4 moieties with human Fc variants conferring extended plasma t1/2 In a cynomolgus model of T cell-dependent Ab response, the CTLA4-Ig variant MEDI5265 could be formulated at >100 mg/ml for s.c. administration and showed superior efficacy and significantly prolonged serum t1/2 The combination of higher stability and potency with prolonged pharmacokinetics could be compatible with very infrequent, s.c. dosing while maintaining a similar level of immune suppression to more frequently and i.v. administered licensed therapies.


Assuntos
Abatacepte/farmacologia , Desenho de Fármacos , Imunossupressores/farmacologia , Abatacepte/química , Animais , Antígeno B7-1/imunologia , Antígeno B7-2 , Estabilidade de Medicamentos , Humanos , Imunossupressores/química , Ligação Proteica/imunologia
19.
J Immunol ; 195(6): 2657-65, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26276872

RESUMO

Inhibition of the CD28:CD80/CD86 T cell costimulatory pathway has emerged as an effective strategy for the treatment of T cell-mediated inflammatory diseases. However, patient responses to CD28-ligand blockade by abatacept (CTLA-4-Ig) in conditions such as rheumatoid arthritis are variable and often suboptimal. In this study, we show that the extent to which abatacept suppresses T cell activation is influenced by the strength of TCR stimulation, with high-strength TCR stimulation being associated with relative abatacept insensitivity. Accordingly, cyclosporin A, an inhibitor of T cell stimulation via the TCR, synergized with abatacept to inhibit T cell activation. We also observed that 1,25-dihydroxyvitamin D3 enhanced the inhibition of T cell activation by abatacept, strongly inhibiting T cell activation driven by cross-linked anti-CD3, but with no effect upon anti-CD28 driven stimulation. Thus, like cyclosporin A, 1,25-dihydroxyvitamin D3 inhibits TCR-driven activation, thereby promoting abatacept sensitivity. Vitamin D3 supplementation may therefore be a useful adjunct for the treatment of conditions such as rheumatoid arthritis in combination with abatacept to promote the efficacy of treatment.


Assuntos
Abatacepte/farmacologia , Antígenos CD28/antagonistas & inibidores , Calcitriol/farmacologia , Imunossupressores/farmacologia , Linfócitos T/imunologia , Animais , Apoptose/efeitos dos fármacos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Antígenos CD28/imunologia , Células CHO , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Cricetulus , Ciclosporina/farmacologia , Inflamação/imunologia , Ativação Linfocitária/efeitos dos fármacos , Receptores de Antígenos de Linfócitos T/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T/imunologia
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