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1.
Sci Immunol ; 9(91): eadi0672, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-38181094

RESUMO

Dysbiosis in the gut microbiota affects several systemic diseases, possibly by driving the migration of perturbed intestinal immunocytes to extraintestinal tissues. Combining Kaede photoconvertible mice and single-cell genomics, we generated a detailed map of migratory trajectories from the colon, at baseline, and in several models of intestinal and extraintestinal inflammation. All lineages emigrated from the colon in an S1P-dependent manner. B lymphocytes represented the largest contingent, with the unexpected circulation of nonexperienced follicular B cells, which carried a gut-imprinted transcriptomic signature. T cell emigration included distinct groups of RORγ+ and IEL-like CD160+ subsets. Gut inflammation curtailed emigration, except for dendritic cells disseminating to lymph nodes. Colon-emigrating cells distributed differentially to distinct sites of extraintestinal models of inflammation (psoriasis-like skin, arthritic synovium, and tumors). Thus, specific cellular trails originating in the gut and influenced by microbiota may shape peripheral immunity in varied ways.


Assuntos
Linfócitos B , Microbioma Gastrointestinal , Animais , Camundongos , Disbiose , Perfilação da Expressão Gênica , Inflamação
2.
Nat Immunol ; 24(12): 2053-2067, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37932455

RESUMO

Following acute injury, stromal cells promote tissue regeneration by a diversity of mechanisms. Time-resolved single-cell RNA sequencing of muscle mesenchymal stromal cells (MmSCs) responding to acute injury identified an 'early-responder' subtype that spiked on day 1 and expressed a notable array of transcripts encoding immunomodulators. IL-1ß, TNF-α and oncostatin M each strongly and rapidly induced MmSCs transcribing this immunomodulatory program. Macrophages amplified the program but were not strictly required for its induction. Transfer of the inflammatory MmSC subtype, tagged with a unique surface marker, into healthy hindlimb muscle induced inflammation primarily driven by neutrophils and macrophages. Among the abundant inflammatory transcripts produced by this subtype, Cxcl5 was stroma-specific and highly upregulated with injury. Depletion of this chemokine early after injury revealed a substantial impact on recruitment of neutrophils, a prolongation of inflammation to later times and an effect on tissue regeneration. Mesenchymal stromal cell subtypes expressing a comparable inflammatory program were found in a mouse model of muscular dystrophy and in several other tissues and pathologies in both mice and humans. These 'early-responder' mesenchymal stromal cells, already in place, permit rapid and coordinated mobilization and amplification of critical cell collaborators in response to injury.


Assuntos
Inflamação , Células-Tronco Mesenquimais , Humanos , Camundongos , Animais , Inflamação/metabolismo , Macrófagos/metabolismo , Células-Tronco Mesenquimais/metabolismo , Neutrófilos/metabolismo , Cicatrização
3.
Proc Natl Acad Sci U S A ; 120(14): e2221255120, 2023 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-36972453

RESUMO

Izumo1R is a pseudo-folate receptor with an essential role in mediating tight oocyte/spermatozoa contacts during fertilization. Intriguingly, it is also expressed in CD4+ T lymphocytes, in particular Treg cells under the control of Foxp3. To understand Izumo1R function in Treg cells, we analyzed mice with Treg-specific Izumo1r deficiency (Iz1rTrKO). Treg differentiation and homeostasis were largely normal, with no overt autoimmunity and only marginal increases in PD1+ and CD44hi Treg phenotypes. pTreg differentiation was also unaffected. Iz1rTrKO mice proved uniquely susceptible to imiquimod-induced, γδT cell-dependent, skin disease, contrasting with normal responses to several inflammatory or tumor challenges, including other models of skin inflammation. Analysis of Iz1rTrKO skin revealed a subclinical inflammation that presaged IMQ-induced changes, with an imbalance of Rorγ+ γδT cells. Immunostaining of normal mouse skin revealed the expression of Izumo1, the ligand for Izumo1R, electively in dermal γδT cells. We propose that Izumo1R on Tregs enables tight contacts with γδT cells, thereby controlling a particular path of skin inflammation.


Assuntos
Dermatite , Psoríase , Receptores de Superfície Celular , Dermatopatias , Linfócitos T Reguladores , Animais , Camundongos , Dermatite/metabolismo , Imiquimode , Inflamação/metabolismo , Psoríase/metabolismo , Receptores de Superfície Celular/metabolismo , Pele/metabolismo , Dermatopatias/metabolismo , Linfócitos T Reguladores/metabolismo
4.
Immunity ; 56(4): 829-846.e8, 2023 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-36822206

RESUMO

Specific microbial signals induce the differentiation of a distinct pool of RORγ+ regulatory T (Treg) cells crucial for intestinal homeostasis. We discovered highly analogous populations of microbiota-dependent Treg cells that promoted tissue regeneration at extra-gut sites, notably acutely injured skeletal muscle and fatty liver. Inflammatory meditators elicited by tissue damage combined with MHC-class-II-dependent T cell activation to drive the accumulation of gut-derived RORγ+ Treg cells in injured muscle, wherein they regulated the dynamics and tenor of early inflammation and helped balance the proliferation vs. differentiation of local stem cells. Reining in IL-17A-producing T cells was a major mechanism underlying the rheostatic functions of RORγ+ Treg cells in compromised tissues. Our findings highlight the importance of gut-trained Treg cell emissaries in controlling the response to sterile injury of non-mucosal tissues.


Assuntos
Microbioma Gastrointestinal , Microbiota , Animais , Camundongos , Linfócitos T Reguladores , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Camundongos Endogâmicos C57BL
5.
Clin Exp Immunol ; 211(2): 138-148, 2023 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-35972909

RESUMO

Foxp3+CD4+ regulatory T cells (Tregs) are famous for their role in maintaining immunological tolerance. With their distinct transcriptomes, growth-factor dependencies and T-cell receptor (TCR) repertoires, Tregs in nonlymphoid tissues, termed "tissue-Tregs," also perform a variety of functions to help assure tissue homeostasis. For example, they are important for tissue repair and regeneration after various types of injury, both acute and chronic. They exert this influence by controlling both the inflammatory tenor and the dynamics of the parenchymal progenitor-cell pool in injured tissues, thereby promoting efficient repair and limiting fibrosis. Thus, tissue-Tregs are seemingly attractive targets for immunotherapy in the context of tissue regeneration, offering several advantages over existing therapies. Using skeletal muscle as a model system, we discuss the existing literature on Tregs' role in tissue regeneration in acute and chronic injuries, and various approaches for their therapeutic modulation in such contexts, including exercise as a natural Treg modulator.


Assuntos
Músculo Esquelético , Linfócitos T Reguladores , Tolerância Imunológica
6.
J Exp Med ; 219(5)2022 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-35380608

RESUMO

Subsequent to acute injury, skeletal muscle undergoes a stereotypic regenerative process that reestablishes homeostasis. Various types of innate and adaptive immunocytes exert positive or negative influences at specific stages along the course of muscle regeneration. We describe an unanticipated role for γδT cells in promoting healthy tissue recovery after injection of cardiotoxin into murine hindlimb muscle. Within a few days of injury, IL-17A-producing γδT cells displaying primarily Vγ6+ antigen receptors accumulated at the wound site. Punctual ablation experiments showed that these cells boosted early inflammatory events, notably recruitment of neutrophils; fostered the proliferation of muscle stem and progenitor cells; and thereby promoted tissue regeneration. Supplementation of mice harboring low numbers of IL-17A+ γδT cells with recombinant IL-17A largely reversed their inflammatory and reparative defects. Unexpectedly, the accumulation and influences of γδT cells in this experimental context were microbiota dependent, unveiling an orthogonal perspective on the treatment of skeletal muscle pathologies such as catastrophic wounds, wasting, muscular dystrophies, and myositides.


Assuntos
Interleucina-17 , Microbiota , Desenvolvimento Muscular , Regeneração , Linfócitos T , Animais , Camundongos , Camundongos Endogâmicos C57BL , Músculos , Receptores de Antígenos de Linfócitos T gama-delta
7.
Immunity ; 54(12): 2825-2841.e10, 2021 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-34879221

RESUMO

T cell exhaustion limits anti-tumor immunity and responses to immunotherapy. Here, we explored the microenvironmental signals regulating T cell exhaustion using a model of chronic lymphocytic leukemia (CLL). Single-cell analyses identified a subset of PD-1hi, functionally impaired CD8+ T cells that accumulated in secondary lymphoid organs during disease progression and a functionally competent PD-1int subset. Frequencies of PD-1int TCF-1+ CD8+ T cells decreased upon Il10rb or Stat3 deletion, leading to accumulation of PD-1hi cells and accelerated tumor progression. Mechanistically, inhibition of IL-10R signaling altered chromatin accessibility and disrupted cooperativity between the transcription factors NFAT and AP-1, promoting a distinct NFAT-associated program. Low IL10 expression or loss of IL-10R-STAT3 signaling correlated with increased frequencies of exhausted CD8+ T cells and poor survival in CLL and in breast cancer patients. Thus, balance between PD-1hi, exhausted CD8+ T cells and functional PD-1int TCF-1+ CD8+ T cells is regulated by cell-intrinsic IL-10R signaling, with implications for immunotherapy.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Imunoterapia/métodos , Leucemia Linfocítica Crônica de Células B/imunologia , Receptores de Interleucina-10/metabolismo , Subpopulações de Linfócitos T/imunologia , Animais , Linhagem Celular Tumoral , Células Cultivadas , Microambiente Celular , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Humanos , Imunidade , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Transcrição NFATC/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Receptores de Interleucina-10/genética , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Fator de Transcrição AP-1/metabolismo
8.
J Laryngol Otol ; 135(5): 396-402, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33858541

RESUMO

OBJECTIVE: This study aimed to provide an objective means of identifying patterns in academic publication among ENT trainees during their higher surgical training. METHOD: A cross-sectional survey was distributed to ENT higher surgical trainees. RESULTS: A total of 153 ENT specialty trainees participated, giving a response rate of 46.5 per cent. Across all years of training, the mean number of first author publications was three and the mean number of non-first author publications was two. For trainees at specialty trainee year 8 level, these figures were nine and five, respectively. Participants with doctoral degrees and those in academic programmes published more papers but the mean difference was only significant for the doctoral subgroup (p < 0.0001). Those with additional undergraduate degrees and those in less than full-time training had an overall lower number of publications. CONCLUSION: Participants in the current survey achieved a higher average number of academic publications than is presently required to successfully complete higher surgical training in ENT. It is hoped that these results act as a guide for trainees planning the research component of their training to ensure that they remain competitive at consultant interview.


Assuntos
Autoria , Otolaringologia/educação , Publicações/estatística & dados numéricos , Adulto , Escolha da Profissão , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Reino Unido
9.
Haematologica ; 106(4): 968-977, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32139435

RESUMO

Ibrutinib is a bruton's tyrosine kinase (BTK) inhibitor approved for the treatment of multiple B-cell malignancies, including chronic lymphocytic leukemia (CLL). In addition to blocking B-cell receptor signaling and chemokine receptor-mediated pathways in CLL cells, that are known drivers of disease, ibrutinib also affects the microenvironment in CLL via targeting BTK in myeloid cells and IL-2-inducible T-cell kinase (ITK) in T-cells. These non-BTK effects were suggested to contribute to the success of ibrutinib in CLL. By using the Eµ-TCL1 adoptive transfer mouse model of CLL, we observed that ibrutinib effectively controls leukemia development, but also results in significantly lower numbers of CD8+ effector T-cells, with lower expression of activation markers, as well as impaired proliferation and effector function. Using CD8+ T-cells from a T-cell receptor (TCR) reporter mouse, we verified that this is due to a direct effect of ibrutinib on TCR activity, and demonstrate that co-stimulation via CD28 overcomes these effects. Most interestingly, combination of ibrutinib with blocking antibodies targeting PD-1/PD-L1 axis in vivo improved CD8+ T-cell effector function and control of CLL. In sum, these data emphasize the strong immunomodulatory effects of ibrutinib and the therapeutic potential of its combination with immune checkpoint blockade in CLL.


Assuntos
Leucemia Linfocítica Crônica de Células B , Adenina/análogos & derivados , Animais , Linfócitos T CD8-Positivos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Camundongos , Piperidinas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas , Pirazóis/farmacologia , Pirimidinas/farmacologia , Microambiente Tumoral
10.
J Laryngol Otol ; 134(5): 458-459, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32493525

RESUMO

BACKGROUND: Rigid oesophagoscopy is a widely used therapeutic and diagnostic procedure. Smooth friction-free insertion of the rigid scope is important to prevent oral and oesophageal mucosal damage, as such damage can cause delays in oral intake or more serious complications such as perforation. Protection appliances such as gum guards are useful adjuncts to cushion the teeth in rigid oesophagoscopy; however, there are no specific adjuncts for the edentulous patient. METHODS: In order to investigate different adjuncts, the force required to pull a standard adult rigid oesophagoscope from a metal clamp whilst enclosed in dry gauze, wet gauze, a gum guard or sleek on gauze was recorded, and a prospective audit of post-procedural trauma was performed. RESULTS AND CONCLUSION: Less force was required to create movement of the scope against sleek on gauze, with a lower rate of oral trauma (8 per cent) compared to that reported in the literature. Sleek on gauze is recommended for the edentulous patient.


Assuntos
Esofagoscópios/efeitos adversos , Esofagoscopia/métodos , Complicações Intraoperatórias/prevenção & controle , Boca Edêntula/complicações , Boca/lesões , Fenômenos Biomecânicos , Desenho de Equipamento , Esofagoscopia/efeitos adversos , Humanos , Protetores Bucais , Padrões de Prática Médica , Estudos Prospectivos
11.
Viruses ; 13(1)2020 12 30.
Artigo em Inglês | MEDLINE | ID: mdl-33396578

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes coronavirus disease 2019 (COVID-19), a lung disease that may progress to systemic organ involvement and in some cases, death. The identification of the earliest predictors of progressive lung disease would allow for therapeutic intervention in those cases. In an earlier clinical study, individuals with moderate COVID-19 were treated with either arbidol (ARB) or inhaled interferon (IFN)-α2b +/-ARB. IFN treatment resulted in accelerated viral clearance from the upper airways and in a reduction in the circulating levels of the inflammatory biomarkers IL-6 and C-reactive protein (CRP). We have extended the analysis of this study cohort to determine whether IFN treatment had a direct effect on virus-induced lung abnormalities and also to ascertain whether any clinical or immune parameters are associated with worsening of lung abnormalities. Evidence is provided that IFN-α2b treatment limits the development of lung abnormalities associated with COVID-19, as assessed by CT images. Clinical predictors associated with worsening of lung abnormalities include low CD8+ T cell numbers, low levels of circulating albumin, high numbers of platelets, and higher levels of circulating interleukin (IL)-10, IL-6, and C-reactive protein (CRP). Notably, in this study cohort, IFN treatment resulted in a higher percentage of CD8+ T cells, lower tumor necrosis factor (TNF)-α levels and, as reported earlier, lower IL-6 levels. Independent of treatment, age and circulating levels of albumin and CRP emerged as the strongest predictors of the severity of lung abnormalities.


Assuntos
Antivirais/uso terapêutico , Tratamento Farmacológico da COVID-19 , Interferon-alfa/uso terapêutico , Pulmão/anormalidades , Administração por Inalação , Antivirais/administração & dosagem , Biomarcadores/sangue , Proteína C-Reativa , Linfócitos T CD8-Positivos , COVID-19/fisiopatologia , China , Estudos de Coortes , Citocinas/imunologia , Quimioterapia Combinada , Humanos , Indóis/administração & dosagem , Indóis/uso terapêutico , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Interleucina-10 , Interleucina-6 , Pulmão/diagnóstico por imagem , Pulmão/patologia , SARS-CoV-2/efeitos dos fármacos
12.
Leuk Lymphoma ; 61(2): 351-356, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31519123

RESUMO

Chronic lymphocytic leukemia (CLL) is associated with an accumulation of oligoclonal CD8+ effector T-cells, which control leukemia progression in mice, but gradually acquire a dysfunctional phenotype along with disease progression. Exhaustion of CD8+ T-cells is characterized by increased expression of inhibitory receptors like PD-1, decreased proliferation, and reduced effector function such as cytokine production, which reduces anti-tumor control. Despite the accumulation of exhausted PD-1+ CD8+ T-cells in secondary lymphoid organs of CLL patients, immune checkpoint blockade as a means to reinvigorate anti-tumor T-cell activity has not shown the expected efficacy. This highlights the need for a better understanding of T-cell exhaustion in CLL. Here, we uncover the transcriptional program of T-cell exhaustion in CLL by comparing naïve with dysfunctional effector CD8+ T-cells with high PD-1 expression from mice after adoptive transfer of Eµ-TCL1 leukemic cells. Our data provide clear evidence for activation-induced dysfunction of CD8+ T-cells in the CLL microenvironment and assess the heterogeneity in the expression of functionally relevant proteins in specific clusters of CD8+ T-cells at a single-cell level.


Assuntos
Leucemia Linfocítica Crônica de Células B , Animais , Linfócitos T CD8-Positivos , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Ativação Linfocitária , Camundongos , Fenótipo , Microambiente Tumoral
13.
Br J Haematol ; 189(1): 133-145, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31724172

RESUMO

Chronic lymphocytic leukaemia (CLL) is associated with alterations in T cell number, subset distribution and function. Among these changes, an increase in CD4+ T cells was reported. CD4+ T cells are a heterogeneous population and distinct subsets have been described to exert pro- and anti-tumour functions. In CLL, controversial reports describing the dominance of IFNγ-expressing Th1 T cells or of IL-4-producing Th2 T cells exist. Our study shows that blood of CLL patients is enriched in Th1 T cells producing high amounts of IFNγ. Moreover, we observed that their frequency remains relatively stable in CLL patients over a time course of five years. Furthermore, we provide evidence for an accumulation of Th1 T cells in the Eµ-TCL1 mouse model of CLL. As TBET (encoded by Tbx21) is a crucial transcription factor for Th1 polarization, we generated Tbx21-/- bone marrow chimaeric mice which showed a lower number of IFNγ-producing Th1 T cells, and used them for adoptive transfer of Eµ-TCL1 leukaemia. Disease development in these mice was, however, comparable to that in wild-type controls, excluding a major role for TBET-expressing Th1 cells in Eµ-TCL1 leukaemia. Collectively, our data highlight that Th1 T cells accumulate in CLL but reducing their number has no impact on disease development.


Assuntos
Regulação Leucêmica da Expressão Gênica/imunologia , Leucemia Linfocítica Crônica de Células B/imunologia , Proteínas de Neoplasias/imunologia , Neoplasias Experimentais/imunologia , Proteínas com Domínio T/imunologia , Células Th1/imunologia , Animais , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/genética , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Proteínas com Domínio T/genética , Células Th1/patologia
14.
Sci Adv ; 5(9): eaax0800, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31523711

RESUMO

Mobile gravimetry is important in metrology, navigation, geodesy, and geophysics. Atomic gravimeters could be among the most accurate mobile gravimeters but are currently constrained by being complex and fragile. Here, we demonstrate a mobile atomic gravimeter, measuring tidal gravity variations in the laboratory and surveying gravity in the field. The tidal gravity measurements achieve a sensitivity of 37 µGal/ Hz (1 µGal = 10 nm/s2) and a long-term stability of better than 2 µGal, revealing ocean tidal loading effects and recording several distant earthquakes. We survey gravity in the Berkeley Hills with an uncertainty of around 0.04 mGal and determine the density of the subsurface rocks from the vertical gravity gradient. With simplicity and sensitivity, our instrument paves the way for bringing atomic gravimeters to field applications.

16.
Rev Sci Instrum ; 90(7): 073103, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31370459

RESUMO

Atom interferometers require precise control of digital, analog, and radio frequency signals for effective operation. In this paper, we propose and implement a control system for mobile atom interferometers. The system consists of a microcontroller and peripherals to synthesize radio frequency signals and to read or write analog signals. We use the system to operate a mobile atomic gravimeter by controlling 7 analog outputs, 16 digital outputs, 2 radio frequency channels, and 1 analog input. Our control system eliminates dead time between repetitions of the measurement and, consequently, improves the sampling rate of our atomic gravimeter, while maintaining the sensitivity per repetition compared to the system based on a desktop computer.

18.
Mol Immunol ; 110: 77-87, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-29173971

RESUMO

Tumor-promoting inflammation and escape from immune-mediated tumor destruction have been recognized as hallmarks of cancer, and myeloid cells are key players in these processes. By exploiting the tremendous plasticity of myeloid cells, tumors induce a variety of tumor-supportive and immunosuppressive cell phenotypes like tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). The relevance of these cell types in hematopoietic malignancies has only recently gained a stronger attention. Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells that expand in secondary lymphoid organs and the bone marrow, and accumulate in the blood of patients. A large body of evidence suggests that the interactions between CLL cells and non-malignant cells in the tumor microenvironment play a key role in the pathology of this disease. CLL is associated with an inflammatory milieu and defective immune responses. A severe skewing of myeloid and T cells toward leukemia-supportive and immunosuppressive phenotypes have been observed in patient samples and the Eµ-TCL1 mouse model of CLL. Myeloid cells were thereby shown to enhance survival of CLL cells and contribute to apoptosis-resistance, to suppress anti-tumoral immunity, and to be involved in immune deficiency of leukemia patients. In addition, treatment regimens that are currently used for CLL target not only directly the malignant cells, but have also an impact on non-malignant bystander cells, including myeloid cells. This review summarizes current literature on these aspects and gives a perspective on how our current knowledge might be used to design novel immunotherapeutic approaches that can be combined with CLL-targeting drugs to achieve better therapeutic responses in CLL patients.


Assuntos
Efeito Espectador/imunologia , Leucemia Linfocítica Crônica de Células B/imunologia , Células Mieloides/fisiologia , Microambiente Tumoral/imunologia , Animais , Linfócitos B/patologia , Linfócitos B/fisiologia , Efeito Espectador/fisiologia , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Macrófagos/patologia , Macrófagos/fisiologia , Camundongos , Células Supressoras Mieloides/fisiologia , Linfócitos T/patologia , Linfócitos T/fisiologia
19.
Int J Cancer ; 144(11): 2762-2773, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30468254

RESUMO

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been shown to be highly effective in patients with chronic lymphocytic leukemia (CLL) and is approved for CLL treatment. Unfortunately, resistance and intolerance to ibrutinib has been observed in several studies, opening the door for more specific BTK inhibitors. CC-292 (spebrutinib) is a BTK inhibitor with increased specificity for BTK and less inhibition of other kinases. Our in vitro studies showed that CC-292 potently inhibited B-cell receptor signaling, activation, proliferation and chemotaxis of CLL cells. In in vivo studies using the adoptive transfer TCL1 mouse model of CLL, CC-292 reduced tumor load and normalized tumor-associated expansion of T cells and monocytes, while not affecting T cell function. Importantly, the combination of CC-292 and bendamustine impaired CLL cell proliferation in vivo and enhanced the control of CLL progression. Our results demonstrate that CC-292 is a specific BTK inhibitor with promising performance in combination with bendamustine in CLL. Further clinical trials are warranted to investigate the therapeutic efficacy of this combination regimen.


Assuntos
Acrilamidas/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cloridrato de Bendamustina/farmacologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Acrilamidas/uso terapêutico , Adulto , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Idoso , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cloridrato de Bendamustina/uso terapêutico , Medula Óssea/patologia , Modelos Animais de Doenças , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Cultura Primária de Células , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas/genética , Pirimidinas/uso terapêutico , Células Tumorais Cultivadas
20.
Leukemia ; 33(3): 625-637, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30267008

RESUMO

Chronic lymphocytic leukemia (CLL) is associated with substantial alterations in T-cell composition and function. However, the role of T-cells in CLL remains largely controversial. Here, we utilized the Eµ-TCL1 mouse model of CLL as well as blood and lymph node samples of CLL patients to investigate the existence of anti-tumoral immune responses in CLL, and to characterize involved immune cell populations. Thereby, we identified an oligoclonal CD8+ effector T-cell population that expands along with CLL progression and controls disease development. We further show that a higher percentage of CD8+ effector T-cells produces IFNγ, and demonstrate that neutralization of IFNγ results in faster CLL progression in mice. Phenotypical and functional analyses of expanded CD8+ effector T-cells show significant differences in disease-affected tissues in mice, with cells in secondary lymphoid organs harboring hallmarks of activation-induced T-cell exhaustion. Notably, we further describe a respective population of exhausted CD8+ T-cells that specifically accumulate in lymph nodes, but not in peripheral blood of CLL patients. Collectively, these data emphasize the non-redundant role of CD8+ T-cells in suppressing CLL progression and highlight their dysfunction that can be exploited as target of immunotherapy in this malignancy.


Assuntos
Linfócitos T CD8-Positivos/patologia , Leucemia Linfocítica Crônica de Células B/patologia , Tecido Linfoide/patologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Humanos , Imunoterapia/métodos , Interferon gama/metabolismo , Leucemia Linfocítica Crônica de Células B/metabolismo , Linfonodos/patologia , Ativação Linfocitária/fisiologia , Tecido Linfoide/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
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