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1.
Scand J Immunol ; : e12868, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32052490

RESUMO

Renal dysfunctions are major predictors of co-morbidities and mortality in HIV-infected individuals. Unconventional T cells have been shown to regulate kidney functions. However, there is dearth of information on the effect of HIV-associated nephropathies on γδ and DN T cells. It is also not clear whether γδ T cell perturbations observed during the early stages of HIV infection occur before immune activation. In this study, we investigated the relationship between creatinine and urea on the number of unconventional T cells in HIV-infected individuals at the early and chronic stages of infection. Persons in the chronic stage of infection were divided into treatment naïve and exposed groups. Treatment exposed individuals were further subdivided into groups with undetectable and detectable HIV-1RNA in their blood. Creatinine and urea levels were significantly higher among persons in the early HIV infection compared with the other groups. Proportions of γδ T, γδ + CD8, γδ + CD16 cells were also significantly reduced in the early stage of HIV infection (P < .01). Markers of immune activation, CD4 + HLA-DR and CD8 + HLA-DR, were also significantly reduced during early HIV infection (P < .01). Taken together, our findings suggest that high levels of renal markers as well as reduced proportions of gamma delta T cells are associated with the early stages of HIV infection. This event likely occurs before systemic immune activation reaches peak levels. This study provides evidence for the need for early HIV infection diagnosis and treatment.

2.
J Leukoc Biol ; 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32034803

RESUMO

Vitamin C (VitC) is an essential vitamin that needs to be provided through exogenous sources. It is a potent anti-oxidant, and an essential cofactor for many enzymes including a group of enzymes that modulate epigenetic regulation of gene expression. Moreover, VitC has a significant influence on T-cell differentiation, and can directly interfere with T-cell signaling. Conventional CD4 and CD8 T cells express the αß TCR and recognize peptide antigens in the context of MHC presentation. The numerically small population of γδ T cells recognizes antigens in an MHC-independent manner. γδ T cells kill a broad variety of malignant cells, and because of their unique features, are interesting candidates for cancer immunotherapy. In this review, we summarize what is known about the influence of VitC on T-cell activation and differentiation with a special focus on γδ T cells. The known mechanisms of action of VitC on αß T cells are discussed and extrapolated to the effects observed on γδ T-cell activation and differentiation. Overall, VitC enhances proliferation and effector functions of γδ T cells and thus may help to increase the efficacy of γδ T cells applied as cancer immunotherapy in adoptive cell transfer.

3.
J Leukoc Biol ; 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31967358

RESUMO

Dissection of the role and function of human γδ T cells and their heterogeneous subsets in cancer, inflammation, and auto-immune diseases is a growing and dynamic research field of increasing interest to the scientific community. Therefore, harmonization and standardization of techniques for the characterization of peripheral and tissue-resident γδ T cells is crucial to facilitate comparability between published and emerging research. The application of commercially available reagents to classify γδ T cells, in particular the combination of multiple Abs, is not always trouble-free, posing major demands on researchers entering this field. Occasionally, even entire γδ T cell subsets may remain undetected when certain Abs are combined in flow cytometric analysis with multicolor Ab panels, or might be lost during cell isolation procedures. Here, based on the recent literature and our own experience, we provide an overview of methods commonly employed for the phenotypic and functional characterization of human γδ T cells including advanced polychromatic flow cytometry, mass cytometry, immunohistochemistry, and magnetic cell isolation. We highlight potential pitfalls and discuss how to circumvent these obstacles.

4.
Methods Enzymol ; 631: 223-237, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31948549

RESUMO

Vγ9Vδ2 T cells can exhibit potent anti-tumor activity and have gained much attention as an interesting tool for cancer immunotherapy by adoptive cell transfer. In this chapter, we explain the different approaches for the in vitro expansion of Vγ9Vδ2 T cells for their subsequent adoptive transfer and present a detailed protocol for the successful in vitro expansion at the laboratory scale. Finally, we discuss strategies for optimization and parameters necessary for the adaption to a clinical scale protocol.

5.
Methods Enzymol ; 631: 429-441, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31948561

RESUMO

The enhancement of immune responses against tumor cells is a main focus of cancer immunotherapy. Immunotherapeutic approaches comprise a broad range of clinical applications including adjuvant therapies, check point inhibitors, cellular therapies, oncolytic viruses or targeted biologics such as bispecific antibodies. The usage of bispecific antibodies is one promising approach to enhance cytotoxicity and to selectively target effector cells to tumor-associated antigens. Here, we discuss the real-time cell analysis system as a suitable in vitro method to determine the interaction of tumor cell with effector cells alone or within a heterogeneous mixture of immune cells in peripheral blood or within tumor-infiltrating cells. The determination of cytotoxic effector cell activity using the real-time cell analyzer is highly useful to monitor the dynamic cellular interplay over extended periods of time.

6.
J Leukoc Biol ; 2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31833593

RESUMO

Epithelial ovarian cancer displays the highest mortality of all gynecological tumors. A relapse of the disease even after successful surgical treatment is a significant problem. Resistance against the current platinum-based chemotherapeutic standard regime requires a detailed ex vivo immune profiling of tumor-infiltrating cells and the development of new therapeutic strategies. In this study, we phenotypically and functionally characterize tumor cells and autologous tumor-derived αß and γδ T lymphocyte subsets. Tumor-infiltrating (TIL) and tumor-ascites lymphocytes (TAL) were ex vivo isolated out of tumor tissue and ascites, respectively, from high-grade ovarian carcinoma patients (FIGO-stage IIIa-IV). We observed an increased γδ T cell percentage in ascites compared to tumor-tissue and blood of these patients, whereas CD8+ αß T cells were increased within TAL and TIL. The number of Vδ1 and non-Vδ1/Vδ2-expressing γδ T cells was increased in the ascites and in the tumor tissue compared to the blood of the same donors. Commonly in PBL, the Vγ9 chain of the γδ T cell receptor is usually associated exclusively with the Vδ2 chain. Interestingly, we detected Vδ1 and non-Vδ1/Vδ2 T cells co-expressing Vγ9, which is so far not described for TAL and TIL. Importantly, our data demonstrated an expression of human epidermal growth factor receptor (HER)-2 on high-grade ovarian tumors, which can serve as an efficient tumor antigen to target CD3 TIL or selectively Vγ9-expressing γδ T cells by bispecific antibodies (bsAbs) to ovarian cancer cells. Our bsAbs efficiently enhance cytotoxicity of TIL and TAL against autologous HER-2-expressing ovarian cells.

7.
Front Immunol ; 10: 2012, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31555265

RESUMO

One of the mandates of the International Union of Immunological Societies (IUIS) is to promote immunological education to young scientists across the globe, including a large focus on those from low and low-to-middle income countries (LIC and LMIC). It strives to achieve this goal through the Education Committee (EDU), which is one of ten committees of the IUIS. To this end, EDU organizes three to four one-week courses per year in close cooperation with regional immunological societies and local organizers. Initially, the focus has been on Africa, addressing the most relevant topics and health issues facing specific countries or regions in the continent. The idea was then extended to Latin America and now also includes courses in Asia. The faculty of all courses is a blend of international and local/regional experts also known for their teaching expertise. The courses are highly interactive, and include "meet-the-speakers" sessions, poster walks, and sessions on grant or PhD project writing, and on practical aspects of becoming a successful scientist. Importantly, all the IUIS-EDU courses use a combination of pre- and during-course on-line learning followed by consolidation of knowledge in a collegial setting. This "flipped" classroom approach ensures that participants have acquired the basic knowledge needed to optimize their participation in the course. Immunopaedia is the IUIS-endorsed immunology learning site used for this purpose. All faculty members are requested to contribute material related to their specific topic while students must learn the on-line material before coming in person to the course. All course participants have free access to all Immunopaedia material indefinitely. The implementation of regional immunology courses targeted to local health issues in areas of the world where PhD students, post-doctoral, and early career scientists often do not have access to open on-line resources and contact with renowned experts in the field has proven to be highly successful. The long-term impact of this structured educational program is already visible through the large number of young scientists who are now connected via Immunopaedia and who are forming networks in regions where there had been very little contact before and building new Immunological Societies.

8.
Front Immunol ; 10: 2044, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31555275

RESUMO

Acquired immune evasion is one of the mechanisms that contributes to the dismal prognosis of cancer. Recently, we observed that different γδ T cell subsets as well as CD8+ αß T cells infiltrate the pancreatic tissue. Interestingly, the abundance of γδ T cells was reported to have a positive prognostic impact on survival of cancer patients. Since γδ T cells utilize TNF-related apoptosis inducing ligand (TRAIL) for killing of tumor cells in addition to granzyme B and perforin, we investigated the role of the TRAIL-/TRAIL-R system in γδ T cell-cytotoxicity toward pancreatic ductal adenocarcinoma (PDAC) and other cancer cells. Coculture of the different cancer cells with γδ T cells resulted in a moderate lysis of tumor cells. The lysis of PDAC Colo357 cells was independent of TRAIL as it was not inhibited by the addition of neutralizing anti-TRAIL antibodies or TRAIL-R2-Fc fusion protein. In accordance, knockdown (KD) of death receptors TRAIL-R1 or TRAIL-R2 in Colo357 cells had no effect on γδ T cell-mediated cytotoxicity. However, KD of decoy receptor TRAIL-R4, which robustly enhanced TRAIL-induced apoptosis, interestingly, almost completely abolished the γδ T cell-mediated lysis of these tumor cells. This effect was associated with a reduced secretion of granzyme B by γδ T cells and enhanced PGE2 production as a result of increased expression level of synthetase cyclooxygenase (COX)-2 by TRAIL-R4-KD cells. In contrast, knockin of TRAIL-R4 decreased COX-2 expression. Importantly, reduced release of granzyme B by γδ T cells cocultured with TRAIL-R4-KD cells was partially reverted by bispecific antibody [HER2xCD3] and led in consequence to enhanced lysis of tumor cells. Likewise, inhibition of COX-1 and/or COX-2 partially enhanced γδ T cell-mediated lysis of TRAIL-R4-KD cells. The combination of bispecific antibody and COX-inhibitor completely restored the lysis of TRAIL-R4-KD cells by γδ T cells. In conclusion, we uncovered an unexpected novel role of TRAIL-R4 in tumor cells. In contrast to its known pro-tumoral, anti-apoptotic function, TRAIL-R4 augments the anti-tumoral cytotoxic activity of γδ T cells.

9.
Front Immunol ; 10: 1690, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31379875

RESUMO

Apart from their activity in combating infections, neutrophils play an important role in regulating the tumor microenvironment. Neutrophils can directly kill (antibody-coated) cancer cells, and support other immune anti-tumoral strategies. On the other hand, neutrophils can also exert pro-tumorigenic activities via the production of factors which promote cancer growth, angiogenesis and metastasis formation. The balance of anti- and pro-cancer activity is influenced by the particularly delicate interplay that exists between neutrophils and T lymphocytes. In murine models, it has been reported that γδ T cells are a major source of IL-17 that drives the recruitment and pro-tumorigenic differentiation of neutrophils. This, however, contrasts with the well-studied anti-tumor activity of γδ T cells in experimental models and the anti-tumor activity of human γδ T cells. In this article, we first review the reciprocal interactions between neutrophils, tumor cells and T lymphocytes with a special focus on their interplay with γδ T cells, followed by the presentation of our own recent results. We have previously shown that zoledronic acid (ZOL)-activated neutrophils inhibit γδ T-cell proliferation due to the production of reactive oxygen species, arginase-1 and serine proteases. We now demonstrate that killing of ductal pancreatic adenocarcinoma (PDAC) cells by freshly isolated resting human γδ T cells was reduced in the presence of neutrophils and even more pronounced so after activation of neutrophils with ZOL. In contrast, direct T-cell receptor-dependent activation by γδ T cell-specific pyrophosphate antigens or by bispecific antibodies enhanced the cytotoxic activity and cytokine/granzyme B production of resting human γδ T cells, thereby overriding the suppression by ZOL-activated neutrophils. Additionally, the coculture of purified neutrophils with autologous short-term expanded γδ T cells enhanced rather than inhibited γδ T-cell cytotoxicity against PDAC cells. Purified neutrophils alone also exerted a small but reproducible lysis of PDAC cells which was further enhanced in the presence of γδ T cells. The latter set-up was associated with improved granzyme B and IFN-γ release which was further increased in the presence of ZOL. Our present results demonstrate that the presence of neutrophils can enhance the killing capacity of activated γδ T cells. We discuss these results in the broader context of regulatory interactions between neutrophils and T lymphocytes.

10.
Cell Mol Life Sci ; 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300870

RESUMO

Dipeptidyl peptidase 4 (DPP4, CD26) is a serine protease detected on several immune cells and on epithelial cells of various organs. Besides the membrane-bound enzyme, a catalytically active soluble form (sCD26/DPP4) is detected in several body fluids. Both variants cleave off dipeptides from the N-termini of various chemokines, neuropeptides, and hormones. CD26/DPP4 plays a fundamental role in the regulation of blood glucose levels by inactivating insulinotropic incretins and CD26/DPP4 inhibitors are thus routinely used in diabetes mellitus type 2 therapy to improve glucose tolerance. Such inhibitors might also prevent the CD26/DPP4-mediated inactivation of the T-cell chemoattractant CXCL10 released by certain tumors and thus improve anti-tumor immunity and immunotherapy. Despite its implication in the regulation of many (patho-)physiological processes and its consideration as a biomarker and therapeutic target, the cellular source of sCD26/DPP4 remains highly debated and mechanisms of its release are so far unknown. In line with recent reports that activated T lymphocytes could be a major source of sCD26/DPP4, we now demonstrate that CD26/DPP4 is stored in secretory granules of several major human cytotoxic lymphocyte populations and co-localizes with effector proteins such as granzymes, perforin, and granulysin. Upon stimulation, vesicular CD26/DPP4 is rapidly translocated to the cell surface in a Ca2+-dependent manner. Importantly, activation-induced degranulation leads to a massive release of proteolytically active sCD26/DPP4. Since activated effector lymphocytes serve as a major source of sCD26/DPP4, these results might explain the observed disease-associated alterations of sCD26/DPP4 serum levels and also indicate a so far unknown role of CD26/DPP4 in lymphocyte-mediated cytotoxicity.

11.
Cell Mol Immunol ; 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171862

RESUMO

γδ T cells are of interest as effector cells for cellular immunotherapy due to their HLA-non-restricted lysis of many different tumor cell types. Potential applications include the adoptive transfer of in vitro-expanded γδ T cells. Therefore, it is important to optimize the culture conditions to enable maximal proliferative and functional activity. Vitamin C (L-ascorbic acid) is an essential vitamin with multiple effects on immune cells. It is a cofactor for several enzymes, has antioxidant activity, and is an epigenetic modifier. Here, we investigated the effects of vitamin C (VC) and its more stable derivative, L-ascorbic acid 2-phosphate (pVC), on the proliferation and effector function of human γδ T cells stimulated with zoledronate (ZOL) or synthetic phosphoantigens (pAgs). VC and pVC did not increase γδ T-cell expansion within ZOL- or pAg-stimulated PBMCs, but increased the proliferation of purified γδ T cells and 14-day-expanded γδ T-cell lines in response to γδ T-cell-specific pAgs. VC reduced the apoptosis of γδ T cells during primary stimulation. While pVC did not prevent activation-induced death of pAg-restimulated γδ T cells, it enhanced the cell cycle progression and cellular expansion. Furthermore, VC and pVC enhanced cytokine production during primary activation, as well as upon pAg restimulation of 14-day-expanded γδ T cells. VC and pVC also increased the oxidative respiration and glycolysis of γδ T cells, but stimulus-dependent differences were observed. The modulatory activity of VC and pVC might help to increase the efficacy of γδ T-cell expansion for adoptive immunotherapy.

13.
Neurodegener Dis Manag ; 9(4): 193-203, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31099300

RESUMO

Aim: Blood-based biomarkers related to immune- and neuroregulatory processes may be indicative of dementia but lack standardization and proof-of-principle studies. Materials & methods: The blood serum collection protocol as well as the analytic procedure to quantify the markers BDNF, IGF-1, VEGF, TGF-ß 1, MCP-1 and IL-18 in blood serum were standardized and their concentrations were compared between groups of 81 Alzheimer's disease patients and 79 healthy controls. Results: Applying standardized methods, results for the quantification of the six markers in blood serum are stable and their concentrations significantly differ for all analytes except VEGF between patients diagnosed with Alzheimer's disease and healthy controls. Conclusion: Analyzing a panel of six markers in blood serum under standardized conditions may serve as a diagnostic tool in primary dementia care in the future.

14.
Front Immunol ; 10: 569, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30972064

RESUMO

The functional plasticity and anti-tumor potential of human γδ T cells have been widely studied. However, the epigenetic regulation of γδ T-cell/tumor cell interactions has been poorly investigated. In the present study, we show that treatment with the histone deacetylase inhibitor Valproic acid (VPA) significantly enhanced the expression and/or release of the NKG2D ligands MICA, MICB and ULBP-2, but not ULBP-1 in the pancreatic carcinoma cell line Panc89 and the prostate carcinoma cell line PC-3. Under in vitro tumor co-culture conditions, the expression of full length and the truncated form of the NKG2D receptor in γδ T cells was significantly downregulated. Furthermore, using a newly established flow cytometry-based method to analyze histone acetylation (H3K9ac) in γδ T cells, we showed constitutive H3K9aclow and inducible H3K9achigh expression in Vδ2 T cells. The detailed analysis of H3K9aclow Vδ2 T cells revealed a significant reversion of TEMRA to TEM phenotype during in vitro co-culture with pancreatic ductal adenocarcinoma cells. Our study uncovers novel mechanisms of how epigenetic modifiers modulate γδ T-cell differentiation during interaction with tumor cells. This information is important when considering combination therapy of VPA with the γδ T-cell-based immunotherapy for the treatment of certain types of cancer.

15.
J Cell Physiol ; 2019 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-30784062

RESUMO

Dysfunction of regulatory T cells (Tregs) may contribute to certain immune-related pregnancy complications. Forkhead box protein 3 (FOXP3) is the key transcription factor of Treg. We performed a systematic review and meta-analysis to evaluate the possible association between FOXP3 polymorphisms -924A/G (rs2232365) and -3279C/A (rs3761548) and immune-related pregnancy complications. After reviewing 78 fully published studies, 10 studies fulfilled previously defined eligibility criteria and were used for meta-analysis. Two single nucleotide polymorphisms showed a significant correlation with increased or reduced risk for immune-related pregnancy complications. For rs3761548, women with allele A were significantly at a higher risk than women carrying allele C (odds ratio = 1.29, 95% confidence interval: 1.20-1.38; p = 0.001). For rs2232365, women with GG or AG genotype were at a higher risk than women with genotype AA, thereby, allele G was significantly associated with a higher risk than allele A. Our meta-analysis supports the notion that immune-related pregnancy complications might be linked to genetic variations in the FOXP3 gene.

16.
Mol Immunol ; 107: 44-53, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30658247

RESUMO

Granulysin (GNLY) is a cationic antimicrobial, proinflammatory, and cytotoxic effector protein primarily expressed in human cytotoxic T and NK cells. Its two variants, the 15 kDa precursor and the mature 9 kDa protein processed by proteolysis, act on different microbes or infected and transformed target cells and utilize mechanistically different effector activities. In human peripheral blood lymphocytes of healthy individuals, both forms of GNLY are detected in TCR αß+ (CD4+ and CD8+) T cells, TCR γδ+ T cells, and CD3-CD56+ NK cells. In general, classical cytotoxic cells (i.e. CD8+ TCR αß+ T cells, TCR γδ+ T cells, and NK cells) contain effector proteins in higher abundance in more cells of the subset as compared to TCR αß+ CD4+ T cells. Imaging flow cytometry analyses demonstrate that the subcellular localization and internal pools of 9 kDa and 15 kDa GNLY are virtually non-overlapping. The 9 kDa form is enriched in dense granules that also contain granzymes (Grz) and carry CD107a, whereas 15 kDa GNLY is associated with CD107a-negative lysosome-related effector vesicles. We further demonstrate that 15 kDa GNLY serves as an additional indicator for non-classical, PKC-dependent degranulation while the liberation of granules containing 9 kDa GNLY requires calcium mobilization. Our studies provide a deeper insight into the subcellular localization and release mechanisms of the individual GNLY species. This information will not only be useful for the interpretation of GNLY-related pathophysiologies, but also for the development of therapeutic interventions employing distinct GNLY effector functions for microbial targeting or immunoregulation.


Assuntos
Antígenos de Diferenciação de Linfócitos T/metabolismo , Degranulação Celular , Vesículas Citoplasmáticas/metabolismo , Lisossomos/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/fisiologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/fisiologia , Proteína Ligante Fas/metabolismo , Humanos , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos/metabolismo , Peso Molecular , Transporte Proteico
17.
Oncoimmunology ; 8(1): e1522471, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30546961

RESUMO

TGF-ß is a pleiotropic cytokine with multiple roles in immunity. Apart from its suppressive activity, TGF-ß is a driving cytokine in the differentiation of induced regulatory T cells (iTreg) but also in the polarization of interleukin-9 (IL-9) producing T helper 9 (Th9) T cells. Human Vδ2 expressing γδ T cells exert potent cytotoxicity towards a variety of solid tumor and leukemia/lymphoma target cells and thus are in the focus of current strategies to develop cell-based immunotherapies. Here we report that TGF-ß unexpectedly augments the cytotoxic effector activity of short-term expanded Vδ2 T cells when purified γδ T cells are activated with specific pyrophosphate antigens and IL-2 or IL-15 in the presence of TGF-ß. TGF-ß up-regulates the expression of CD54, CD103, interferon-γ, IL-9 and granzyme B in γδ T cells while CD56 and CD11a/CD18 are down-regulated. Moreover, we show that CD103 (αE/ß7 integrin) is recruited to the immunological synapse in γδ T cells. Increased cytotoxic activity of TGF-ß-exposed γδ T cells is reduced by anti-CD103 and further diminished upon additional anti-CD11a antibody treatment, pointing to a role of cellular adhesion in the enhanced cytolytic activity. Furthermore, magnetically sorted CD103-positive Vδ2 T cells exhibit superior cytolytic activity. In view of the importance of CD103 for tissue homing of lymphocytes, our results suggest that adoptive transfer of CD103-expressing Vδ2 T cells might favor their homing to solid tumors.

19.
Gut ; 68(1): 25-39, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29730603

RESUMO

OBJECTIVE: Vedolizumab, a monoclonal antibody directed against the integrin heterodimer α4ß7, is approved for the treatment of Crohn's disease and ulcerative colitis. The efficacy of vedolizumab has been suggested to result from inhibition of intestinal T cell trafficking although human data to support this conclusion are scarce. We therefore performed a comprehensive analysis of vedolizumab-induced alterations in mucosal and systemic immunity in patients with inflammatory bowel disease (IBD), using anti-inflammatory therapy with the TNFα antibody infliximab as control. DESIGN: Immunophenotyping, immunohistochemistry, T cell receptor profiling and RNA sequencing were performed using blood and colonic biopsies from patients with IBD before and during treatment with vedolizumab (n=18) or, as control, the anti-TNFα antibody infliximab (n=20). Leucocyte trafficking in vivo was assessed using single photon emission computed tomography and endomicroscopy. RESULTS: Vedolizumab was not associated with alterations in the abundance or phenotype of lamina propria T cells and did not affect the mucosal T cell repertoire or leucocyte trafficking in vivo. Surprisingly, however, α4ß7 antibody treatment was associated with substantial effects on innate immunity including changes in macrophage populations and pronounced alterations in the expression of molecules involved in microbial sensing, chemoattraction and regulation of the innate effector response. These effects were specific to vedolizumab, not observed in response to the TNFα antibody infliximab, and associated with inhibition of intestinal inflammation. CONCLUSION: Our findings suggest that modulation of innate immunity contributes to the therapeutic efficacy of vedolizumab in IBD. TRIAL REGISTRATION NUMBER: NCT02694588.


Assuntos
Imunidade Adaptativa/efeitos dos fármacos , Anticorpos Monoclonais Humanizados/uso terapêutico , Fármacos Gastrointestinais/uso terapêutico , Imunidade Inata/efeitos dos fármacos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Adulto , Biópsia , Estudos de Casos e Controles , Feminino , Humanos , Imuno-Histoquímica , Imunofenotipagem , Infliximab/uso terapêutico , Integrinas/antagonistas & inibidores , Masculino , Fenótipo , Estudos Prospectivos , Análise de Sequência de RNA , Linfócitos T/imunologia , Tomografia Computadorizada de Emissão de Fóton Único
20.
Scand J Immunol ; 89(4): e12747, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30593678

RESUMO

Obesity is associated with chronic low-grade inflammation of the adipose tissue (AT) that might develop into systemic inflammation, insulin resistance (IR) and an increased risk of type 2 diabetes mellitus (T2DM) in severe obese rodents and humans. In the lean state, small normal adipocytes and AT macrophages interact with each other to maintain metabolic homeostasis but during obesity, enlarged adipocytes secrete inflammatory mediators and express immune receptors to recruit immune cells and aggravate the inflammation. The better understanding of the obesity-related inflammatory milieu and the sequential events leading to IR could be helpful in designing new preventive and therapeutic strategies. The present review will discuss the cellular and molecular abnormalities participating in the pathogenesis of obesity in obese individuals as well as high-fat diet (HFD)-fed mice, a mouse model of obesity.


Assuntos
Diabetes Mellitus Tipo 2/imunologia , Inflamação/imunologia , Resistência à Insulina/imunologia , Obesidade/imunologia , Animais , Dieta Hiperlipídica , Modelos Animais de Doenças , Homeostase , Humanos , Camundongos
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