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Objectives: To evaluate bone mineral density (BMD) and bone quality, with assessment of the cortical and trabecular compartments, in patients with psoriasis (PsO) alone or with psoriatic arthritis (PsA). Methods: Patients with PsA and patients with PsO alone were evaluated and compared to control subjects matched for age, sex and body mass index category. Areal BMD (aBMD) was determined for the lumbar spine, femoral neck, total hip and total body using dual-energy X-ray absorptiometry (DXA). Bone quality was evaluated by using trabecular bone score (TBS) at the lumbar spine, and by 3D DXA-based analysis (3D Shaper) for the proximal femur. Results: One hundred ninety-six subjects including 52 patients with PsA and 52 patients with PsO and their respective paired controls were analyzed. Patients with PsA had comparable aBMD, TBS and 3D DXA analysis parameters compared to their paired controls. After adjustment for confounders, patients with PsO alone were characterized by a higher aBMD at the left femur and higher cortical 3D DXA derived parameters (total hip cortical surface BMD and total hip cortical thickness) than their paired controls. TBS was decreased in PsO compared to their controls. Conclusion: Patients with PsA had normal bone mass and bone quality parameters. Patients with PsO were characterized by higher femoral neck bone density by DXA and cortical parameters by 3D DXA-based analysis, supporting no increased risk for hip fracture. Conversely, bone texture by TBS assessment was decreased in patients with PsO, which may be associated with impaired vertebral bone resistance.
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Rheumatoid arthritis (RA) is a chronic immune-mediated disease managed by conventional synthetic drugs, such as methotrexate (MTX), and targeted drugs including biological agents. Cell-based therapeutic approaches are currently developed in RA, mainly mesenchymal stroma cell-based approaches. Early-stage apoptotic cells possess direct and indirect anti-inflammatory properties. During the elimination of dying cells (a process called efferocytosis), specific mechanisms operate to control immune responses. There are compelling evidences in experimental models of arthritis indicating that apoptotic cell administration may benefit joint inflammation, and may even have therapeutic effects on arthritis. Additionally, it has been demonstrated that apoptotic cells could be administered with standard treatments of RA, such as MTX or TNF inhibitors (TNFi), given even a synergistic response with TNFi. Interestingly, apoptotic cell infusion has been successfully experienced to prevent acute graft-vs.-host disease after hematopoietic cell transplantation in patients with hematologic malignancies, with a good safety profile. In this mini-review, the apoptotic cell-based therapy development in arthritis is discussed, as well as its transfer in the short-term to an innovative treatment for patients with RA. The use of apoptotic cell-derived factors, including secretome or phosphatidylserine-containing liposomes, in RA are also discussed.
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Anti-Inflamatórios/uso terapêutico , Artrite Reumatoide/terapia , Terapia Baseada em Transplante de Células e Tecidos/métodos , Inflamação/terapia , Lipossomos/uso terapêutico , Fosfatidilserinas/uso terapêutico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Animais , Antirreumáticos/uso terapêutico , Apoptose , Humanos , Imunomodulação , Lipossomos/metabolismo , Fosfatidilserinas/metabolismoRESUMO
Immune senescence is associated with age-related diseases (i.e. infectious disease, cardiovascular diseases and cancers). Chronic kidney disease patients die prematurely when compared with general population, because of a higher occurrence of infections, cardiovascular events and cancer. These diseases are commonly observed in the elderly population and frequently associated with immune senescence. Indeed, chronic kidney disease causes a premature aging of the T lymphocyte compartment, widely related to a decrease in thymic function, a phenomenon that plays a key role in the onset of age-related diseases in chronic kidney disease patients. The degree of immune senescence also influences patients' outcome after renal transplantation, particularly the risk of acute rejection and infections. Partial reversion of pre-transplant immune senescence is observed for some renal transplant patients. In conclusion, to reduce the increasing incidence of morbidity and mortality of chronic kidney disease patients, a better knowledge of uremia-induced immune senescence would help to pave the way to build clinical studies and promote innovative therapeutic approaches. We believe that therapeutic reversion and immune senescence prevention approaches will be part of the management of chronic kidney disease patients in the future.
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Senilidade Prematura/imunologia , Imunossenescência , Insuficiência Renal Crônica/imunologia , HumanosRESUMO
Immune checkpoint blockade has proven its efficacy in hypermutated subtypes of metastatic colorectal cancers (mCRC). Immunogenic potential can also be observed with conventional chemotherapies, but this property has never been explored thoroughly in CRC patients. The CRC therapeutic arsenal includes oxaliplatin, a well-characterized platinum drug already described as immunogenic. Here, we investigated the impact of the oxaliplatin-based treatment on mCRC immunopeptidome. We demonstrated that oxaliplatin-resistant CRC cell lines overexpressed telomerase reverse transcriptase (TERT), colorectal-associated-tumor antigen-1 (COA-1) and mesothelin tumor-associated antigens. We identified new HLA class-II-restricted and promiscuous peptides derived from COA-1 and mesothelin. The two naturally processed peptides COA-1331-345 and Meso366-380 appear to be the most immunogenic in mCRC patients. A prospective cohort of 162 mCRC patients enabled us to explore the impact of oxaliplatin exposure on the antitumor-specific immune response. Interestingly, chemotherapy-naive mCRC patients present high immune CD4 T-cell responses directed against TERT, COA-1 and mesothelin-derived peptides. These antitumor T-cell responses were maintained after 3 months of oxaliplatin-based treatment. Altogether, these findings highlight the interest of immunostimulatory agents to improve the management of chemoresistant mCRC patients. Finally, the high frequency of immune responses targeting the new immunogenic peptides derived from COA-1 and mesothelin support their use in immunomonitoring strategies.
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Antígenos de Neoplasias/genética , Linfócitos T CD4-Positivos/imunologia , Neoplasias Colorretais/tratamento farmacológico , Oxaliplatina/administração & dosagem , Regulação para Cima , Antígenos de Neoplasias/química , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Resistencia a Medicamentos Antineoplásicos , Proteínas Ligadas por GPI/química , Proteínas Ligadas por GPI/genética , Regulação Neoplásica da Expressão Gênica , Células HT29 , Humanos , Mesotelina , Metástase Neoplásica , Oxaliplatina/farmacologia , Peptídeos/genética , Peptídeos/imunologia , Estudos ProspectivosRESUMO
High-risk human papillomavirus (HPV) infection is a causal factor in oropharyngeal and gynecological malignancies, and development of HPV-targeted immunotherapy could be used to treat patients with these cancers. T cell-mediated adoptive immunotherapy targeting E6 and E7, two HPV16 proteins consistently expressed in tumor cells, appears to be both attractive and safe. However, isolation of HPV-specific T cells is difficult owing to the low frequency of these cell precursors in the peripheral blood. In addition, HPV-positive cancer cells often down-regulate major histocompatibility complex (MHC) class I expression ex vivo, limiting the efficacy of MHC class I-restricted approaches. Of particular interest is that both CD4 and CD8 T cells can mediate the responses. Given that CD4 T cells play a critical role in coordinating effective antitumor responses, the generation of a T helper response in patients with HPV16-associated malignancies would unleash the ultimate potential of immunotherapy. In this view, T-cell receptor (TCR) gene transfer could be a relevant strategy to generate HPV16-E7-specific and MHC class II-restricted T cells in sufficient numbers. An HPV16-E7/HLA-DRB1*04 TCR has been isolated from a cancer patient with complete response, and retroviral particles encoding this TCR have been produced. The transgenic TCR is highly expressed in transduced T cells, with a functional inducible caspase-9 suicide gene safety cassette. TCR transgenic T cells are HPV16-E770-89 specific and HLA-DRB1*04 restricted, as determined by interferon (IFN)-γ secretion. CD8 and CD4 T cells are equivalently transduced and secrete interleukin-2 and IFN-γ when cultured with appropriate targets. We also demonstrate that TCR transgenic T cells recognize the endogenously processed and presented HPV16-E770-89 peptide. In conclusion, our data indicate that the production of MHC class II-restricted HPV16-E7-specific T cells is feasible through TCR gene transfer and could be used for immunotherapy.
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Cadeias HLA-DRB1/imunologia , Imunoterapia Adotiva , Neoplasias/imunologia , Neoplasias/terapia , Proteínas E7 de Papillomavirus/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Animais , Apresentação de Antígeno/imunologia , Citocinas/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Feminino , Ordem dos Genes , Técnicas de Transferência de Genes , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Cadeias HLA-DRB1/genética , Humanos , Imunofenotipagem , Camundongos , Proteínas E7 de Papillomavirus/genética , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Especificidade do Receptor de Antígeno de Linfócitos T , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transdução Genética , Transgenes , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Axial spondyloarthritis (Ax SpA) refers to chronic inflammatory rheumatic diseases that mainly affect the axial skeleton, leading to erosions and new bone formation in the sacroiliac joints and/or the spine. Ax SpA includes the radiographic form of the disease, ie, ankylosing spondylitis (AS), and the nonradiographic Ax SpA (non-Rx Ax SpA) forms. Anti-tumor necrosis factor alpha (TNFα) agents are used in the treatment of Ax SpA in patients who do not respond to or are intolerant to nonsteroidal anti-inflammatory drugs. In these patients, anti-TNFα agents show promising results by targeting the inflammatory process and providing symptomatic relief. Golimumab is a fully human anti-TNFα agent that is currently approved for the treatment of both AS and non-Rx Ax SpA in Europe. This review focuses on the results of clinical trials with golimumab for the treatment of AS (GO-RAISE studies) and non-Rx Ax SpA (GO-AHEAD study) and on the effects of this agent on imaging findings (radiographic progression, magnetic resonance imaging inflammation) as well as on biological parameters. Overall, golimumab is a valid therapeutic option in patients with AS and non-Rx Ax SpA in Europe.
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Anti-Inflamatórios não Esteroides/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Espondilite Anquilosante/tratamento farmacológico , Anti-Inflamatórios não Esteroides/farmacologia , Anticorpos Monoclonais/farmacologia , Antirreumáticos/farmacologia , Ensaios Clínicos como Assunto , Humanos , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
Cancer-specific splice variants gain significant interest as they generate neo-antigens that could be targeted by immune cells. CD20, a membrane antigen broadly expressed in mature B cells and in B cell lymphomas, is subject to an alternative splicing named D393-CD20 leading to loss of membrane expression of the spliced isoform. D393-CD20 expression is detectable in transformed B cells and upregulated in various lymphoma B cells. In this study, we show that D393-CD20 is translated in malignant B cells and that D393-CD20 specific CD4 T cells producing IFN-γ are present in B-cell lymphoma patients. Then, we have investigated whether the 20mer D393-CD20 peptide spanning the splicing site might be targeted by the immune system and we have shown that D393-CD20-specific CD4 Th1 clones could directly recognize malignant B cell lines and kill autologous lymphoma B cells indicating that D393-CD20-derived epitopes are naturally processed and presented on tumor cells. Finally, D393-CD20 peptide-based vaccination induced specific CD8 and CD4 T cell responses in HLA-humanized transgenic mice suggesting the presentation of D393-CD20 derived peptides on both HLA Class-I and -II. These findings support further investigations on the potential use of D393-CD20 directed specific immunotherapy in B cell malignancies.
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Processamento Alternativo , Antígenos CD20/genética , Antígenos CD20/imunologia , Linfoma de Células B/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Linhagem Celular Tumoral , Epitopos de Linfócito T/imunologia , Humanos , Imunização , Linfoma de Células B/genética , Linfoma de Células B/terapia , Camundongos , Camundongos Transgênicos , Peptídeos/administração & dosagem , Peptídeos/imunologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismoRESUMO
Accumulating evidence demonstrates the importance of CD4+ T cells in antitumor immune responses. Identifying promiscuous MHC class II-binding peptides derived from relevant tumor-associated antigens that specifically target CD4+ helper T cells in vivo represent a powerful approach to fully exploit these cells for anticancer immunotherapy.
RESUMO
PURPOSE: To evaluate CD4(+) helper functions and antitumor effect of promiscuous universal cancer peptides (UCP) derived from telomerase reverse transcriptase (TERT). EXPERIMENTAL DESIGN: To evaluate the widespread immunogenicity of UCPs in humans, spontaneous T-cell responses against UCPs were measured in various types of cancers using T-cell proliferation and ELISPOT assays. The humanized HLA-DRB1*0101/HLA-A*0201 transgenic mice were used to study the CD4(+) helper effects of UCPs on antitumor CTL responses. UCP-based antitumor therapeutic vaccine was evaluated using HLA-A*0201-positive B16 melanoma that express TERT. RESULTS: The presence of a high number of UCP-specific CD4(+) T cells was found in the blood of patients with various types of cancer. These UCP-specific T cells mainly produce IFN-γ and TNF-α. In HLA transgenic mice, UCP vaccinations induced high avidity CD4(+) T(H)1 cells and activated dendritic cells that produced interleukin-12. UCP-based vaccination breaks self-tolerance against TERT and enhances primary and memory CTL responses. Furthermore, the use of UCP strongly improves the efficacy of therapeutic vaccination against established B16-HLA-A*0201 melanoma and promotes tumor infiltration by TERT-specific CD8(+) T cells. CONCLUSIONS: Our results showed that UCP-based vaccinations strongly stimulate antitumor immune responses and could be used to design efficient immunotherapies in multiple types of cancers.
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Vacinas Anticâncer/imunologia , Melanoma Experimental/terapia , Fragmentos de Peptídeos/imunologia , Linfócitos T/imunologia , Telomerase/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/fisiologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/fisiologia , Linhagem Celular Tumoral , Proliferação de Células , Citotoxicidade Imunológica , Células Dendríticas/imunologia , Humanos , Melanoma Experimental/imunologia , Camundongos , Camundongos Transgênicos , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/fisiologia , Células Th1/imunologia , Células Th1/fisiologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A primary HCMV infection or virus reactivation may cause severe disease in hosts with a deficient immune system. The virus can disturb both innate and adaptive immunity by targeting dendritic cell (DC) functions. Monocytes, the precursors of DCs in vivo (MoDCs), are the primary targets of HCMV; they can also harbor latent virus. The DCs generated from infected monocytes (CMV-MoDCs) have an altered phenotype and functional defects. We have shown that CMV-MoDCs do not secrete IL-12 in response to lipopolysaccharide stimulation, cannot ingest dead cells, induce T(H)1 differentiation, or the proliferation of naive allogeneic CD4(+) T cells. We found that the GM-CSF signaling in an entire population of CMV-MoDCs was impaired, although only half of the cells were productively infected, and that IL-6 secretion and suppressors of cytokine signaling 3 induction contributed to this bystander effect. We also showed that MoDCs derived ex vivo from monocytes of viremic patients had the same altered phenotype as CMV-MoDCs, including decreased STAT5 phosphorylation, indicating defective GM-CSF signaling. We have thus described a new mechanism of HCMV-induced immunosupression, indicated how infection may disturb both GM-CSF-dependent physiologic processes and proposed GM-CSF-based therapeutic approaches.