Decreased Cytokine Plasma Levels and Changes in T-Cell Activation Are Associated With Hemodynamic Improvement and Clinical Outcomes After Percutaneous Mitral Commissurotomy in Patients With Rheumatic Mitral Stenosis

Mitral stenosis (MS) is a consequence of rheumatic heart disease that leads to heart failure requiring mechanical intervention. Percutaneous mitral commissurotomy (PMC) is the treatment of choice for the intervention, and currently there are no soluble markers associated with hemodynamic improvement after PMC. This study aims to determine the changes in cytokine/chemokine plasma levels, as well as T cell activation after PMC, and to investigate their association with immediate hemodynamic improvement and clinical outcomes. Plasma samples from eighteen patients with well-defined MS who underwent PMC and 12 healthy controls were analyzed using BioPlex immunoassay. We observed that 16 out of the 27 (60%) molecules assessed were altered in patients' plasma pre-PMC as compared to control group. Of those, IL-1β, IL-12, IL-6, IL-4, PDGF, and CCL11 showed significant decrease after PMC. Stratifying the patients according to adverse outcome after a 28-month median follow up, we detected a significant reduction of IL-1β, IL-12, IL-6, IL-4, IFN-γ, CXCL-10, VEGF, FGF and PDGF post-PMC in patients without events, but not in those who presented adverse events during the follow-up. Patients with adverse outcomes had lower IL-10 pre-PMC, as compared to the ones without adverse events. In addition, the frequency of CD8+ activated memory cells was increased after PMC, while the frequency of CD4+ activated memory cells did not change. Our results show an association between the decrease of specific cytokines and changes in T cell activation with hemodynamic improvement post-PMC, as well as with long-term outcomes, suggesting their possible use as soluble markers for hemodynamic recovery after MS intervention.

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Immune-Mediated Adverse Events Associated with Ipilimumab CTLA-4 Blockade Therapy: The Underlying Mechanisms and Clinical Management

Scientifica ◽

10.1155/2013/857519 ◽

2013 ◽

Vol 2013 ◽

pp. 1-19 ◽

Cited By ~ 73

Author(s):

Ahmad Tarhini

Keyword(s):

T Cell ◽

Adverse Events ◽

T Cell Activation ◽

Cell Activation ◽

Treatment Guidelines ◽

Cell Mediated Immunity ◽

Low Grade ◽

Immune Mediated ◽

Organ Systems ◽

Treatment Naïve

Immunomodulation with the anti-CTLA-4 monoclonal antibody ipilimumab has been shown to extend overall survival (OS) in previously treated and treatment-naive patients with unresectable stage III or IV melanoma. Blockade of CTLA-4 signaling with ipilimumab prolongs T-cell activation and restores T-cell proliferation, thus amplifying T-cell-mediated immunity and the patient's capacity to mount an effective antitumor immune response. While this immunostimulation has unprecedented OS benefits in the melanoma setting, it can also result in immune-mediated effects on various organ systems, leading to immune-related adverse events (irAEs). Ipilimumab-associated irAEs are common and typically low grade and manageable, but can also be serious and life threatening. The skin and gastrointestinal tract are most frequently affected, while hepatic, endocrine, and neurologic events are less common. With proper management, most irAEs resolve within a relatively short time, with a predictable resolution pattern. Prompt and appropriate management of these irAEs is essential and treatment guidelines have been developed to assist oncologists and their teams. Implementation of these irAE management algorithms will help ensure that patients are able to benefit from ipilimumab therapy with adequate control of toxicities.

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CTIM-16. PHASE 2 STUDY OF PEMBROLIZUMAB PLUS TTFields PLUS TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED glioblastoma (2-THE-TOP)

Neuro-Oncology ◽

10.1093/neuonc/noab196.208 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi53-vi53

Author(s):

David Tran ◽

Ashley Ghinaseddin ◽

Dongjiang Chen ◽

Maryam Rahman

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Checkpoint Inhibitors ◽

Clonal Expansion ◽

Phase 2 ◽

Newly Diagnosed ◽

Serious Adverse Events ◽

Phase 2 Study

Abstract INTRODUCTION Emerging data indicate that TTFields, the new anti-mitotic treatment for GBM, stimulate immunity via the type-1 interferon (T1IFN) pathway of STING and AIM2 inflammasomes. Thus, we hypothesize that TTFields synergize with immune checkpoint inhibitors to induce anti-tumor immunity in GBM. METHODS We conduct a phase 2 study combining pembrolizumab, TTFields and maintenance TMZ in 25 patients with newly diagnosed GBM (ndGBM). To distinguish immune effects of TTFields from pembrolizumab, TTFields is started at cycle 1 of TMZ and pembrolizumab (200mg Q3Wks) at cycle 2. The primary endpoint is PFS vs. the historical control of TTFields plus TMZ (JAMA/318:2306-2316). Secondary endpoints include toxicity, immune signature of TTFields vs. pembrolizumab by single-cell RNAseq of PBMCs, and OS. RESULTS As of 05/24/2021, 25 patients with a median age of 61 years were enrolled. Eight (32%) and 4 (16%) had biopsy only and partial resection, respectively. Eighteen (72%) had unmethylated MGMT and 3 (12%) had an IDH mutation. The median follow-up was 14.7 months. Twelve (48%) were progression-free, and 15 (60%) were alive. Of 19 patients with follow-up >=9 months, the median PFS was >=11.2 months vs. 6.7 months in the control. Six (24%) patients with measureable tumors achieved partial to complete response. The most common serious adverse events were thrombosis, seizure, and metabolic disturbances in 4 (16%), 3 (12%), and 2 (8%) patients, respectively. We sequenced 193,760 PBMCs in 12 patients before pembrolizumab and detected robust post-TTFields T cell activation in 11 of 12 patients via the T1IFN trajectory with a strong correlation with the TCRab clonal expansion Simpson index (Spearman coefficient r=-0.8, P=0.014). Importantly, we defined a T cell-based gene signature of TTFields effects on TCRab clonal expansion. CONCLUSION The triple combination is well tolerated and shows early evidence of efficacy in ndGBM patients. Survival and molecular data will be updated.

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Immune Activation, Immunosenescence, and Osteoprotegerin as Markers of Endothelial Dysfunction in Subclinical HIV-Associated Atherosclerosis

Mediators of Inflammation ◽

10.1155/2014/192594 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 6

Author(s):

Alessandra D’Abramo ◽

Maria Antonella Zingaropoli ◽

Alessandra Oliva ◽

Claudia D’Agostino ◽

Samir Al Moghazi ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Immune Activation ◽

Plasma Levels ◽

Cell Activation ◽

Intima Media Thickness ◽

Cd8 T Cell ◽

Cell Phenotype ◽

Control Group ◽

Hiv Patients

HIV-infected patients have a significantly greater risk of cardiovascular disease. Several markers including osteoprotegerin have been shown to be involved in the development and progression of atherosclerosis. We investigated the relationship between T-cell phenotype, osteoprotegerin, and atherosclerosis evaluated by carotid intima-media thickness (c-IMT) in 94 HIV+ patients on suppressive antiretroviral therapy with Framingham score <10%. As for the control group, 24 HIV-negative subjects were enrolled. c-IMT was assessed by ultrasound. CD4+/CD8+ T-cell activation (CD38+ HLADR+) and senescence (CD57+ CD28−) were measured by flow cytometry. IL-6 and OPG levels were measured by ELISA kit. c-IMT was higher in HIV+ than in controls. Among HIV+ patients, 44.7% had pathological c-IMT (≥0.9 mm). CD8+ T-cell activation and senescence and OPG plasma levels were higher in HIV+ patients than in controls. Subjects with pathological c-IMT exhibited higher CD8+ immune activation and immunosenescence and OPG levels than subjects with normal c-IMT. Multivariate analysis showed that age, CD8+ CD38+ HLADR+, and CD8+ CD28− CD57+ were independently associated with pathological c-IMT. Several factors have been implicated in the pathogenesis of atherosclerosis in HIV patients. Immune activation and immunosenescence of CD8+ T cell together with OPG plasma levels might be associated with the development and progression of early atherosclerosis, even in the case of viral suppression.

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Optimization of T Cell Redirecting Strategies: Obtaining Inspirations From Natural Process of T Cell Activation

Frontiers in Immunology ◽

10.3389/fimmu.2021.664329 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yiyuan Gao ◽

Yuedi Wang ◽

Feifei Luo ◽

Yiwei Chu

Keyword(s):

T Cells ◽

T Cell ◽

Clinical Outcomes ◽

T Cell Activation ◽

Cell Activation ◽

Immunological Synapse ◽

Cell Receptor ◽

T Cell Response ◽

Antigen Receptors ◽

Cell Therapies

Chimeric antigen receptors (CARs) or bispecific antibodies (bsAbs) redirected T cell against tumors is one of the most promising immunotherapy approaches. However, insufficient clinical outcomes are still observed in treatments of both solid and non-solid tumors. Limited efficacy and poor persistence are two major challenges in redirected T cell therapies. The immunological synapse (IS) is a vital component during the T cell response, which largely determines the clinical outcomes of T cell-based therapies. Here, we review the structural and signaling characteristics of IS formed by natural T cells and redirected T cells. Furthermore, inspired by the elaborate natural T cell receptor-mediated IS, we provide potential strategies for higher efficacy and longer persistence of redirected T cells.

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Short- and Long-Term Immunological Responses in Chronic HCV/HIV Co-Infected Compared to HCV Mono-Infected Patients after DAA Therapy

Pathogens ◽

10.3390/pathogens10111488 ◽

2021 ◽

Vol 10 (11) ◽

pp. 1488

Author(s):

Stefania Farcomeni ◽

Sonia Moretti ◽

Caterina Fimiani ◽

Lucia Fontanelli Sulekova ◽

Fenicia Vescio ◽

...

Keyword(s):

Immune System ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Liver Stiffness ◽

Cd8 T Cell ◽

Peripheral Blood Mononuclear ◽

Indoleamine 2 ◽

The Impact

Background: Direct-acting antivirals (DAAs) treatment, although highly efficacious for the treatment of hepatitis C virus (HCV) infection, may not completely reconstitute the HCV-mediated dysregulated immune system, especially in patients co-infected with human immunodeficiency virus (HIV) and HCV. Objectives: We aimed to evaluate the impact of HCV eradication following DAA therapy on the immune system and liver disease improvement through comparative monitoring of 10 HCV mono-infected and 10 HCV/HIV co-infected patients under combined antiretroviral therapy (cART). Early and late longitudinal phenotypic changes in peripheral blood mononuclear cell (PBMC) subsets, T-cell activation, differentiation and exhaustion, as well as inflammatory biomarkers, indoleamine 2-3 dioxygenase (IDO) activity, and liver stiffness, APRI and FIB-4 scores were assessed. Materials and Methods: Samples were obtained at baseline (T0), week 1 (T1), week 2 (T2), week 12 (T3, end of treatment, EOT), and month 9 (T4, end of follow-up, 36 weeks post EOT). Results: All patients achieved a sustained virological response (SVR 12) after DAA treatment. Overall, changes of the T-cell immune phenotypes were greater in HCV/HIV co-infected than in HCV mono-infected, due to an increase in CD4+ and CD8+ T-cell percentages and of CD8+ T-cell activation and memory markers, in particular at the end of follow-up. On the other end, HCV mono-infected showed changes in the activation profile and in the memory CD4+ T-cell compartment. In HCV/HIV co-infected, a decrease in the IDO activity by DAA treatment was observed; conversely, in HCV mono-infected, it resulted unmodified. Regarding inflammatory mediators, viral suppression was associated with a reduction in IP-10 levels, while interferon regulatory factor (IRF)-7, interferon (IFN)-β, and interferon (IFN)-γ levels were downregulated during therapy and increased post therapy. A decrease in liver stiffness, APRI, and FIB-4 scores was also observed. Conclusions: Our study suggests that, although patients achieved HCV eradication, the immune activation state in both HCV mono-infected and HCV/HIV co-infected patients remains elevated for a long time after the end of DAA therapy, despite an improvement of liver-specific outcomes, meanwhile highlighting the distinct immunophenotypic and inflammatory biomarker profile between the groups of patients.

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Persistently high levels of immune activation and their correlation with the HIV-1 proviral DNA and 2-LTR circles loads, in a cohort of Mexican individuals following long-term and fully suppressive treatment.

10.21203/rs.2.21753/v1 ◽

2020 ◽

Author(s):

Aurelio Orta-Resendiz ◽

Monica Viveros-Rogel ◽

Luis L Fuentes-Romero ◽

Moises Vergara-Mendoza ◽

Damaris P Romero-Rodriguez ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Immune Activation ◽

Cell Activation ◽

Cd8 T Cell ◽

Chronic Patients ◽

Ki 67 ◽

Proviral Dna

Abstract Background The main cause of the persistently high levels of immune activation in HIV positive patients undergoing suppressive chronic cART is still unknown. Previous findings have suggested a link between ongoing residual viral replication originating from the HIV reservoir and the immune activation levels. However, there is no clear evidence of this assumption. The aim of this study was to investigate the correlation between the reservoir and the levels of immune activation in chronic patients under fully suppressive cART. Methods We conducted a prospective longitudinal study in a cohort of HIV positive patients undergoing cART for more than 5 years without any documented blips. We quantified the HIV proviral DNA and the 2-LTR circles loads from PBMCs, the levels of immune activation and proliferation markers of T-cells (CD38+, Ki-67+), and the levels of plasmatic IL-7 at enrollment and 1-year of follow-up. Correlation analysis and group comparison were performed. Results 29 participants with a median of 8 years (IQR, 6.9-9.4) under suppressive cART were enrolled and successfully followed at 1 year. In this cohort, we found higher levels of CD8+ T-cell activation (CD38+) after 1-year (P = .000). There was a very weak correlation between the levels of immune activation and the proviral DNA of CD4+ T-cell and CD8+ T-cell. The levels of Ki-67+ T-cells declined on time without significant differences, and there was no significant correlation with the proportion of activated T-cells. The plasmatic levels of IL-7 decreased at the follow-up observation (P = .094), but there was no correlation with the levels of immune activation either. Conclusions We found a weak correlation of the levels of CD4+ and CD8+ T-cell activation with the proviral DNA and 2-LTR circles. This suggests the likely occurrence of further mechanisms driving chronic versus early immune activation other than viral replication by itself in subjects under chronic suppressive cART. More importantly, we highlight the relevance of decreasing T-cell activation in chronic patients to lower the risk of morbidity and early mortality by investigating other activation pathways in specifically chronic phases.

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HLA-mediated tumor escape mechanisms that may impair immunotherapy clinical outcomes via T-cell activation

Oncology Letters ◽

10.3892/ol.2017.6784 ◽

2017 ◽

Vol 14 (4) ◽

pp. 4415-4427 ◽

Cited By ~ 21

Author(s):

Josefa A. Rodríguez

Keyword(s):

T Cell ◽

Clinical Outcomes ◽

T Cell Activation ◽

Cell Activation ◽

Tumor Escape

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T-Cell Activation and Malnutrition Adversely Impact on Endothelial Progenitor Cell Mobilization in Patients on Extracorporeal Maintenance Dialysis Therapy

Blood Purification ◽

10.1159/000381661 ◽

2015 ◽

Vol 39 (4) ◽

pp. 313-322 ◽

Cited By ~ 1

Author(s):

Edouard Tuaillon ◽

Isabelle Jaussent ◽

Marion Morena ◽

Annie Rodrigez ◽

Leila Chenine ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Endothelial Progenitor ◽

Randomised Study ◽

Circulating Endothelial Progenitor Cells ◽

Hla Dr ◽

Cell Mobilization ◽

Cd8 Memory T Cells

Background: The number of circulating endothelial progenitor cells (EPCs) decreases on account of chronic kidney disease (CKD). Methods: Twenty patients were enrolled in this prospective and randomised study in two parallel arms: conventional haemodialysis versus online haemodiafiltration. EPCs number and T-cell activation were analysed at baseline and monthly during a 4-month period of follow-up. Results: CD38bright and HLA-DR+ expression among CD8 memory T cells were negatively associated with both CD34+ (r = -0.70, p = 0.0006) and CD34+ CD133+ (r = -0.62, p = 0.004) cell numbers. Conversely, a positive correlation was observed between CD34+ and CD34+ CD133+ cells with transferrin (r = 0.75, p = 0.0001 and r = 0.47, p = 0.04, respectively), and CD34+ CD133+ cells with transthyretin (r = 0.51, p = 0.02). No significant association was observed between dialysis modality and the evolution of the EPC number. Conclusions: Chronic T-cell activation may be a component of the malnutrition inflammation complex syndrome that adversely influences EPC mobilization in CKD patients.

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Exacerbation of Psoriasis under Efalizumab Therapy

Journal of Cutaneous Medicine and Surgery ◽

10.2310/7750.2008.07087 ◽

2009 ◽

Vol 13 (2) ◽

pp. 106-109 ◽

Cited By ~ 4

Author(s):

Efstathios Rallis ◽

Constantinos Verros ◽

Evmorfia Karanikola ◽

Argyro Valaskatzi ◽

Markos Papaconstantis

Keyword(s):

Monoclonal Antibody ◽

T Cell ◽

Adverse Events ◽

Blood Cell ◽

T Cell Activation ◽

Plaque Psoriasis ◽

Lymphocyte Count ◽

Cell Activation ◽

Total White Blood Cell ◽

Blood Cell Count

Background: Efalizumab is a recombinant humanized IgG1-κ isotype monoclonal antibody that binds to CD11a, inhibiting T-cell activation. It has been approved for the treatment of moderate to severe plaque psoriasis. Efalizumab has been associated with the development of skin eruptions during the administration period, and this probably represents the potential psoriasis events observed during its administration. Objective: We report a case of exacerbation of psoriasis under efalizumab administration. A reversible increase in lymphocyte count with normal total white blood cell count was also noticed. Conclusion: Larger series are probably needed to establish clinical and histopathologic criteria and to determine the terminology used regarding the psoriasis adverse events seen with efalizumab treatment.

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