Expansion of CD4+CD25+ helper T cells without regulatory function in smoking and COPD

<p>Abstract</p> <p>Background</p> <p>Regulatory T cells have been implicated in the pathogenesis of COPD by the increased expression of CD25 on helper T cells along with enhanced intracellular expression of FoxP3 and low/absent CD127 expression on the cell surface.</p> <p>Method</p> <p>Regulatory T cells were investigated in BALF from nine COPD subjects and compared to fourteen smokers with normal lung function and nine never-smokers.</p> <p>Results</p> <p>In smokers with normal lung function, the expression of CD25⁺CD4⁺was increased, whereas the proportions of FoxP3⁺and CD127⁺were unchanged compared to never-smokers. Among CD4⁺cells expressing high levels of CD25, the proportion of FoxP3⁺cells was decreased and the percentage of CD127⁺was increased in smokers with normal lung function. CD4⁺CD25⁺cells with low/absent CD127 expression were increased in smokers with normal lung function, but not in COPD, when compared to never smokers.</p> <p>Conclusion</p> <p>The reduction of FoxP3 expression in BALF from smokers with normal lung function indicates that the increase in CD25 expression is not associated with the expansion of regulatory T cells. Instead, the high CD127 and low FoxP3 expressions implicate a predominantly non-regulatory CD25⁺helper T-cell population in smokers and stable COPD. Therefore, we suggest a smoking-induced expansion of predominantly activated airway helper T cells that seem to persist after COPD development.</p

Increased levels of (class switched) memory B cells in peripheral blood of current smokers

There is increasing evidence that a specific immune response contributes to the pathogenesis of COPD. B-cell follicles are present in lung tissue and increased anti-elastin titers have been found in plasma of COPD patients. Additionally, regulatory T cells (Tregs) have been implicated in its pathogenesis as they control immunological reactions. We hypothesize that the specific immune response in COPD is smoke induced, either by a direct effect of smoking or as a result of smoke-induced lung tissue destruction (i.e. formation of neo-epitopes or auto antigens). Furthermore, we propose that Tregs are involved in the suppression of this smoke-induced specific immune response

Convergent Sets of Data from In Vivo and In Vitro Methods Point to an Active Role of Hsp60 in Chronic Obstructive Pulmonary Disease Pathogenesis

BACKGROUND: It is increasingly clear that some heat shock proteins (Hsps) play a role in inflammation. Here, we report results showing participation of Hsp60 in the pathogenesis of chronic obstructive pulmonary diseases (COPD), as indicated by data from both in vivo and in vitro analyses. METHODS AND RESULTS: Bronchial biopsies from patients with stable COPD, smoker controls with normal lung function, and non-smoker controls were studied. We quantified by immunohistochemistry levels of Hsp10, Hsp27, Hsp40, Hsp60, Hsp70, Hsp90, and HSF-1, along with levels of inflammatory markers. Hsp10, Hsp40, and Hsp60 were increased during progression of disease. We found also a positive correlation between the number of neutrophils and Hsp60 levels. Double-immunostaining showed that Hsp60-positive neutrophils were significantly increased in COPD patients. We then investigated in vitro the effect on Hsp60 expression in bronchial epithelial cells (16HBE) caused by oxidative stress, a hallmark of COPD mucosa, which we induced with H\u2082O\u2082. This stressor determined increased levels of Hsp60 through a gene up-regulation mechanism involving NFkB-p65. Release of Hsp60 in the extracellular medium by the bronchial epithelial cells was also increased after H\u2082O\u2082 treatment in the absence of cell death. CONCLUSIONS: This is the first report clearly pointing to participation of Hsps, particularly Hsp60, in COPD pathogenesis. Hsp60 induction by NFkB-p65 and its release by epithelial cells after oxidative stress can have a role in maintaining inflammation, e.g., by stimulating neutrophils activity. The data open new scenarios that might help in designing efficacious anti-inflammatory therapies centered on Hsp60 and applicable to COP

Матер. III съезда фармакологов России, 23-27 сентября 2007 г. (Тез 533)

Pupure J., Fernandes M.A.S., Oliveira C.R., Moreno A.J.M., Santos M.S., Kalvinsh I., Isajevs S., Klusa V. Mitochndria-regulating effects of mildronate in azidothymidine-induced toxicity Proceedings of the III Congress of Pharmacology Russia, Saint-Petersburg, 23–27 September 2007. Abstr 533. Psychopharmacol Biol Narcol 2007 Sept; 7 Suppl (Pt 2, M–Ja): 2-1911–2-1911 [in English]AZT (azidothymidine) is the first antiMHIV drug used in AIDS treatment, and it is still most commonly used in drug combinations. AZT inhibits polymerase g which is responsible for HIVM1 mitochondrial DNA replication, changes the structure of mitochondria by its incorporation into mitochondria [Peters et al., 1993]. Therefore the use of AZT is limited due to its severe side effects — myopathies, especially cardiomyopathies, lipodystrophy, hepatic steatosis, lactic acidosis and others [Badley et al., 2003]. We have suggested that AZTMinduced toxicity may be prevented by drugs capable of regulating mitochondrial processes. Hence, we have used mildronate, a cardioprotective drug of azaMbutyrobetaine class, which was shown to protect rat heart mitochondria from free fatty acid detergentMlike action by inhibiting carnitine palmitoyl transferase 1 [Dambrova et al., 2002]. Besides, mildronate protects the energy metabolism against the H2O2Minduced derangement in isolated rat heart (Akahira et al., 1997) and improves cardiac sarcoplasmic reticulum Ca2+ uptake activity [Hayashi et al., 2000]. In the present study, AZT and mildronate were administered in male mice intraperitoneally, per se and in combinations during a twoMweek period at doses previously found as the most active ones: AZT 50 mg/kg, and mildronate 50, 100 and 200 mg/kg. After termination of drug administration, mice were sacrificed and their heart and brain tissue were removed. Immunohistochemical assessment of nuclear factor kappa B (NFMkBp65) in the heart, and morphological assessment of heart and brain tissue was performed. The obtained results showed that AZT treatment significantly increased NFMkBp65 expression, indicating manifestation of oxidative stress leading to mitochondrial damage. AZT caused also morphological — inflammatory and degenerative — alterations in mice heart tissue. In brain tissue AZT caused degeneration of neurons in the molecular layer and external granular layer. Mildronate in combination with AZT reduce these AZTMinduced pathologic actions both in heart and brain tissue, demonstrating its powerful protective action. One may suggest that mildronate’s protective activity is provided via targeting mitochondrial processes. That indicates usefulness of mildronate’s combination with antiMHIV and other mitochondriaMcompromized drugs.  Pupure J., Fernandes M.A.S., Oliveira C.R., Moreno A.J.M., Santos M.S., Kalvinsh I., Isajevs S., Klusa V. . Матер. III съезда фармакологов России. Психофармакол биол наркол 2007 Спец Вып; 7 (Ч 2, М&ndash;Я): 2-1911&ndash;2-1911 (Тез 533

Associations of epstein-barr virus-positive gastric adenocarcinoma with circulating mediators of inflammation and immune response

Epstein-Barr virus (EBV)-positive gastric adenocarcinoma exhibits locally intense inflammation but systemic manifestations are uncertain. Our study examined whether circulating mediators of inflammation and immune response differ by tumor EBV status. From a Latvian series of 302 gastric cancer cases, we measured plasma levels of 92 immune-related proteins in the 28 patients with EBV-positive tumors and 34 patients with EBV-negative tumors. Eight markers were statistically significantly higher with tumor EBV positivity: chemokine C-C motif ligand (CCL) 20 (Odds Ratio (OR) = 3.6; p-trend = 0.001), chemokine C-X-C motif ligand 9 (OR = 3.6; p-trend = 0.003), programmed death-ligand 1 (PD-L1; OR = 3.4; p-trend = 0.004), interleukin (IL)-10 (OR = 2.4; p-trend = 0.019), CCL19 (OR = 2.3; p-trend = 0.019), CCL11 (OR = 2.2; p-trend = 0.026), IL-17A (OR = 2.0; p-trend = 0.038) and CCL8 (OR = 1.9; p-trend = 0.049). Systemic responses to EBV-positive gastric cancer are characterized by alterations in chemokines and PD-L1. Profiling of these molecules may enable non-invasive diagnosis of EBV status when tumor tissue is unavailable. Our findings provide theoretical justification for clinical evaluations of immune checkpoint therapy for EBV-positive gastric cancer

Матер. III съезда фармакологов России, 23-27 сентября 2007 г. (Тез 533)

Pupure J., Fernandes M.A.S., Oliveira C.R., Moreno A.J.M., Santos M.S., Kalvinsh I., Isajevs S., Klusa V. Mitochndria-regulating effects of mildronate in azidothymidine-induced toxicity Proceedings of the III Congress of Pharmacology Russia, Saint-Petersburg, 23–27 September 2007. Abstr 533. Psychopharmacol Biol Narcol 2007 Sept; 7 Suppl (Pt 2, M–Ja): 2-1911–2-1911 [in English]AZT (azidothymidine) is the first antiMHIV drug used in AIDS treatment, and it is still most commonly used in drug combinations. AZT inhibits polymerase g which is responsible for HIVM1 mitochondrial DNA replication, changes the structure of mitochondria by its incorporation into mitochondria [Peters et al., 1993]. Therefore the use of AZT is limited due to its severe side effects — myopathies, especially cardiomyopathies, lipodystrophy, hepatic steatosis, lactic acidosis and others [Badley et al., 2003]. We have suggested that AZTMinduced toxicity may be prevented by drugs capable of regulating mitochondrial processes. Hence, we have used mildronate, a cardioprotective drug of azaMbutyrobetaine class, which was shown to protect rat heart mitochondria from free fatty acid detergentMlike action by inhibiting carnitine palmitoyl transferase 1 [Dambrova et al., 2002]. Besides, mildronate protects the energy metabolism against the H2O2Minduced derangement in isolated rat heart (Akahira et al., 1997) and improves cardiac sarcoplasmic reticulum Ca2+ uptake activity [Hayashi et al., 2000]. In the present study, AZT and mildronate were administered in male mice intraperitoneally, per se and in combinations during a twoMweek period at doses previously found as the most active ones: AZT 50 mg/kg, and mildronate 50, 100 and 200 mg/kg. After termination of drug administration, mice were sacrificed and their heart and brain tissue were removed. Immunohistochemical assessment of nuclear factor kappa B (NFMkBp65) in the heart, and morphological assessment of heart and brain tissue was performed. The obtained results showed that AZT treatment significantly increased NFMkBp65 expression, indicating manifestation of oxidative stress leading to mitochondrial damage. AZT caused also morphological — inflammatory and degenerative — alterations in mice heart tissue. In brain tissue AZT caused degeneration of neurons in the molecular layer and external granular layer. Mildronate in combination with AZT reduce these AZTMinduced pathologic actions both in heart and brain tissue, demonstrating its powerful protective action. One may suggest that mildronate’s protective activity is provided via targeting mitochondrial processes. That indicates usefulness of mildronate’s combination with antiMHIV and other mitochondriaMcompromized drugs.  Pupure J., Fernandes M.A.S., Oliveira C.R., Moreno A.J.M., Santos M.S., Kalvinsh I., Isajevs S., Klusa V. . Матер. III съезда фармакологов России. Психофармакол биол наркол 2007 Спец Вып; 7 (Ч 2, М&ndash;Я): 2-1911&ndash;2-1911 (Тез 533

Associations of epstein-barr virus-positive gastric adenocarcinoma with circulating mediators of inflammation and immune response

Epstein-Barr virus (EBV)-positive gastric adenocarcinoma exhibits locally intense inflammation but systemic manifestations are uncertain. Our study examined whether circulating mediators of inflammation and immune response differ by tumor EBV status. From a Latvian series of 302 gastric cancer cases, we measured plasma levels of 92 immune-related proteins in the 28 patients with EBV-positive tumors and 34 patients with EBV-negative tumors. Eight markers were statistically significantly higher with tumor EBV positivity: chemokine C-C motif ligand (CCL) 20 (Odds Ratio (OR) = 3.6; p-trend = 0.001), chemokine C-X-C motif ligand 9 (OR = 3.6; p-trend = 0.003), programmed death-ligand 1 (PD-L1; OR = 3.4; p-trend = 0.004), interleukin (IL)-10 (OR = 2.4; p-trend = 0.019), CCL19 (OR = 2.3; p-trend = 0.019), CCL11 (OR = 2.2; p-trend = 0.026), IL-17A (OR = 2.0; p-trend = 0.038) and CCL8 (OR = 1.9; p-trend = 0.049). Systemic responses to EBV-positive gastric cancer are characterized by alterations in chemokines and PD-L1. Profiling of these molecules may enable non-invasive diagnosis of EBV status when tumor tissue is unavailable. Our findings provide theoretical justification for clinical evaluations of immune checkpoint therapy for EBV-positive gastric cancer

Germinal centers determine the prognostic relevance of tertiary lymphoid structures and are impaired by corticosteroids in lung squamous cell carcinoma

In solid tumors, the presence of lymph node-like structures called tertiary lymphoid structures (TLS) is associated with improved patient survival. However, little is known about how TLS develop in cancer, how their function affects survival, and whether they are affected by cancer therapy. In this study, we used multispectral microscopy, quantitative pathology, and gene expression profiling to analyze TLS formation in human lung squamous cell carcinoma (LSCC) and in an experimental model of lung TLS induction. We identified a niche of CXCL13+ perivascular and CXCL12+LTB+ and PD-L1+ epithelial cells supporting TLS formation. We also characterized sequential stages of TLS maturation in LSCC culminating in the formation of germinal centers (GC). In untreated patients, TLS density was the strongest independent prognostic marker. Furthermore, TLS density correlated with GC formation and expression of adaptive immune response-related genes. In patients treated with neoadjuvant chemotherapy, TLS density was similar, but GC formation was impaired and the prognostic value of TLS density was lost. Corticosteroids are coadministered with chemotherapy to manage side effects in LSCC patients, so we evaluated whether they impaired TLS development independently of chemotherapy. TLS density and GC formation were each reduced in chemotherapy-naïve LSCC patients treated with corticosteroids before surgery, compared with untreated patients, a finding that we confirmed in the experimental model of lung TLS induction. Overall, our results highlight the importance of GC formation in TLS during tumor development and treatment. ©2017 American Association for Cancer Research