Residual T cell activation and skewed CD8+ T cell memory differentiation despite antiretroviral therapy-induced HIV suppression

Publication date: Available online 5 June 2018
Source:Clinical Immunology
Author(s): Ramla F. Tanko, Andreia P. Soares, Lindi Masson, Nigel J. Garrett, Natasha Samsunder, Quarraisha Abdool Karim, Salim S. Abdool Karim, Catherine Riou, Wendy A. Burgers
HIV infection results in excessive T cell activation and dysfunction which may persist even during effective antiretroviral therapy (ART). The dynamics of immune 'deactivation' and extent to which T cell memory subsets normalize after ART are unclear. We longitudinally assessed the influence of 1 year of ART on the phenotype of T cells in HIV-infected African women, relative to matched HIV-uninfected women, using activation (CD38, HLA-DR) and differentiation markers (CD27, CD45RO). ART induced a substantial reduction in T cell activation, but remained higher than HIV-uninfected controls. ART largely normalized the distribution of CD4+ T cell memory subsets, while the distribution of CD8+ T cell memory subsets remained significantly skewed compared to HIV-uninfected individuals. Thus, there was a considerable but only partial reversal of T cell defects upon ART. Understanding T cell impairment may provide important insights into mechanisms of HIV pathogenesis in the era of ART.



https://ift.tt/2Lpx7cB

Residual T cell activation and skewed CD8+ T cell memory differentiation despite antiretroviral therapy-induced HIV suppression

Publication date: Available online 5 June 2018
Source:Clinical Immunology
Author(s): Ramla F. Tanko, Andreia P. Soares, Lindi Masson, Nigel J. Garrett, Natasha Samsunder, Quarraisha Abdool Karim, Salim S. Abdool Karim, Catherine Riou, Wendy A. Burgers
HIV infection results in excessive T cell activation and dysfunction which may persist even during effective antiretroviral therapy (ART). The dynamics of immune 'deactivation' and extent to which T cell memory subsets normalize after ART are unclear. We longitudinally assessed the influence of 1 year of ART on the phenotype of T cells in HIV-infected African women, relative to matched HIV-uninfected women, using activation (CD38, HLA-DR) and differentiation markers (CD27, CD45RO). ART induced a substantial reduction in T cell activation, but remained higher than HIV-uninfected controls. ART largely normalized the distribution of CD4+ T cell memory subsets, while the distribution of CD8+ T cell memory subsets remained significantly skewed compared to HIV-uninfected individuals. Thus, there was a considerable but only partial reversal of T cell defects upon ART. Understanding T cell impairment may provide important insights into mechanisms of HIV pathogenesis in the era of ART.



https://ift.tt/2Lpx7cB

Leonurine ameliorates the inflammatory responses in lipopolysaccharide-induced endometritis

Publication date: August 2018
Source:International Immunopharmacology, Volume 61
Author(s): Haichong Wu, Ailing Dai, Xingxing Chen, Xiaoyan Yang, Xiaohua Li, Cuiqin Huang, Kangfeng Jiang, Ganzhen Deng
Endometritis is the inflammation of the endometrium that is associated with lower conception rates, increased intervals from calving to first service, and more culls for failure to conceive, which leads to serious economic losses in the dairy industry. Leonurine, a natural active compound of Leonurus cardiaca, has been proved to possess various biological activities. However, there is still no study about its anti-inflammatory effects on LPS-induced endometritis. The present study aimed to demonstrate the underlying mechanism responsible for the anti-inflammatory effects of leonurine on LPS induced endometritis in mice and in bovine endometrial epithelial cells (bEECs). The results of pathological section displayed that leonurine alleviated LPS induced uterine injury. qRT-PCR and ELISA experiments suggested that leonurine inhibited the expression levels of TNF-α and IL-1β in uterus tissues and bEECs. Molecular studies showed that TLR4 expression and nuclear factor (NF)-κB activation were both inhibited by leonurine treatment. These results suggested that the therapeutic effects of leonurine on LPS-induced endometritis in mice and bEECs may act by inhibiting the expression of TLR4 and its downstream mediated NF-κB pathway. Accordingly, leonurine may serve as an effective drug in preventing and treating LPS induced endometritis.



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Bone marrow derived M2 macrophages protected against lipopolysaccharide-induced acute lung injury through inhibiting oxidative stress and inflammation by modulating neutrophils and T lymphocytes responses

Publication date: August 2018
Source:International Immunopharmacology, Volume 61
Author(s): Fang Wang, Xiazhen Fu, Xinwan Wu, Jianhai Zhang, Jiali Zhu, Yun Zou, Jinbao Li
Acute lung injury (ALI) is characterized by aggravated inflammatory responses and the subsequent alveolar-capillary injury for which there are no specific therapies available currently. The present study was designed to investigate the protective roles of bone marrow derived M2 macrophages (M2 BMDMs) in lipopolysaccharide (LPS) induced ALI. M2 BMDMs were obtained from bone marrow cells stimulated with M-CSF and IL-4. Mice received M2 BMDMs intratracheally 3 h after LPS administration. Histology and wet/dry (W/D) weight ratio, activated immune cells and total protein were detected. Cytokines production were measured in vivo and vitro study. The effects of PD-L1 blockade on M2 BMDMs were calculated. The results showed that M2 BMDMs administration reduced the infiltration of neutrophils, inhibited the oxidative stress, while increased the counts of CD3⁺T lymphocytes as well as CD4⁺CD25⁺ regulatory T lymphocytes. Further, M2 BMDMs suppressed the TNF-α, IL-1β and IL-6 production, while increased the IL-10 production. Blockade of PD-L1/PD-1 pathway reversed cytokines production of M2 BMDMs in the BALF. These findings indicated that M2 BMDMs might be a promising therapeutic strategy for LPS-induced ALI through inhibiting oxidative stress and inflammation by modulating neutrophils and T lymphocytes responses.



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Paeonol attenuates acute lung injury by inhibiting HMGB1 in lipopolysaccharide-induced shock rats

Publication date: August 2018
Source:International Immunopharmacology, Volume 61
Author(s): Xia Liu, Qin Xu, Liyan Mei, Hang Lei, Quan Wen, Jifei Miao, Huina Huang, Dongfeng Chen, Shaohui Du, Saixia Zhang, Jianhong Zhou, Rudong Deng, Yiwei Li, Chun Li, Hui Li
High-mobility group box 1 (HMGB1) is a highly conserved DNA-binding nuclear protein that facilitates gene transcription and the DNA repair response. However, HMGB1 may be released by necrotic cells as well as activated monocytes and macrophages following stimulation with lipopolysaccharide (LPS), interleukin-1β (IL-1β), or tumor necrosis factor-α (TNF-α). Extracellular HMGB1 plays a critical role in the pathogenesis of acute lung injury (ALI) through activating the nuclear transcription factor κB (NF-κB) P65 pathway, thus, it may be a promising therapeutic target in shock-induced ALI. Paeonol (Pae) is the main active component of Paeonia suffruticosa, which has been used to inhibit the inflammatory response in traditional Chinese medicine. We have proven that Pae inhibits the expression, relocation and secretion of HMGB1 in vitro. However, the role of Pae in the HMGB1-NF-κB pathway remains unknown. We herein investigated the role of Pae in LPS-induced ALI rats. In this study, LPS induced a marked decrease in the mean arterial pressure (MAP) and survival rate (only 25% after 72 h), and induced severe pathological changes in the lung tissue of rats, which was accompanied by elevated expression of HMGB1 and its downstream protein NF-κB P65. Treatment with Pae significantly improved the survival rate (>60%) and MAP, and attenuated the pathological damage to the lung tissue in ALI rats. Western blotting revealed that Pae also inhibited the total expression of HMGB1, NF-κB P65 and TNF-α in the lung tissue of ALI rats. Moreover, Pae increased the expression of HMGB1 in the nucleus, inhibited the production of HMGB1 in the cytoplasm, and decreased the expression of P65 both in the nucleus and cytoplasm of lung tissue cells in LPS-induced ALI rats. The results were in agreement with those observed in the in vitro experiment. These findings indicate that Pae may be a potential treatment for ALI through its repression of the HMGB1-NF-κB P65 signaling pathway.



https://ift.tt/2sAvsKs

Biomarker-Driven and Molecularly Targeted Therapies for Pancreatic Adenocarcinoma

Publication date: Available online 5 June 2018
Source:Seminars in Oncology
Author(s): David B. Zhen, Andrew Coveler, Silvia Zanon, Michele Reni, E. Gabriela Chiorean
Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease with few effective treatment options. Our knowledge of molecular alterations in PDAC has significantly grown and helped identify new therapeutic targets. The success of immune checkpoint inhibition in mismatch repair deficient tumors, PARP inhibitors for tumors with DNA repair defects, and targeting hyaluronan (HA) with PEGPH20 in patients with high expressing (HA-high) tumors are examples of promising biomarker-driven therapies. We review the major biological mechanisms in PDAC and discuss current and future directions for molecularly targeted therapies in this disease.



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Cosmetics, Vol. 5, Pages 35: From Mice to Men: An Evolutionary Conserved Breakdown of the Epidermal Calcium Gradient and Its Impact on the Cornified Envelope

Cosmetics, Vol. 5, Pages 35: From Mice to Men: An Evolutionary Conserved Breakdown of the Epidermal Calcium Gradient and Its Impact on the Cornified Envelope

Cosmetics doi: 10.3390/cosmetics5020035

Authors: Maria Karolin Streubel Claudia Neuhofer Johannes Bischof Peter Steinbacher Elisabeth Russe Gottfried Wechselberger Klaus Richter Mark Rinnerthaler

In previous publications, we could establish that a hallmark of human skin aging is the breakdown of the epidermal calcium gradient. This redistribution of calcium has many implications, including a restructuring of the cornified envelope, a reduced epidermal barrier function, a change in lipid composition, a reduced skin hydration, and an increased skin pH. Especially the age-dependent change in the cornified envelope composition was solely studied in human foreskin samples. The aim of this study was to confirm that this effect is neither restricted to UV-protected skin area nor limited to a specific sex. In addition, we wanted to show that the collapse of the epidermal calcium gradient is not only a hallmark of human skin aging, but is also evolutionarily conserved in mammals. By using such techniques as IHC, Western blot analysis, and RT-PCR, we could demonstrate the following: (1) A change in the epidermal calcium gradient is in fact the most important sign of epidermal aging in mammals (as shown in female human eyelids and mouse skin samples of the external ear-shell); (2) The disturbed calcium homeostasis affects the expression and crosslinking of most cornified-envelope-specific genes such as loricrin and filaggrin. In this way, we could establish that the age-dependent altered composition of the cornified envelope is a typical sign of skin aging not only in humans, but in mice, too. This makes the mouse an important model organism to study these changes.

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