Frontiers in immunology
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Frontiers in immunology · Jan 2018
ReviewMesenchymal Stromal Cell Secretome: Influencing Therapeutic Potential by Cellular Pre-conditioning.
Mesenchymal stromal cells (MSCs) are self-renewing, culture-expandable adult stem cells that have been isolated from a variety of tissues, and possess multipotent differentiation capacity, immunomodulatory properties, and are relatively non-immunogenic. Due to this unique set of characteristics, these cells have attracted great interest in the field of regenerative medicine and have been shown to possess pronounced therapeutic potential in many different pathologies. MSCs' mode of action involves a strong paracrine component resulting from the high levels of bioactive molecules they secrete in response to the local microenvironment. ⋯ Rather than being a constant mixture of molecular factors, MSCs' secretome is known to be dependent on the diverse stimuli present in the microenvironment that MSCs encounter. As such, the composition of the MSCs' secretome can be modulated by preconditioning the MSCs during in vitro culture. This manuscript reviews the existent literature on how preconditioning of MSCs affects the therapeutic potential of their secretome, focusing on MSCs' immunomodulatory and regenerative features, thereby providing new insights for the therapeutic use of MSCs' secretome.
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Frontiers in immunology · Jan 2018
ReviewInvolvement and Possible Role of Eosinophils in Asthma Exacerbation.
Eosinophils are involved in the development of asthma exacerbation. Recent studies have suggested that sputum and blood eosinophil counts are important factors for predicting asthma exacerbation. In severe eosinophilic asthma, anti-interleukin (IL)-5 monoclonal antibody decreases blood eosinophil count and asthma exacerbation frequency. ⋯ Lipopolysaccharide (LPS), which induces IL-8 from epithelial cells, is also increased in the lower airways of corticosteroid-resistant asthma. IL-8 or LPS-stimulated neutrophils increase the transbasement membrane migration of eosinophils, even in the absence of chemoattractants for eosinophils. Therefore, eosinophils are likely to contribute to the development of asthma exacerbation through several mechanisms, including activation by Th2 cytokines, such as IL-5 or GM-CSF or by virus infection-related proteins, such as CXCL10, and interaction with other cells, such as neutrophils.
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Frontiers in immunology · Jan 2018
ReviewCAR T Cell Therapy of Non-hematopoietic Malignancies: Detours on the Road to Clinical Success.
Chimeric antigen receptor (CAR)-engineered T cells represent a breakthrough in personalized medicine. In this strategy, a patient's own T lymphocytes are genetically reprogrammed to encode a synthetic receptor that binds a tumor antigen, allowing T cells to recognize and kill antigen-expressing cancer cells. As a result of complete and durable responses in individuals who are refractory to standard of care therapy, CAR T cells directed against the CD19 protein have been granted United States Food and Drug Administration (FDA) approval as a therapy for treatment of pediatric and young adult acute lymphoblastic leukemia and diffuse large B cell lymphoma. ⋯ Here, we review the history and status of CAR T cell therapy for solid tumors, potential T cell-intrinsic determinants of response and resistance as well as extrinsic obstacles to the success of this approach for much more prevalent non-hematopoietic malignancies. In addition, we summarize recent strategies and innovations that aim to augment the potency of CAR T cells in the face of multiple immunosuppressive barriers operative within the solid tumor microenvironment. Advances in the field of CAR T cell biology over the coming years in the areas of safety, reliability and efficacy against non-hematopoietic cancers will ultimately determine how transformative adoptive T cell therapy will be in the broader battle against cancer.
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Frontiers in immunology · Jan 2018
ReviewImmunothrombotic Activity of Damage-Associated Molecular Patterns and Extracellular Vesicles in Secondary Organ Failure Induced by Trauma and Sterile Insults.
Despite significant improvements in injury prevention and emergency response, injury-related death and morbidity continues to increase in the US and worldwide. Patients with trauma, invasive operations, anti-cancer treatment, and organ transplantation produce a host of danger signals and high levels of pro-inflammatory and pro-thrombotic mediators, such as damage-associated molecular patterns (DAMPs) and extracellular vesicles (EVs). DAMPs (e.g., nucleic acids, histone, high-mobility group box 1 protein, and S100) are molecules released from injured, stressed, or activated cells that act as endogenous ligands of innate immune receptors, whereas EVs (e.g., microparticle and exosome) are membranous vesicles budding off from plasma membranes and act as messengers between cells. ⋯ Blocking or neutralizing DAMPs using antibodies or small molecules has been demonstrated to ameliorate sepsis and SOF in animal models. Furthermore, a membrane immobilized with nucleic acid-binding polymers captured and removed multiple DAMPs and EVs from extracellular fluids, thereby preventing the onset of DAMP- and EV-induced inflammatory and thrombotic complications in vitro and in vivo. In this review, we will summarize the current state of knowledge of DAMPs, EVs, and SOF and discuss potential therapeutics and preventive intervention for organ failure secondary to trauma, surgery, anti-cancer therapy, and allogeneic transplantation.
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Frontiers in immunology · Jan 2018
ReviewNiches for the Long-Term Maintenance of Tissue-Resident Memory T Cells.
Tissue-resident memory T cells (TRM cells) are a population of immune cells that reside in the lymphoid and non-lymphoid organs without recirculation through the blood. These important cells occupy and utilize unique anatomical and physiological niches that are distinct from those for other memory T cell populations, such as central memory T cells in the secondary lymphoid organs and effector memory T cells that circulate through the tissues. CD8+ TRM cells typically localize in the epithelial layers of barrier tissues where they are optimally positioned to act as sentinels to trigger antigen-specific protection against reinfection. ⋯ The short-lived nature of RAMD potentially explains the short lifespans of CD8+ TRM cells in this particular tissue. Clearly, a better understanding of the niche-dependent maintenance of TRM cells will be important for the development of vaccines designed to promote barrier immunity. In this review, we discuss recent advances in our understanding of the properties and nature of tissue-specific niches that maintain TRM cells in different tissues.