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Species and Cell Types / Human / Immune System / Lymphocyte / T Cell


Dynamic Differences of Immunological Parameters Between Severe and Non-severe COVID-19 Patients

Abstract: Objective. We aimed to compare the dynamic differences of immunological parameters between severe and non-severe COVID-19 patients. Methods. The cytokine profiles and lymphocyte subsets of 664 patients with COVID-19 (31 severe cases and 633 non-severe cases) were longitudinally analyzed. Results. Compared with non-severe cases, severe cases had a higher age (64 vs. 40 years, p<0.001), more common comorbidity (74.2% vs. 20.5%, p<0.001), and lymphopenia (0.7 vs. 1.4×109/L, p <0.001). Severe cases had markedly higher levels of IL-6, IL-8, and IL-10 from baseline to 35 days after admission than non-severe cases (p<0.001). No significant differences were observed in the dynamic levels of IL-1β, IL-2, IL-4, IL-5, IL-12, IL-17, TNF-α, IFN-α, and IFN-γ between severe and non-severe COVID-19 patients (p>0.05). The absolute counts of lymphocytes, CD3+ T cells, CD4+ T cells, CD8+ T cells, and CD45+ T cells were markedly lower in severe patients with COVID-19 compared with those in non-severe patients from baseline to 35 days after admission (p<0.001). No significant differences were observed in the dynamic levels of white cells count, CD19+ B cells count, and NK cells count between severe and non-severe COVID-19 patients (p>0.05). The decrease of T lymphocyte subsets reached its peak at day 1 to 3 after admission, and they gradually increased in the non-severe group, but sustained at low levels in the severe group at day 4 to 35 after admission. Conclusion. The dynamic changes of cytokine profiles and T lymphocyte subsets are related with the severity of COVID-19. ... Read more

Defining the Role of T Lymphocytes in the Immunopathogenesis of Neuromyelitis Optica Spectrum Disorder

Abstract: Auto-reactive T cells are fundamental to many autoimmune processes, including neuromyelitis optica spectrum disorder (NMOSD). Several lines of evidence indicate that an antibody against aquaporin-4 (AQP4) is present in NMOSD patients. Further, this AQP4 antibody is pathogenic and can cause profound neurological damage. T cells are fundamental to many autoimmune processes, including NMOSD. Here we review work from animal models to discuss mechanisms by which auto-reactive T cells modulate the process by which antibodies cross the blood-brain barrier and orchestrate the local inflammatory milieu underlying NMOSD pathophysiology. We also examine clinical studies that document the presence of AQP4-specific T cells and the unique cytokine profile of NMOSD patients. This work encourages a renewed and broadened attention to the fundamental role of T cells in neuroautoimmune conditions which will hopefully lead to new therapies and better patients' outcomes. ... Read more

Long-term T Cell Responses in the Brain After an Ischemic Stroke

Abstract: Stroke, which occurs during a loss of blood flow to the brain, is a global disease that accounts for 10% of yearly mortality. But stroke is also a leading cause of long-term adult disability, with recovery continuing for months to years after initial stroke onset. This long-term functional recovery from stroke encompasses changes in neuronal structure and function, and occurs throughout the post-stroke brain. Much less understood is whether the adaptive immune cells that infiltrated the brain during acute post-stroke neuroinflammation remain long-term, and if their presence supports or hinders functional recovery. Studies show that T cell subsets and their derived cytokines exhibit diverse protective and detrimental effects in the immediate acute phase following stroke. Interestingly, T cells are also important in regulating physiological behavior, which hints at a potential role in functional recovery after stroke. Moreover, T cell egress into the post-stroke brain might actually peak weeks after stroke onset, suggesting a long-term role for the adaptive immune system in the injured CNS. However, the significance of T cells in the long-term functional and behavioral recovery and repair phase of stroke remains largely unexplored. We summarize here recent work in delineating the beneficial and detrimental effects of T cells after a stroke, including antigen-specific and non-specific effects of T cells in the post-stroke recovery phase. We also highlight the role of T cells in other CNS diseases that may suggest mechanisms for future study of these adaptive immune cells in the ischemic brain. ... Read more

Consider the Chemokines: a Review of the Interplay Between Chemokines and T Cell Subset Function

Abstract: Subsets of T cells can be classified by the functions executed or by the anatomic location at which they operate. In vitro analysis of T cell subsets and even commercial kits for subset separation often incorporate chemokine receptors into the panel of markers to distinguish among them, but what is the functional significance of these receptors? In this review, we discuss chemokine receptors that are expressed exclusively on different T cell subsets as well as those that are commonly expressed across subsets with the goal of linking receptor expression to cellular localization and intended cellular function. By understanding the chemokine network, we can better predict T cell migration and the immune reactivity of a given tissue environment. This is of particular importance for the chemokine expression patterns of solid tumor microenvironments as it relates to T cell infiltration. A successful immunotherapeutic strategy needs to incorporate not only the activation state of cytotoxic T cells but also the likelihood that these cells come into contact with tumor cells. We highlight what is currently known about chemokine expression by tumors of various origins and how this relates to immune suppression or activation. Chemokine signaling represents a promising area of potential anti-tumor intervention and the current state of agonists or antagonists is discussed. Overall, this review relates chemokine signaling to T cell function and emphasizes the importance of chemokines and chemokine receptors in tumor infiltration by T cells. ... Read more

Role of Ion Channels in Natural Killer Cell Function Towards Cancer

Abstract: Progression of cancer to advanced states is associated with treatment resistance and metastatic spread -- features that are linked to poor prognosis and patient mortality. Investigations into potential new treatments to reduce cancer spread are ongoing, with immunotherapy generating much interest. Natural killer (NK) cells are part of the body's innate immune system and are known for their ability to target and lyse cancer cells. Ion channels have previously been linked to the growth and development of tumors, but recent research suggests that these channels may also serve to alter immune cell functioning. This review examines the current understanding as to the role of ion channels in NK cells and how manipulation of these channels may increase NK effectiveness in targeting and removing cancer cells. With a large number of existing FDA-approved drugs targeting ion channels, potential exists for drug repurposing in order to improve immunotherapy and thus patient outcomes. ... Read more

The Role of B cells in Multiple Sclerosis: More Than Antibodies

Abstract: Multiple sclerosis (MS) is a multicomponent disease that is marked by continual inflammation, demyelination and irreparable damage to the central nervous system. While it was long thought to be mediated by T cells, B cells are now understood to be a central component of MS pathology. Dysfunction and aberrant activity of antigen presenting cells, T cells and B cells are all part of the pathophysiology of the disease. B cells and plasma cells contribute to disease progression through multiple mechanisms, including cytokine secretion, antibody production and antigen presentation. More recent evidence suggests that B cells may play a larger role than previously thought in driving acute episodes of MS. In this review we explore the classical understanding of MS, the evidence and current understanding of B cells in the central nervous system in health and disease, and the interactions present between B cells in the central nervous system and the peripheral nervous system. Lastly, we explore targeted immunological treatments which affect B cells and how this has informed our understanding of MS. ... Read more

Recent Advances in Engineered T Cell Therapies Targeting B Cell Malignancies

Abstract: Immunotherapy using engineered autologous T cells has been attempted for decades, but clinical trials have only recently demonstrated efficacy. The combination of enhanced manufacturing techniques, highly efficient engineering, appropriate target selection and synthetic receptors with potent T cell activating domains has led to the development of highly-active cellular therapy products. B-cell malignancies have served as the paradigmatic diseases to initially evaluate and subsequently hone engineered T cells targeting cancer. Two engineered receptors, transgenic T cell receptors (tTCRs) and chimeric antigen receptors (CARs), have been explored clinically at several different institutions. The most profound success has been in pediatric and adult acute lymphoblastic leukemia, in which complete response rates after treatment with CD19-directed CAR T cells approach 90%. Success has been slightly less impressive in slower-growing diseases such as chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), and experience is much more limited in the plasma cell disease multiple myeloma. A great deal of investigation is underway to understand the differences in response rates observed, and enhance the efficacy of these therapies in B cell cancers. Here, we review landmark and recent clinical trials, as well as pre-clinical work that demonstrates significant promise in propelling this field further in the coming years. ... Read more

Regulatory T Cell-based Therapies for Autoimmunity

Abstract: Autoimmune disorders are long-term diseases that adversely affect the quality of life for patients, and they are one of the top ten leading causes of death. While each autoimmune disorder is unique, they all are caused by a breakdown of tolerance against endogenous proteins. This leads to auto-inflammatory events that promote the destruction of organs in a humoral and cellular immune mediated manner. Treatment options for autoimmunity can involve the use of chemical and biologic agents that suppress inflammation. While these treatment options for patients have shown to be beneficial in autoimmunity, they can result in patients being vulnerable to opportunistic infections. Newer therapies aim to identify methods to specifically block auto-inflammatory immune cells while allowing for an intact immune response to other antigens. T regulatory (Treg) cells are a subtype of the adoptive immune cell that is capable of suppressing inflammatory events in an antigen-specific manner, but they are often poorly functioning within autoimmune patients. Treg cells have been well characterized for their immune modulating capabilities and preclinical and early clinical studies support their therapeutic potential for antigen-specific immune suppression. This review will examine the current understanding of Treg cell function and the therapeutic potential of enhancing Treg cells in patients with inflammatory disorders. ... Read more

Novel Approaches to Cancer Immunotherapy

Abstract: Our understanding of tumor immunology has exploded in the past 3 decades. The complex relationships between tumor cells, the tumor microenvironment and the immune system cells, especially the cytotoxic and helper T cells and the regulatory T cells are beginning to be elucidated. In this review, we will attempt to provide a brief primer of tumor immunology. Cytokine therapy has historically been the mainstay of immunotherapy in cancers such as melanoma and kidney cancer. We will review some of the advances made with cancer vaccines, with a focus on peptide vaccines, tumor cell vaccines and immune cell vaccines. The pros and cons of nucleic acid-based vaccines including DNA and RNA vaccines will be discussed. Adoptive cell therapy has made significant progress utilizing chimeric antigen-receptor transduced T cells, especially in hematologic malignancies. We will also consider the key targets in checkpoint inhibition, and summarize some of the preclinical and clinical data with respect to checkpoint inhibition. Progress made in the novel immunotherapeutic approach of oncolytic viral therapy will be analyzed. PDL-1 expression by tumor cells and tumor infiltrating lymphocytes has been looked at as a biomarker in clinical trials. Limitations to such an approach and potential candidates for future predictive biomarkers of response to immunotherapy and biomarkers of autoimmunity and adverse reactions will be considered. ... Read more

Immune Evasion Pathways and the Design of Dendritic Cell-based Cancer Vaccines

Abstract: Emerging data is suggesting that the process of dendritic cell (DC) tolerization is an important step in tumorigenesis. Our understanding of the networks within the tumor microenvironment that functionally tolerize DC function is evolving while methods for genetically manipulating DC populations in situ continue to develop. A more intimate understanding of the paracrine signaling pathways which mediate immune evasion by subverting DC function promises to provide novel strategies for improving the clinical efficacy of DC-based cancer vaccines. This will likely require a better understanding of both the antigen expression profile and the immune evasion network of the tumor and its associated stromal tissues. ... Read more

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