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


New Approaches for the Immunotherapy of Acute Myeloid Leukemia

Abstract: Acute myeloid leukemia (AML) is a set of related diseases characterized by the immortalization and uncontrolled expansion of myeloid precursor cells. Core therapy for AML has remained unchanged for nearly 30 years, and survival rates remain unsatisfactory. However, advances in the immunotherapy of AML have created opportunities for improved outcomes. Enforcing a tumor-specific immune response through the re-direction of the adaptive immune system, which links remarkable specificity with potent cytotoxic effector functions, has proven particularly compelling. This may be coupled with immune checkpoint blockade and conventional therapies for optimal effect. Engineered antibodies are currently in use in AML and the repertoire of available therapeutics will expand. NK cells have shown effectiveness in this disease. New methods to optimize the targeting and activation of AML cells show potential. Most significantly, adoptive immunotherapy with tumor-specific T cells, and particularly T cells re-directed using genetically introduced TCR or chimeric antigen receptors, have particular promise. Each of these approaches has unique benefits and challenges that we explore in this review. ... Read more

Immune Effects of Targeted Radiation Therapy for Cancer

Abstract: Radiation therapy plays an important role in the treatment of the majority of cancers, and is commonly used to treat both localized and metastatic disease. Immunotherapy has recently been firmly integrated into the treatment of metastatic melanoma, and holds significant promise in treating a variety of other cancers. Although large field radiation has historically been appreciated for its immunosuppressive ability, targeted radiation can induce substantial changes in the tumor microenvironment beyond cellular cytotoxicity that evoke innate and adaptive immune responses. Previous studies have highlighted radiation-induced changes in proinflammatory cytokines, chemokines, effector, and immunosuppressive T cell subsets, as well as in immune receptors on tumor cells. Some of these changes in localized and systemic immune mediators have been linked to expansion of tumor-reactive T cells, improved clinical responses, and increased overall survival in preclinical and clinical models. Taken together, this evidence suggests that targeted radiation therapy can impact anti-tumor immune responses, and may potentially be combined with immunotherapy for synergistic effect. ... Read more

T Cell Chemokine Receptor Patterns as Pathogenic Signatures in Autoimmunity

Abstract: Autoimmune diseases arise from aberrant activation of immune cells directed against endogenous autoantigens expressed throughout the human body. While the initiating triggers remain poorly understood, the self-perpetuating phase of these diseases is directly linked to the ongoing recruitment of inflammatory cells that traffic to the affected anatomical sites. T lymphocytes are prominent drivers of many autoimmune diseases and the targeted trafficking of these cells to infiltrate the affected organs is often a common denominator. The regulation of T cell trafficking involves the coordinated expression of specific patterns of chemokines and the reciprocal expression of cognate chemokine receptors on T cell membranes. Thereby, chemokines direct the specific trafficking of a wide array of responsive activated immune cells. Specific patterns of chemokine receptor expression can correlate with disease activity in an autoimmune disease, confirming the importance of further characterizing the T cells that infiltrate specific sites of autoimmunity. Herein, we will review our current understanding of the roles of chemokines in two common autoimmune diseases: rheumatoid arthritis and multiple sclerosis. We also discuss the implications for chemokine receptor signatures in autoimmune pathogenesis, and how these may provide novel targets for therapeutic intervention. ... Read more

Enterovirus Persistence as a Mechanism in the Pathogenesis of Type 1 Diabetes

Abstract: Beyond acute clinical conditions, the role of enteroviruses (EVs) in chronic human diseases has been described. Although they are considered as highly cytolytic viruses, EVs can persist in various tissues. The persistence is believed to play a major role in the pathogenesis of EV related chronic diseases such as type 1 diabetes (T1D). T1D is characterized by an autoimmune destruction of pancreatic beta cells, and results from interplay between a genetic predisposition, the immune system, and environmental factors. EVs and especially group B coxsackieviruses (CVB) have been the most incriminated as exogenous agents involved in the development of T1D. Enteroviral persistence is the result of a virus-host coevolution combining a cell resistance to lysis through mutations or down-regulation of viral receptor, and a decrease of the viral replication by genomic modifications or the production of a stable double-stranded RNA form. CVB can persist in pancreatic cells and therefore could trigger, in genetically predisposed individuals, the autoimmune destruction of beta cells mainly through an activation of inflammation. The persistence of the virus in other tissues such as intestine, blood cells, and thymus has been described, and could also contribute to some extent to the enteroviral pathogenesis of T1D. The molecular and cellular mechanisms of CVB persistence and the link with the development of T1D should be investigated further. ... Read more

MicroRNAs Regulate Immune System Via Multiple Targets

Abstract: MicroRNAs (miRNAs) represent the most abundant class of regulators of gene expression. Each miRNA may suppress multiple mRNA targets, while one mRNA can be targeted by many miRNAs for precise control of a wide range of cellular processes. The important role of miRNAs in the immune system is highlighted by the conditional Dicer knockout mouse, which exhibited profound aberrant development and function of immune cells. One particular miRNA, miR-155, is highly expressed and plays important role in lymphocytes. In this review we focused on the role of miRNA, especially miR-155, via their predicted and known mRNA targets in innate and adaptive immunity. Finally, we discussed the potential of miRNAs as novel targets for the diagnosis and therapy of immune system diseases. ... Read more

Advances in Mechanisms of Systemic Lupus Erythematosus

Abstract: Systemic lupus erythematosus (SLE) is a complex autoimmune disease associated with hormonal, environmental, and genetic factors and linked to the tolerance breakdown of B and T cells to self-antigens. SLE is characterized by the presence in patient serum of autoantibodies raised against nuclear components. Association of these antibodies to self-antigens, complement factors, DNA, and particular proteins will form circulating immune complexes (CIC) which can deposit in several organs, causing tissue damage and clinical manifestations. Historically, SLE is considered as an adaptive immune system disorder. Over the past decade, advances in the understanding of SLE pathogenesis placed the innate immune system as a key player in perpetuating and amplifying this systemic disease. In this review, we summarize some recent key advances in understanding the SLE immune-pathogenesis with a particular focus on newly discovered key factors from the innate immune system and how they influence the pathogenic adaptive immune system: neutrophils and neutrophil extracellular traps (NETs), plasmacytoid dendritic cells (pDCs) and type I interferons, basophils and autoreactive IgE, monocytes/macrophages and the inflammasome. Recent advances on B and T cell involvement in the SLE pathogenesis mechanisms are also discussed. Although the disease is clinically, genetically, and immunologically heterogeneous between affected individuals, the latest discoveries are offering new promising therapeutic strategies. ... Read more

Understanding Autoimmunity in the Eye: From Animal Models to Novel Therapies

Abstract: In recent years considerable headway has been made on understanding the mechanisms underlying inflammatory diseases of the eye. This includes the role of the innate vs. adaptive arms of the immune systems in disease, the concept that distinct immune pathways can drive end-organ pathology, and the role as well as limitations of immune privilege in controlling the innate and adaptive effector responses that lead to eye pathology and loss of vision. These insights have largely been derived from basic studies in established and in newly developed animal models of uveitis. The increased understanding of disease mechanisms has the potential to guide development of rational therapies for human uveitis. Many novel biologics currently in use or being evaluated have been developed, or validated, in animal models of autoimmune and inflammatory disease, including experimental uveitis. Paradoxically, and fueled in part by dwindling research budgets, a campaign has been gathering momentum against use of animal models in preclinical research, as being poorly representative of responses in humans. Given the extensive genetic similarity between humans and laboratory rodents as revealed by the Human, Mouse and Rat Genome Projects, and the finding that almost all known disease-associated genes have orthologs in mice and rats, perhaps the problem is our still-insufficient understanding of mechanisms and inadequate knowledge of species differences, resulting in poor choice of models, rather than in an inherent unsuitability of animal models to represent human disease. ... Read more

Mesenchymal Stem Cell-Based Therapy for Type 1 Diabetes

Abstract: Diabetes has increasingly become a worldwide health problem, causing huge burden on healthcare system and economy. Type 1 diabetes (T1D), traditionally termed "juvenile diabetes" because of an early onset age, is affecting 5~10% of total diabetic population. Insulin injection, the predominant treatment for T1D, is effective to ameliorate the hyperglycemia but incompetent to relieve the autoimmunity and to regenerate lost islets. Islet transplantation, an experimental treatment for T1D, also suffers from limited supply of human islets and poor immunosuppression. The recent progress in regenerative medicine, especially stem cell therapy, has suggested several novel and potential cures for T1D. Mesenchymal stem cell (MSC) based cell therapy is among one of them. MSCs are a type of adult stem cells residing in bone marrow, adipose tissue, umbilical cord blood, and many other tissues. MSCs, with self-renewal potential and transdifferentiation capability, can be expanded in vitro and directed to various cell lineages with relatively less efforts. MSCs have well-characterized hypoimmunogenicity and immunomodulatory effect. All these features make MSCs attractive for treating T1D. Here, we review the properties of MSCs and some of the recent progress using MSCs as a new therapeutic in the treatment of T1D. We also discuss the strength and limitations of using MSC therapy in human trials. ... Read more

Immunotherapy with Chimeric Antigen Receptors for Multiple Myeloma

Abstract: Chimeric antigen receptors (CARs) are synthetic transmembrane proteins that are used to redirect autologous T cells with a new specificity for antigens on the surface of cancer cells. Impressive results from early phase clinical trials of anti-CD19 CARs for B cell malignancies have generated great enthusiasm for developing this approach for other diseases, particularly hematologic malignancies. Here we review efforts to develop CARs for the treatment of multiple myeloma. Clinical trials are underway investigating CARs against Kappa light chain, CD138, and Lewis Y antigen. CARs against BCMA, CS1, and CD38 are in pre-clinical testing. While initial clinical trials of novel CARs will focus on relapsed/refractory disease, CARs will also likely be studied as a consolidation strategy after response to first-line therapy or in conjunction with autologous hematopoietic stem cell transplantation. ... Read more

Advances in Cellular Therapy for the Treatment of Leukemia

Abstract: Adoptive immunotherapy in the form of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a treatment modality for acute and chronic leukemias that has been in practice for several decades. Drawbacks to transplantation include toxicity from chemotherapy/radiation conditioning regimens, additional toxicity from graft versus host disease, and reliance on appropriate human leukocyte antigen matched donors. Newer modalities with increased specificity of donor cells to tumor cells in addition to therapies that do not require engraftment for anti-tumor effect reduce the risk of graft versus host disease and may create a more robust graft versus leukemia response. Without the need for engraftment, or at the very least in the absence of a 100% engraftment requirement, conditioning regimens may be minimized. Three methods of adoptive immunotherapy that may offer some of these advantages over traditional transplantation are donor lymphocyte infusions (DLI), chimeric antigen receptor modified T cells (CAR T cells), and cellular immunotherapy. DLIs and cellular therapy consist of transfusing T lymphocytes from the donor to recipient in an unmanipulated form. Alternatively, donor T lymphocytes can be modified with addition of chimeric antigen receptors for specific antigen directed killing of tumor cells. Significant responses and survival benefit have been reported with these modalities. Herein, we review the mechanisms for these newer adoptive immune therapies, clinical indications for their use, and potential future directions. ... Read more

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