Frontiers in immunology
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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
Pro-Inflammatory Th1 and Th17 Cells Are Suppressed During Human Experimental Endotoxemia Whereas Anti-Inflammatory IL-10 Producing T-Cells Are Unaffected.
Sepsis is one of the leading causes of the deaths in hospitals. During sepsis, patients are exposed to endotoxemia, which may contribute to the dysregulation of the immune system frequently observed in sepsis. This dysregulation leads to impaired pro-inflammatory responses and may increase the risk for secondary infections in sepsis. The experimental human endotoxemia model is widely used as a model system to study the acute effects of endotoxemia. Under physiological circumstances, the immune system is tightly regulated. Effector T-cells exert pro-inflammatory function and are restrained by regulatory T-cells (Tregs), which modulate pro-inflammatory effector responses. Endotoxemia may induce inadequate Treg activity or render effector T-cells dysfunctional. It was the aim of the study to investigate effector T-cell and Treg responses in an experimental human endotoxemia model. ⋯ Effector THs fail to produce pro-inflammatory Th1-/Th17-associated cytokines after LPS challenge. In contrast, IL-10 production by Treg is not affected. Thus, endotoxemia-induced suppression of pro-inflammatory THs might be considered as a contributing factor to immunoparalysis in sepsis.
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Frontiers in immunology · Jan 2018
Clinical TrialFunctional, Antigen-Specific Stem Cell Memory (TSCM) CD4+ T Cells Are Induced by Human Mycobacterium tuberculosis Infection.
Maintenance of long-lasting immunity is thought to depend on stem cell memory T cells (TSCM), which have superior self-renewing capacity, longevity and proliferative potential compared with central memory (TCM) or effector (TEFF) T cells. Our knowledge of TSCM derives primarily from studies of virus-specific CD8+ TSCM. We aimed to determine if infection with Mycobacterium tuberculosis (M. tb), the etiological agent of tuberculosis, generates antigen-specific CD4+ TSCM and to characterize their functional ontology. ⋯ Human infection with M. tb induced distinct, antigen-specific CD4+ TSCM cells endowed with effector functions, including expression of cytotoxic molecules and Th1 cytokines, and displayed chemokine receptor profiles consistent with memory Th1/17 cells. Induction of CD4+ TSCM should be considered for vaccination approaches that aim to generate long-lived memory T cells against M. tb.
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Frontiers in immunology · Jan 2018
Case ReportsTreating Heart Inflammation With Interleukin-1 Blockade in a Case of Erdheim-Chester Disease.
Pericarditis is an inflammatory heart disease, which may be idiopathic or secondary to autoimmune or auto-inflammatory diseases and often leads to severe or life-threatening complications. Colchicine and non-steroidal anti-inflammatory drugs represent the mainstay of treatment, whereas use of corticosteroids is associated with recurrence of disease flares. While effective and safe anti-inflammatory therapies remain an unmet clinical need, emerging clinical and experimental evidence points at a promising role of inhibition of the pro-inflammatory cytokine interleukin-1 (IL-1). ⋯ Anakinra was maintained as monotherapy, and the patient remained asymptomatic in the absence of disease flares for the following year. Recent studies point at inhibition of IL-1 activity as an attractive treatment option for patients with refractory idiopathic recurrent pericarditis. Anakinra treatment may also have a role in patients with pericarditis in the setting of systemic inflammatory disorders, such as ECD.
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Frontiers in immunology · Jan 2018
Human CD8+HLA-DR+ Regulatory T Cells, Similarly to Classical CD4+Foxp3+ Cells, Suppress Immune Responses via PD-1/PD-L1 Axis.
We have previously identified a human CD8+HLA-DR+ regulatory T cell subset with the ability to suppress proliferation of autologous PBMCs responder cells through cell contact and CTLA-4 co-inhibitory molecule. The present study characterizes the complete phenotype of CD8+HLA-DR+ Treg cells which showed great similarities with classical CD4+ cells expressing forkhead box P3 (FOXP3). The shared features included the expression of programmed cell death protein 1 (PD-1), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), C-C chemokine receptor type 4 and 5 (CCR4 and CCR5), low expression of CD127, and a memory and effector-like phenotype. ⋯ After PBMCs stimulation, CD8+HLA-DR+ Treg cells showed an increased frequency of IFN-γ and TNFα positive cells and higher degranulation. These data strongly argue against CD8+HLA-DR+ Treg being exhausted cells. Overall, the data presented in this study indicate that CD8+HLA-DR+ Treg and CD4+FOXP3+ Treg share phenotypic and functional features, which may provide cues to similar involvements in the control of antitumor immune responses and autoimmunity.