Frontiers in immunology
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Frontiers in immunology · Jan 2018
Expression of Programmed Death-Ligand 1 by Human Colonic CD90+ Stromal Cells Differs Between Ulcerative Colitis and Crohn's Disease and Determines Their Capacity to Suppress Th1 Cells.
The role of programmed cell death protein 1 (PD-1) and its ligands in the dysregulation of T helper immune responses observed in the inflammatory bowel disease (IBD) is unclear. Recently, a novel concept emerged that CD90+ colonic (myo)fibroblasts (CMFs), also known as stromal cells, act as immunosuppressors, and are among the key regulators of acute and chronic inflammation. The objective of this study was to determine if the level of the PD-1 ligands is changed in the IBD inflamed colonic mucosa and to test the hypothesis that changes in IBD-CMF-mediated PD-1 ligand-linked immunosuppression is a mechanism promoting the dysregulation of Th1 cell responses. ⋯ We present evidence showing that increased PD-L1 expression suppresses Th1 cell activity in UC. In contrast, loss of PD-L1 expression observed in CD contributes to the persistence of the Th1 inflammatory milieu in CD. Our data suggest that dysregulation of the Th1 responses in the inflamed colonic mucosa of IBD patients is promoted by the alterations in PD-L1 expression in the mucosal mesenchymal stromal cell compartment.
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Frontiers in immunology · Jan 2018
Sialylated Autoantigen-Reactive IgG Antibodies Attenuate Disease Development in Autoimmune Mouse Models of Lupus Nephritis and Rheumatoid Arthritis.
Pro- and anti-inflammatory effector functions of IgG antibodies (Abs) depend on their subclass and Fc glycosylation pattern. Accumulation of non-galactosylated (agalactosylated; G0) IgG Abs in the serum of rheumatoid arthritis and systemic lupus erythematosus (SLE) patients reflects severity of the diseases. In contrast, sialylated IgG Abs are responsible for anti-inflammatory effects of the intravenous immunoglobulin (pooled human serum IgG from healthy donors), administered in high doses (2 g/kg) to treat autoimmune patients. ⋯ In accordance, the transfer of small amounts of immune complexes containing sialylated IgG Abs was sufficient to attenuate the development of nephritis. We further showed that administration of sialylated collagen type II (Col II)-specific IgG Abs attenuated the disease symptoms in a model of Col II-induced arthritis and reduced pathogenic Th17 cell and autoantigen-specific IgG Ab responses. We conclude that sialylated autoantigen-specific IgG Abs may represent a promising tool for treating pathogenic T and B cell immune responses in autoimmune diseases.
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Frontiers in immunology · Jan 2018
ReviewPerspectives on Chimeric Antigen Receptor T-Cell Immunotherapy for Solid Tumors.
Chimeric antigen receptor (CAR) T-cell therapy entails the genetic engineering of a patient's T-cells to express membrane spanning fusion receptors with defined specificities for tumor-associated antigens. These CARs are capable of eliciting robust T-cell activation to initiate killing of the target tumor cells. This therapeutic approach has produced unprecedented clinical outcomes in the treatment of "liquid" hematologic cancers, but to date has not produced comparable responses in targeting solid malignancies. ⋯ This mini-review summarizes these hurdles and describes some recent approaches and innovations to genetically re-engineer CAR T-cells to counter inhibitory influences found in the tumor microenvironment. Novel immunotherapy drug combinations to potentiate the activity of CAR T-cells are also discussed. As our understanding of the immune landscape of tumors improves and our repertoire of immunotherapeutic drugs expands, it is envisaged that the efficacy of CAR T-cells against solid tumors might be potentiated using combination therapies, which it is hoped may lead to meaningful improvements in clinical outcome for patients with refractory solid malignancies.
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Frontiers in immunology · Jan 2018
ReviewConcepts Collide: Genomic, Immune, and Microbial Influences on the Tumor Microenvironment and Response to Cancer Therapy.
Cancer research has seen unprecedented advances over the past several years, with tremendous insights gained into mechanisms of response and resistance to cancer therapy. Central to this has been our understanding of crosstalk between the tumor and the microenvironment, with the recognition that complex interactions exist between tumor cells, stromal cells, overall host immunity, and the environment surrounding the host. This is perhaps best exemplified in cancer immunotherapy, where numerous studies across cancer types have illuminated our understanding of the genomic and immune factors that shape responses to therapy. ⋯ The gut microbiome plays a central role, with recent evidence revealing that the gut microbiome influences the overall immune set-point, through diverse effects on local and systemic inflammatory processes. Indeed, quantifiable differences in the gut microbiome have been associated with disease and treatment outcomes in patients and pre-clinical models, though precise mechanisms of microbiome-immune interactions are yet to be elucidated. Complexities are discussed herein, with a discussion of each of these variables as they relate to treatment response.
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Frontiers in immunology · Jan 2018
ReviewCD38: A Target for Immunotherapeutic Approaches in Multiple Myeloma.
Multiple Myeloma (MM) is a hematological cancer characterized by proliferation of malignant plasma cells in the bone marrow (BM). MM represents the second most frequent hematological malignancy, accounting 1% of all cancer and 13% of hematological tumors, with ~9,000 new cases per year. Patients with monoclonal gammopathy of undetermined significance (MGUS) and asymptomatic smoldering MM (SMM) usually evolve to active MM in the presence of increased tumor burden, symptoms and organ damage. ⋯ Among them, immunotherapy represents a promising approach. Here, we summarized recent findings regarding CD38-targeted immunotherapy of MM in pre-clinical models and clinical trials, including (i) mAbs (daratumumab and isatuximab), (ii) radioimmunotherapy, and (iii) adoptive cell therapy, using chimeric antigen receptor (CAR)-transfected T cells specific for CD38. Finally, we discussed the efficacy and possible limitations of these therapeutic approaches for MM patients.