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Today, 28 Ιουνίου 2016, 8:52:55 πμ
Regulatory issues in immunity to liver and blood-stage malaria
Today, 28 Ιουνίου 2016, 5 hours ago
Natalija Van Braeckel-Budimir | Samarchith P Kurup | John T Harty
Eosinophilic bioactivities in severe asthma
Today, 28 Ιουνίου 2016, 6 hours ago | Tara F. Carr, Sergejs Berdnikovs, Hans-Uwe Simon, Bruce S. Bochner and Lanny J. Rosenwasser
Asthma is clearly related to airway or blood eosinophilia, and asthmatics with significant eosinophilia are at higher risk for more severe disease. Eosinophils actively contribute to innate and adaptive immune...
Particularities of allergy in the Tropics
Today, 28 Ιουνίου 2016, 6 hours ago | Luis Caraballo, Josefina Zakzuk, Bee Wah Lee, Nathalie Acevedo, Jian Yi Soh, Mario Sánchez-Borges, Elham Hossny, Elizabeth García, Nelson Rosario, Ignacio Ansotegui, Leonardo Puerta, Jorge Sánchez and Victoria Cardona
Allergic diseases are distributed worldwide and their risk factors and triggers vary according to geographical and socioeconomic conditions. Allergies are frequent in the Tropics but aspects of their prevalenc...
Eosinophilic bioactivities in severe asthma
Today, 28 Ιουνίου 2016, 7 hours ago | Tara F. Carr, Sergejs Berdnikovs, Hans-Uwe Simon, Bruce S. Bochner and Lanny J. Rosenwasser
Asthma is clearly related to airway or blood eosinophilia, and asthmatics with significant eosinophilia are at higher risk for more severe disease. Eosinophils actively contribute to innate and adaptive immune...
Particularities of allergy in the Tropics
Today, 28 Ιουνίου 2016, 7 hours ago | Luis Caraballo, Josefina Zakzuk, Bee Wah Lee, Nathalie Acevedo, Jian Yi Soh, Mario Sánchez-Borges, Elham Hossny, Elizabeth García, Nelson Rosario, Ignacio Ansotegui, Leonardo Puerta, Jorge Sánchez and Victoria Cardona
Allergic diseases are distributed worldwide and their risk factors and triggers vary according to geographical and socioeconomic conditions. Allergies are frequent in the Tropics but aspects of their prevalenc...
Additional Treatments for High-Risk Obstetric Antiphospholipid Syndrome: a Comprehensive Review
Yesterday, 27 Ιουνίου 2016, 7:39:10 μμ
Abstract
Most investigators currently advocate prophylactic-dose heparin plus low-dose aspirin as the preferred treatment of otherwise healthy women with obstetric antiphospholipid syndrome, whilst women with a history of vascular thrombosis alone or associated with pregnancy morbidity are usually treated with therapeutic heparin doses in association with low-dose aspirin in an attempt to prevent both thrombosis and pregnancy morbidity. However, the protocols outlined above fail in about 20 % of pregnant women with antiphospholipid syndrome. Identifying risk factors associated with pregnancy failure when conventional therapies are utilized is an important step in establishing guidelines to manage these high-risk patients. Some clinical and laboratory risk factors have been found to be related to maternal–foetal complications in pregnant women on conventional therapy. However, the most efficacious treatments to administer to high-risk antiphospholipid syndrome women in addition to conventional therapy in order to avoid pregnancy complications are as yet unestablished. This is a comprehensive review on this topic and an invitation to participate in a multicentre study in order to identify the best additional treatments to be used in this subset of antiphospholipid syndrome patients.Lymphocyte Disturbances in Primary Antiphospholipid Syndrome and Application to Venous Thromboembolism Follow-Up
Yesterday, 27 Ιουνίου 2016, 7:39:10 μμ
Abstract
Among patients with venous thromboembolism (VTE), the persistent detection of antiphospholipid (aPL) antibodies (Ab) represents an independent high risk factor for recurrence. However, oral anticoagulation vitamin K antagonist therapy, frequently used in these patients, is problematic in assessing and/or confirming a diagnosis of primary aPL syndrome (pAPS), suggesting use of alternative strategies. For this reason, and by analogy with other autoimmune diseases, a flow cytometer approach testing peripheral T cell subsets (CD3, CD4, and CD8), B cell subsets (B1, transitional, naive, and memory), and NK cells can be proposed. As an example and to validate the concept, pAPS patients selected from the monocentric VTE case–control EDITH’s cohort were selected during their follow-up. As suspected and in contrast to non-APS VTE patients, other autoimmune diseases, and controls, pAPS VTE patients displayed specific lymphocyte disturbances. Quantitative and qualitative modifications were related to total CD4+ T cell reduction, a lower CD4/CD8 ratio, and disturbance in B cell homeostasis with increased proportions of B1 cells, transitional B cells (CD24++CD38++), and naive B cells (IgD+CD27−), while memory B cells (IgD+CD27+ and IgD−CD27+) were reduced. Interestingly, the absolute number of CD4+ T cells positively correlated with IgG anti-cardiolipin Ab levels. Altogether, disturbances of T and B cell homeostasis characterized pAPS VTE patients during their follow-up. This suggests a means of profiling that could be used in addition to existing criteria to characterize them.Cardiac Impairment in Rheumatoid Arthritis and Influence of Anti-TNFα Treatment
Yesterday, 27 Ιουνίου 2016, 7:39:10 μμ
Abstract
There is evidence that rheumatoid arthritis (RA) is associated with higher overall and cardiovascular (CV) morbidity and mortality as compared with general population. Increased prevalence of traditional risk factors and chronic inflammation, that has been recognized as independent CV risk factor, may play an important role in atherosclerosis and subsequently ischemic heart disease development. However, myocardial dysfunction as a result of chronic inflammation and secondarily myocardial fibrosis markedly participates on heart failure development. Proinflammatory cytokines, such as C-reactive protein, tumor necrosis factor alpha (TNFα), interleukins 1 and 6, that are markedly increased in RA, play a role in the acceleration of atherosclerosis as well as myocardial fibrosis development. Several studies documented that increased CV risk was associated with seropositivity, disease activity score, citrullination, and duration of RA. Early detection of heart dysfunction is based on echocardiographic detection of diastolic dysfunction resulting from myocardial inflammation and fibrosis. Some studies showed also higher prevalence of left ventricular systolic dysfunction and increased prevalence of cardiac arrhythmias as compared to non-RA population. There are still controversies on the impact of NT-proBNP in predicting cardiac impairment in RA patients. Some authors consider it to be a sensitive noninvasive predictor of subclinical CV disease in these patients and also a predictor of all-cause mortality independently on traditional CV risk factors. However, the correlation with parameters of cardiac function was confirmed only in a few studies. The impact of biological treatment on progression of atherosclerosis and heart failure is still controversial and seems to be not harmful in young patients with normal left ventricular function. The effect of biologics, especially anti-TNFα drugs, is probably related to the cardiac function before treatment. Larger prospective clinical, echocardiographic, and magnetic resonance studies are needed.Modulation of innate immunity in the tumor microenvironment
Yesterday, 27 Ιουνίου 2016, 6:48:55 μμ
Abstract
A recent report from the Center for Disease Control identified melanoma as being among the highest causes of cancer-related mortalities in the USA. While interventions such as checkpoint blockade have made substantial impact in terms of improving response rates and overall survival, a significant number of patients fail to respond to treatment or become resistant to therapy. A better understanding of the tumor microenvironment in these patients becomes imperative for identifying immune suppressive mechanisms that impact the development of effective anti-tumor immune responses. We have investigated innate immune cells (dendritic cells, NK cells) in the tumor microenvironment (TME) in order to devise effective targeted anticancer immune therapies. We find that matrix metalloproteinase-2 (MMP-2), secreted from melanoma cells and stromal cells, cleaves IFNAR1 and stimulates TLR-2 on dendritic cells (DC) within the TME. Both these events independently culminate in programing the DCs to promote pro-tumorigenic TH2 T cell differentiation. In addition, we have shown that NK cells become functionally exhausted in melanoma patients. We identified the expression of Tim-3 as one of the factors responsible for NK cell exhaustion and showed that anti-Tim3 antibodies partially reversed this exhaustion. We have initiated local intervention strategies such as intra-tumoral administration of DC activating Poly-ICLC and compared the efficacy of different TLR agonists and melanoma antigens for use as combination tumor vaccine in clinical trials. Such approaches will provide a unique insight into tumor biology and will facilitate in development of highly effective and cell type-specific immune therapies.Circulating immune cell phenotype can predict the outcome of lenalidomide plus low-dose dexamethasone treatment in patients with refractory/relapsed multiple myeloma
Yesterday, 27 Ιουνίου 2016, 6:48:55 μμ
Abstract
Although the antimyeloma effect of lenalidomide is associated with activation of the immune system, the exact in vivo immunomodulatory mechanisms of lenalidomide combined with low-dose dexamethasone (Len-dex) in refractory/relapsed multiple myeloma (RRMM) patients remain unclear. In this study, we analyzed the association between immune cell populations and clinical outcomes in patients receiving Len-dex for the treatment of RRMM. Peripheral blood samples from 90 RRMM patients were taken on day 1 of cycles 1 (baseline), 2, 3, and 4 of Len-dex therapy. Peripheral blood CD3+, CD4+, and CD8+ cell frequencies were significantly decreased by 3 cycles of therapy, whereas NK cell frequency was significantly increased after the 3rd cycle. For the myeloid-derived suppressor cell (MDSC) subset, the frequency of granulocytic MDSCs transiently increased after the 1st cycle, whereas there was an increase in monocytic MDSC (M-MDSC) frequency after the 1st and 3rd cycles. Among 81 evaluable patients, failure to achieve a response of VGPR or greater was associated with a decrease in CD8+ cell frequency and increase in M-MDSC frequency after 3 cycles of Len-dex treatment. A high proportion of natural killer T (NKT)-like cells (CD3+/CD56+) prior to Len-dex treatment might predict a longer time to progression. In addition, patients with a smaller decrease in the frequency of both CD3+ cells and CD8+ cells by 3 cycles exhibited a longer time to the next treatment. These results demonstrated that early changes in immune cell subsets are useful immunologic indicators of the efficacy of Len-dex treatment in RRMM.Rhinovirus infection in murine chronic allergic rhinosinusitis model
Yesterday, 27 Ιουνίου 2016, 6:13:18 μμ | Sung Bu Lee, Jeong-Ah Song, Go-Eun Choi, Hun Sik Kim, Yong Ju Jang
Background
Patients with chronic rhinosinusitis (CRS) commonly experience aggravation of their symptoms after viral upper respiratory infection (URI). Rhinovirus (RV) is the most common URI-causing virus. However, there is a lack of a mouse model of RV infection and in vivo studies investigating the effect of RV infection on CRS.
Methods
A mouse model of chronic allergic rhinosinusitis (CARS) was established by sensitizing to ovalbumin (OVA) through intraperitoneal injection followed by nasal challenges with OVA for 5 weeks. Both control and CARS mice were euthanized at 48 hours after infection with minor group RV serotype 1B (RV1B). Sinonasal complex samples were evaluated histologically; and interleukin (IL)-6, macrophage inflammatory protein (MIP)-2, IL-13, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ were measured in the nasal lavage fluid. The RV1B-infected areas in control and CARS mice were identified using immunofluorescence.
Results
In the infected control mice group, RV1B increased secretory hyperplasia in the sinonasal mucosa and the production of proinflammatory cytokines including INF-γ, MIP-2, and IL-13. Immunohistochemical analysis of nasal mucosa from RV1B-infected mice presented abundant RV1B staining, which was distributed between the epithelium and the lamina propria. In the CARS group, the RV1B-infected area per unit was significantly higher than that in control mice. However, RV1B infection neither increased the proinflammatory cytokine secretion nor worsened the histology significantly.
Conclusion
We successfully established a mouse model of upper airway RV infection by nasal inoculation with RV1B. Although there was histologically-proven increased RV infection in the CARS model, the infection did not intensify sinonasal inflammation.
Immune checkpoint inhibition in ovarian cancer
Yesterday, 27 Ιουνίου 2016, 4:22:48 μμ | Hamanishi, J., Mandai, M., Konishi, I.
Recent studies have shown that tumor cells acquire escape mechanisms to evade host immunity in the tumor microenvironment. Two key immune checkpoint pathways mediated by immunosuppressive co-signaling, the first via programmed cell death 1 (PD-1) and PD-1 ligand 1 (PD-1/PD-L1) and the second via CTLA-4 and B7 (CTLA-4/B7), have been previously described. Several clinical trials have revealed an outstanding anti-tumor efficacy of immune checkpoint inhibitors (anti-CTLA-4 antibody, anti-PD-1 antibody and/or anti-PD-L1 antibody) in patients with various types of solid malignancies, including non-small cell lung cancer, melanoma, renal cell cancer and ovarian cancer. In this review, we examine pre-clinical studies that described the local immune status and immune checkpoint signals in ovarian cancer, highlight recent clinical trials that evaluated immune checkpoint inhibitors against ovarian cancer and discuss the clinical issues regarding immune checkpoint inhibitors.
Chimeric antigen receptor-modified T cells strike back
Yesterday, 27 Ιουνίου 2016, 4:22:48 μμ | Frigault, M. J., Maus, M. V.
Chimeric antigen receptors (CARs) are engineered molecules designed to endow a polyclonal T-cell population with the ability to recognize tumor-associated surface antigens. In their simplest form, CARs comprise a targeting moiety in the form of a single-chain variable fragment from an antibody connected to various intracellular signaling domains allowing for T-cell activation. This powerful approach combines the specificity of an antibody with the cytotoxic ability of a T cell. There has been much excitement since early phase trials of CAR-T cells targeting CD19 expressed on B-cell malignancies demonstrated remarkable efficacy in inducing long-term, stable remissions in otherwise relapsed/refractory disease. Despite these successes, we have just begun to understand the intricacies of CAR biology with efforts underway to utilize this platform in the treatment of other, previously refractory malignancies. Challenges currently include identification of viable cancer targets, management strategies for potentially severe and irreversible toxicities and overcoming the immunosuppressive nature of the tumor microenvironment. This review will focus on basic CAR structure and function, previous success and new approaches aimed at the broader application of CAR-T-cell therapy.
Vaccine adjuvants as potential cancer immunotherapeutics
Yesterday, 27 Ιουνίου 2016, 4:22:48 μμ | Temizoz, B., Kuroda, E., Ishii, K. J.
Accumulated evidence obtained from various clinical trials and animal studies suggested that cancer vaccines need better adjuvants than those that are currently licensed, which include the most commonly used alum and incomplete Freund’s adjuvant, because of either a lack of potent anti-tumor immunity or the induction of undesired immunity. Several clinical trials using immunostimulatory adjuvants, particularly agonistic as well as non-agonistic ligands for TLRs, C-type lectin receptors, retinoic acid-inducible gene I-like receptors and stimulator of interferon genes, have revealed their therapeutic potential not only as vaccine adjuvants but also as anti-tumor agents. Recently, combinations of such immunostimulatory or immunomodulatory adjuvants have shown superior efficacy over their singular use, suggesting that seeking optimal combinations of the currently available or well-characterized adjuvants may provide a better chance for the development of novel adjuvants for cancer immunotherapy.
Introduction: Cancer Immunology Special Issue--Immunotherapy
Yesterday, 27 Ιουνίου 2016, 4:22:48 μμ | Kawakami, Y.
T-cell adoptive immunotherapy using tumor-infiltrating T cells and genetically engineered TCR-T cells
Yesterday, 27 Ιουνίου 2016, 4:22:48 μμ | Ikeda, H.
Immunotherapy has received the expectation that it should contribute to the therapy of cancer patients for >100 years. At long last, recent clinical trials of immunotherapy with immune checkpoint inhibitors and adoptive cell therapy with genetically engineered T cells have reported their remarkable efficacies. Nowadays, it is expected that T-cell adoptive immunotherapy can not only control tumor progression but even cure cancer in some patients. Conversely, severe adverse events associated with efficacy have frequently been reported in clinical trials, suggesting that the assessment and control of safety will be indispensable in the future development of the therapy. New approaches in T-cell adoptive immunotherapy such as reduction of adverse events, targeting of new antigens or utilization of allogeneic cells will open a new gate for less harmful and more effective immunological treatment of cancer patients.
The present status and future prospects of peptide-based cancer vaccines
Yesterday, 27 Ιουνίου 2016, 4:22:48 μμ | Hirayama, M., Nishimura, Y.
Tumor cells commonly express several antigens, such as tumor-associated antigens (TAAs) or mutation-derived antigens (neoantigens), that can be regarded as foreign antigens and elicit anti-tumor immune responses in cancer patients. Various TAAs or neoantigens expressed in cancer cells have been identified and utilized as targets for cancer vaccines. One approach to elicit tumor-specific immune responses is termed peptide-based cancer vaccination; it involves administrating TAAs or neoantigen-derived peptide for treatment of cancers. There have been several forms of peptide-based cancer vaccines depending on which effector cells, such as CTLs or CD4+ T-helper cells, are targeted to be activated. Many phase I and II clinical trials of peptide-based cancer vaccines using TAA-derived CTL epitopes, T-helper cell epitopes or dendritic cells loaded with TAA-derived peptides for various malignant tumors have been conducted and provide clinical benefits in a small fraction of patients. Nowadays, to improve the efficiency of peptide-based cancer vaccines, combination immunotherapy of peptide-based cancer vaccines with the immune-checkpoint blockade therapies using mAbs specific for CTLA-4, programmed cell death 1 (PD-1), or PD-1 ligand 1 (PD-L1) have been developed for clinical application. Furthermore, along with the recent technological progress in genetic and bioinformatic analysis, it has become easier to identify neoantigens from individual cancer patients. It is expected that peptide-based cancer vaccines targeting neoantigens as a personalized cancer immunotherapy will be developed.
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