Abstract PRACTALL is a joint initiative of the American Academy of Allergy, Asthma and Immunology (AAAAI) with the European Academy of Allergy and Clinical Immunology (EAACI) to provide shared ...evidence-based recommendations on cutting-edge topics in the field of allergy and immunology PRACTALL 2017 is focused on what has been established regarding the role of the microbiome in asthma, atopic dermatitis (AD) and food allergy. This is complemented by outlining important knowledge gaps regarding its role in allergic disease and delineating strategies necessary to fill these gaps. In addition, a review of progress in approaches used to manipulate the microbiome will be addressed, identifying what has and has not worked to serve as a baseline for future directions to intervene in allergic disease development and/or progression.
Interleukin-15 (IL-15) has significant potential in cancer immunotherapy as an activator of antitumor CD8 T and natural killer (NK) cells. The primary objectives of this trial were to determine ...safety, adverse event profile, dose-limiting toxicity, and maximum-tolerated dose of recombinant human IL-15 (rhIL-15) administered as a daily intravenous bolus infusion for 12 consecutive days in patients with metastatic malignancy.
We performed a first in-human trial of Escherichia coli-produced rhIL-15. Bolus infusions of 3.0, 1.0, and 0.3 μg/kg per day of IL-15 were administered for 12 consecutive days to patients with metastatic malignant melanoma or metastatic renal cell cancer.
Flow cytometry of peripheral blood lymphocytes revealed dramatic efflux of NK and memory CD8 T cells from the circulating blood within minutes of IL-15 administration, followed by influx and hyperproliferation yielding 10-fold expansions of NK cells that ultimately returned to baseline. Up to 50-fold increases of serum levels of multiple inflammatory cytokines were observed. Dose-limiting toxicities observed in patients receiving 3.0 and 1.0 μg/kg per day were grade 3 hypotension, thrombocytopenia, and elevations of ALT and AST, resulting in 0.3 μg/kg per day being determined the maximum-tolerated dose. Indications of activity included clearance of lung lesions in two patients.
IL-15 could be safely administered to patients with metastatic malignancy. IL-15 administration markedly altered homeostasis of lymphocyte subsets in blood, with NK cells and γδ cells most dramatically affected, followed by CD8 memory T cells. To reduce toxicity and increase efficacy, alternative dosing strategies have been initiated, including continuous intravenous infusions and subcutaneous IL-15 administration.
Eleven patients with progressive advanced malignancy after administration of a cancer vaccine received a fully human anti-CTLA-4 monoclonal antibody (ipilimumab). The primary end point was to ...determine drug toxicity. Tumor response, tumor-specific CD8+ T-cell immune responses, and modulation of CD4+ CD25+ FoxP3+ regulatory T-cell (Treg) numbers were secondary end points.
Three patients with colon cancer, four with non-Hodgkin's lymphoma, and four with prostate cancer were treated. The first dose was given at 3 mg/kg and subsequent doses were administered monthly at 1.5 mg/kg for a total of four cycles.
Tumor regression was observed in two patients with lymphoma; one of which obtained a partial response of 14-month duration. Ipilimumab was well tolerated with predominantly grade 1/2 toxicities. One drug-related grade 3 toxicity was observed. One patient died within 30 days of treatment due to progressive colon cancer. No increase in vaccine-specific T-cell responses was observed after therapy. Tregs as detected by expression of CD4+CD25+CD62L+ declined at early time points but rebounded to levels at or above baseline values at the time of the next infusion.
Ipilimumab treatment depressed Treg numbers at early time points in the treatment cycle but was not accompanied by an increase in vaccine-specific CD8+ T-cell responses in these patients previously treated with a variety of investigational anticancer vaccines. A partial response was observed in one patient with follicular lymphoma. A phase I/II trial evaluating ipilimumab in patients with follicular lymphoma is currently ongoing.
IL-15 uses the heterotrimeric receptor IL-2/IL-15Rβ and the γ chain shared with IL-2 and the cytokine-specific IL-15Rα. Although IL-15 shares actions with IL-2 that include activation of natural ...killer (NK) and CD8 T cells, IL-15 is not associated with capillary leak syndrome, activation-induced cell death, or with a major effect on the number of functional regulatory T cells. To prepare for human trials to determine whether IL-15 is superior to IL-2 in cancer therapy, recombinant human IL-15 (rhIL-15) was produced under current good manufacturing practices. A safety study in rhesus macaques was performed in 4 groups of 6 animals each that received vehicle diluent control or rhIL-15 at 10, 20, or 50 μg/kg/d IV for 12 days. The major toxicity was grade 3/4 transient neutropenia. Bone marrow examinations demonstrated increased marrow cellularity, including cells of the neutrophil series. Furthermore, neutrophils were observed in sinusoids of enlarged livers and spleens, suggesting that IL-15 mediated neutrophil redistribution from the circulation to tissues. The observation that IL-15 administration was associated with increased numbers of circulating NK and CD8 central and effector-memory T cells, in conjunction with efficacy studies in murine tumor models, supports the use of multiple daily infusions of rhIL-15 in patients with metastatic malignancies.
The first-in-human clinical trial with human bolus intravenous infusion IL15 (rhIL15) was limited by treatment-associated toxicity. Here, we report toxicity, immunomodulation, and clinical activity ...of rhIL15 administered as a 10-day continuous intravenous infusion (CIV) to patients with cancers in a phase I trial.
Patients received treatment for 10 days with CIV rhIL15 in doses of 0.125, 0.25, 0.5, 1, 2, or 4 μg/kg/day. Correlative laboratory tests included IL15 pharmacokinetic (PK) analyses, and assessment of changes in lymphocyte subset numbers.
Twenty-seven patients were treated with rhIL15; 2 μg/kg/day was identified as the MTD. There were eight serious adverse events including two bleeding events, papilledema, uveitis, pneumonitis, duodenal erosions, and two deaths (one due to likely drug-related gastrointestinal ischemia). Evidence of antitumor effects was observed in several patients, but stable disease was the best response noted. Patients in the 2 μg/kg/day group had a 5.8-fold increase in number of circulating CD8
T cells, 38-fold increase in total NK cells, and 358-fold increase in CD56
NK cells. Serum IL15 concentrations were markedly lower during the last 3 days of infusion.
This phase I trial identified the MTD for CIV rhIL15 and defined a treatment regimen that produced significant expansions of CD8
T and NK effector cells in circulation and tumor deposits. This regimen has identified several biological features, including dramatic increases in numbers of NK cells, supporting trials of IL15 with anticancer mAbs to increase antibody-dependent cell-mediated cytotoxicity and anticancer efficacy.
Table of Contents Preamblee79 Introductione81 Methodology and Evidence Reviewe81 Organization of the GWCe82 Document Review and Approvale82 Scope of the CPGe82 Definitions of Urgency and Riske83 ...Clinical Risk Factorse83 Coronary Artery Diseasee83 Heart Failuree85 Role of HF in Perioperative Cardiac Risk Indicese85 Risk of HF Based on Left Ventricular Ejection Fraction: Preserved Versus Reducede85 Risk of Asymptomatic Left Ventricular Dysfunctione85 Role of Natriuretic Peptides in Perioperative Risk of HFe86 Cardiomyopathye86 Valvular Heart Disease: Recommendationse87 Aortic Stenosis: Recommendatione87 Mitral Stenosis: Recommendatione88 Aortic and Mitral Regurgitation: Recommendationse88 Arrhythmias and Conduction Disorderse88 Cardiovascular Implantable Electronic Devices: Recommendatione89 Pulmonary Vascular Disease: Recommendationse90 Adult Congenital Heart Diseasee90 Calculation of Risk to Predict Perioperative Cardiac Morbiditye90 Multivariate Risk Indices: Recommendationse90 Inclusion of Biomarkers in Multivariable Risk Modelse91 Approach to Perioperative Cardiac Testinge91 Exercise Capacity and Functional Capacitye91 Stepwise Approach to Perioperative Cardiac Assessment: Treatment Algorithme93 Supplemental Preoperative Evaluatione95 The 12-Lead Electrocardiogram: Recommendationse95 Assessment of LV Function: Recommendationse96 Exercise Stress Testing for Myocardial Ischemia and Functional Capacity: Recommendationse97 Cardiopulmonary Exercise Testing: Recommendatione97 Pharmacological Stress Testinge97 Noninvasive Pharmacological Stress Testing Before Noncardiac Surgery: Recommendationse97 Radionuclide MPIe98 Dobutamine Stress Echocardiographye98 Stress Testing--Special Situationse99 Preoperative Coronary Angiography: Recommendatione99 Perioperative Therapye99 Coronary Revascularization Before Noncardiac Surgery: Recommendationse100 Timing of Elective Noncardiac Surgery in Patients With Previous PCI: Recommendationse115 Future Research Directionse116 Referencese117 Appendix 1 Author Relationships With Industry and Other Entities (Relevant)e129 Appendix 2 Reviewer Relationships With Industry and Other Entities (Relevant)e131 Appendix 3 Related Recommendations From Other CPGse136 Appendix 4 Abbreviationse137 Preamble The American College of Cardiology (ACC) and the American Heart Association (AHA) are committed to the prevention and management of cardiovascular diseases through professional education and research for clinicians, providers, and patients. Since 1980, the ACC and AHA have shared a responsibility to translate scientific evidence into clinical practice guidelines (CPGs) with recommendations to standardize and improve cardiovascular health.
Primary immunodeficiency disorders (PIDs) represent a range of genetically determined diseases that typically have increased susceptibility to infections and in many cases also have evidence of ...immune dysregulation that often presents as autoimmunity. Most recently, the concept of gain-of-function mutations associated with PIDs has become well recognized and adds a new dimension to the understanding of this group of disorders, moving beyond the more commonly seen loss-of-function mutations. The rapidly expanding genetic defects that have been identified in patients with previously uncharacterized PIDs has opened up the potential for targeted therapy directed at the specific disease-causing abnormality. This has been driven by linking PID-specific genetic defects to the associated unique abnormalities in cellular signaling pathways amenable to directed therapies. These include agents that either block overactive or enhance underresponsive cellular pathways. Selected primary immunodeficiencies were chosen, the genetic defects of which have been recently characterized and are amenable to targeted therapy, as a reflection of the power of precision medicine.
Background Gain-of-function (GOF) mutations in the human signal transducer and activator of transcription 1 (STAT1) manifest in immunodeficiency and autoimmunity with impaired TH 17 cell ...differentiation and exaggerated responsiveness to type I and II interferons. Allogeneic bone marrow transplantation has been attempted in severely affected patients, but outcomes have been poor. Objective We sought to define the effect of increased STAT1 activity on T helper cell polarization and to investigate the therapeutic potential of ruxolitinib in treating autoimmunity secondary to STAT1 GOF mutations. Methods We used in vitro polarization assays, as well as phenotypic and functional analysis of STAT1 -mutated patient cells. Results We report a child with a novel mutation in the linker domain of STAT1 who had life-threatening autoimmune cytopenias and chronic mucocutaneous candidiasis. Naive lymphocytes from the affected patient displayed increased TH 1 and follicular T helper cell and suppressed TH 17 cell responses. The mutation augmented cytokine-induced STAT1 phosphorylation without affecting dephosphorylation kinetics. Treatment with the Janus kinase 1/2 inhibitor ruxolitinib reduced hyperresponsiveness to type I and II interferons, normalized TH 1 and follicular T helper cell responses, improved TH 17 differentiation, cured mucocutaneous candidiasis, and maintained remission of immune-mediated cytopenias. Conclusions Autoimmunity and infection caused by STAT1 GOF mutations are the result of dysregulated T helper cell responses. Janus kinase inhibitor therapy could represent an effective targeted treatment for long-term disease control in severely affected patients for whom hematopoietic stem cell transplantation is not available.
Flow cytometry: Surface markers and beyond Delmonte, Ottavia M.; Fleisher, Thomas A.
Journal of allergy and clinical immunology,
February 2019, 2019-02-00, 20190201, Letnik:
143, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Flow cytometry is a routinely available laboratory method to study cells in suspension from a variety of human sources. Application of this technology as a clinical laboratory method has evolved from ...the identification of cell-surface proteins to characterizing intracellular proteins and providing multiple different techniques to assess specific features of adaptive and innate immune function. This expanded menu of flow cytometric testing approaches has increased the utility of this platform in characterizing and diagnosing disorders of immune function.
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