Benchmarking predictions of MHC class I restricted T cell epitopes in a comprehensively studied model system.

T cell epitope candidates are commonly identified using computational prediction tools in order to enable applications such as vaccine design, cancer neoantigen identification, development of diagnostics and removal of unwanted immune responses against protein therapeutics. Most T cell epitope prediction tools are based on machine learning algorithms trained on MHC binding or naturally processed MHC ligand elution data. The ability of currently available tools to predict T cell epitopes has not been comprehensively evaluated. In this study, we used a recently published dataset that systematically defined T cell epitopes recognized in vaccinia virus (VACV) infected C57BL/6 mice (expressing H-2Db and H-2Kb), considering both peptides predicted to bind MHC or experimentally eluted from infected cells, making this the most comprehensive dataset of T cell epitopes mapped in a complex pathogen. We evaluated the performance of all currently publicly available computational T cell epitope prediction tools to identify these major epitopes from all peptides encoded in the VACV proteome. We found that all methods were able to improve epitope identification above random, with the best performance achieved by neural network-based predictions trained on both MHC binding and MHC ligand elution data (NetMHCPan-4.0 and MHCFlurry). Impressively, these methods were able to capture more than half of the major epitopes in the top N = 277 predictions within the N = 767,788 predictions made for distinct peptides of relevant lengths that can theoretically be encoded in the VACV proteome. These performance metrics provide guidance for immunologists as to which prediction methods to use, and what success rates are possible for epitope predictions when considering a highly controlled system of administered immunizations to inbred mice. In addition, this benchmark was implemented in an open and easy to reproduce format, providing developers with a framework for future comparisons against new tools.

Technical Review on the Management of Eosinophilic Esophagitis: A Report From the AGA Institute and the Joint Task Force on Allergy-Immunology Practice Parameters.

Eosinophilic esophagitis (EoE) is a chronic inflammatory condition of the esophagus. Many new studies have been reported recently that describe EoE management. An expert panel was convened by the American Gastroenterological Association Institute and the Joint Task Force on Allergy-Immunology Practice Parameters to provide a technical review to be used as the basis for an updated clinical guideline. This technical review was developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. Eighteen focused EoE management questions were considered, with 15 answered using the GRADE framework and 3 with a narrative summary. There is moderate certainty in the evidence that topical glucocorticosteroids effectively reduce esophageal eosinophil counts to <15 per high-power field over a short-term treatment period of 4-12 weeks, but very low certainty about the effects of using topical glucocorticosteroids as maintenance therapy. Multiple dietary strategies may be effective in reducing esophageal eosinophil counts to <15 per high-power field over a short-term treatment period, with moderate certainty for elemental diets, low certainty for empiric 2-, 4-, and 6-food elimination diets, and very low certainty that allergy-based testing dietary eliminations have a higher failure rate compared to empiric diet elimination. There is very low certainty for the effect of proton pump inhibitors in patients with esophageal eosinophilia. Although esophageal dilation appears to be relatively safe, there is no evidence that it reduces esophageal eosinophil counts. There is very low certainty in the effects of multiple other medical treatments for EoE: anti-interleukin-5 therapy, anti-interleukin-13 therapy, anti-IgE therapy, montelukast, cromolyn, and anti-TNF therapy.

The pig as a model for immunology research.

The pig is an omnivorous, monogastric species with many advantages to serve as an animal model for human diseases. There are very high similarities to humans in anatomy and functions of the immune system, e g., the presence of tonsils, which are absent in rodents. The porcine immune system resembles man for more than 80% of analyzed parameters in contrast to the mouse with only about 10%. The pig can easily be bred, and there are less emotional problems to use them as experimental animals than dogs or monkeys. Indwelling cannulas in a vein or lymphatic vessel enable repetitive stress-free sampling. Meanwhile, there are many markers available to characterize immune cells. Lymphoid organs, their function, and their role in lymphocyte kinetics (proliferation and migration) are reviewed. For long-term experiments, minipigs (e.g., Göttingen minipig) are available. Pigs can be kept under gnotobiotic (germfree) conditions for some time after birth to study the effects of microbiota. The effects of probiotics can be tested on the gut immune system. The lung has been used for extracorporeal preservation and immune engineering. After genetic modifications are established, the pig is the best animal model for future xenotransplantation to reduce the problem of organ shortage for organ transplantation. Autotransplantation of particles of lymphnodes regenerates in the subcutaneous tissue. This is a model to treat secondary lymphedema patients. There are pigs with cystic fibrosis and severe combined immune deficiency available.

Diagnostic approach to occupational rhinitis: the role of nasal provocation tests.

PURPOSE OF REVIEW: The diagnosis of occupational rhinitis is a challenge. Underdiagnosis is substantial as the clinical presentation is nonspecific and often no occupational history is taken. Detection of occupational rhinitis can be improved by including screening questions on occupational exposure in the assessment of every patient with adult-onset rhinitis. RECENT FINDINGS: Case reports, case series and epidemiological studies continuously demonstrate new sensitizers and irritants capable of inducing allergic or nonallergic (irritant-induced) occupational rhinitis. Recent reviews have focused on the value of immunological tests with specific IgE, skin prick tests or basophil activation tests in demonstrating sensitization to occupational agents. Nasal provocation tests (NPT) can establish a definite diagnosis of allergic occupational rhinitis. Several NPT guidelines have been published, however, focusing exclusively on standardized high-molecular weight allergens. When performing NPT with nonstandardized agents -- like most occupational sensitizers -- adapted protocols are needed. SUMMARY: We provide pragmatic guidance to clinicians taking care of rhinitis patients on how to diagnose occupational rhinitis, based on recent insights from the literature. We focus on the challenges in the diagnostic work-up, on how to identify suspected causes, and on the role of NPT.

Assessing the Training and Research Environment for Genomics, Bioinformatics, and Immunology in Radiation Oncology.

PURPOSE: To assess radiation oncologists' perceptions of training and research opportunities in the fields of genomics, bioinformatics, and immunology. MATERIALS AND METHODS: A 13-item electronic survey was sent to 101 radiation oncology department chairs and administrators. A separate 30-item electronic survey was sent to 132 members of the American Society for Radiation Oncology Science Council as well as to 565 members of the Association of Residents in Radiation Oncology. Survey responses were collected, and results were analyzed using descriptive statistics. RESULTS: Twenty-six department chairs and 91 general respondents submitted responses. Among general respondents, 69% were current trainees and 31% had completed training. The majority of respondents (92%) were affiliated with an academic/university main campus. Approximately half of respondents (43% to 53%) reported no prior formal training in bioinformatics, genomics, or immunology. More than half of department chairs (54% to 58%) and general respondents (57% to 63%) thought that current training opportunities in these areas were absolutely or moderately insufficient. A majority of respondents (53% to 65%) thought that additional training in these areas would provide opportunity for career advancement, and 80% could identify a current or future research project that additional training in these fields would allow them to pursue. More than half of respondents expressed interest in attending a formal training course, and the majority of department chairs (22 of 26 [85%]) reported that they would probably or definitely send trainees or faculty members to a formal training course. CONCLUSION: Among radiation oncologists surveyed, there is a perceived lack of current training opportunities in bioinformatics, genomics, and immunology. A majority of respondents reported an interest in obtaining additional training in these areas and believed that training would provide opportunity for career advancement.

[Epidemiology, diagnostics, therapy, prevention and management of uncomplicated bacterial outpatient acquired urinary tract infections in adult patients : Update 2017 of the interdisciplinary AWMF S3 guideline]. / Epidemiologie, Diagnostik, Therapie, Prävention und Management unkomplizierter, bakterieller, ambulant erworbener Harnwegsinfektionen bei erwachsenen Patienten : Aktualisierung 2017 der interdisziplinären AWMF S3­Leitlinie.

BACKGROUND: Update of the 2010 published evidence-based S3 guideline on epidemiology, diagnostics, therapy and management of uncomplicated, bacterial, outpatient-acquired urinary tract infections in adult patients. The guideline contains current evidence for the rational use of antimicrobial substances, avoidance of inappropriate use of certain antibiotic classes and development of resistance. METHODOLOGY: The update was created under the leadership of the German Association of Urology (DGU). A systematic literature search was conducted for the period 01 January 2008 to 31 December 2015. International guidelines have also been taken into account. Evidence level and risk of bias were used for quality review. RESULTS: Updated information on bacterial susceptibility, success, collateral damage and safety of first- and second-line antibiotics was given. For the treatment of uncomplicated cystitis the first line antibiotics are fosfomycin trometamol, nitrofurantoin, nitroxoline, pivmecillinam, trimethoprim (with consideration of the local resistance rates). Fluoroquinolones and cephalosporins should not be used as first choice antibiotics. In the case of uncomplicated pyelonephritis of mild to moderate forms, preferably cefpodoxime, ceftibuten, ciprofloxacin or levofloxacin should be used as oral antibiotics. CONCLUSION: The updated German S3 guideline provides comprehensive evidence- and consensus-based recommendations on epidemiology, diagnostics, therapy, prevention and management of uncomplicated bacterial outpatient acquired urinary tract infections in adult patients. Antibiotic stewardship aspects have significantly influenced the therapeutic recommendations. A broad implementation in all clinical practice settings is necessary to ensure a foresighted antibiotic policy and thus t improve clinical care.

[Guidelines for vaccination of immunocompromised individuals]. / Impfungen bei Immundefekten/Immunsuppression - Expertenstatement und Empfehlungen.

Immunosuppression of various origins is associated with an increased risk of infection; therefore the prevention of infectious diseases by vaccination is especially important in immunocompromised patients. However, the response to vaccinations is often reduced in these risk groups and the application of live vaccines is contraindicated during immunosuppression.In the following expert statement, recommendations for vaccination were created on the basis of current evidence and theoretical/immunological considerations. A first, general part elaborates on efficacy and safety of vaccinations during immunosuppression, modes of action of immunosuppressive medications and recommended time intervals between immunosuppressive treatments and vaccinations. A core piece of this part is a graduation of immunosuppression into three stages, i. e. no relevant immunosuppression, mild to moderate and severe immunosuppression and the assignment of various medications (including biologicals) to one of those stages; this is followed by an overview of possible and necessary vaccinations in each of those stages.The second part gives detailed vaccination guidelines for common diseases and therapies associated with immunosuppression. Primary immune deficiencies, chronic kidney disease, diabetes mellitus, solid and hematological tumors, hematopoetic stem cell transplantation, transplantation of solid organs, aspenia, rheumatological-, gastroenterologic-, dermatologic-, neurologic diseases, biologicals during pregnancy and HIV infection are dealt with.These vaccination guidelines, compiled for the first time in Austria, aim to be of practical help for physicians to facilitate and improve vaccination coverage in immunocompromised patients and their household members and contact persons.

Standardizing terms, definitions and concepts for describing and interpreting unwanted immunogenicity of biopharmaceuticals: recommendations of the Innovative Medicines Initiative ABIRISK consortium.

Biopharmaceuticals (BPs) represent a rapidly growing class of approved and investigational drug therapies that is contributing significantly to advancing treatment in multiple disease areas, including inflammatory and autoimmune diseases, genetic deficiencies and cancer. Unfortunately, unwanted immunogenic responses to BPs, in particular those affecting clinical safety or efficacy, remain among the most common negative effects associated with this important class of drugs. To manage and reduce risk of unwanted immunogenicity, diverse communities of clinicians, pharmaceutical industry and academic scientists are involved in: interpretation and management of clinical and biological outcomes of BP immunogenicity, improvement of methods for describing, predicting and mitigating immunogenicity risk and elucidation of underlying causes. Collaboration and alignment of efforts across these communities is made difficult due to lack of agreement on concepts, practices and standardized terms and definitions related to immunogenicity. The Innovative Medicines Initiative (IMI; www.imi-europe.org), ABIRISK consortium [Anti-Biopharmaceutical (BP) Immunization Prediction and Clinical Relevance to Reduce the Risk; www.abirisk.eu] was formed by leading clinicians, academic scientists and EFPIA (European Federation of Pharmaceutical Industries and Associations) members to elucidate underlying causes, improve methods for immunogenicity prediction and mitigation and establish common definitions around terms and concepts related to immunogenicity. These efforts are expected to facilitate broader collaborations and lead to new guidelines for managing immunogenicity. To support alignment, an overview of concepts behind the set of key terms and definitions adopted to date by ABIRISK is provided herein along with a link to access and download the ABIRISK terms and definitions and provide comments (http://www.abirisk.eu/index_t_and_d.asp).

Reduction of the number of major representative allergens: from clinical testing to 3-dimensional structures.

Vast amounts of allergen sequence data have been accumulated, thus complicating the identification of specific allergenic proteins when performing diagnostic allergy tests and immunotherapy. This study aims to rank the importance/potency of the allergens so as to logically reduce the number of allergens and/or allergenic sources. Meta-analysis of 62 allergenic sources used for intradermal testing on 3,335 allergic patients demonstrated that in southern China, mite, sesame, spiny amaranth, Pseudomonas aeruginosa, and house dust account for 88.0% to 100% of the observed positive reactions to the 62 types of allergenic sources tested. The Kolmogorov-Smironov Test results of the website-obtained allergen data and allergen family featured peptides suggested that allergen research in laboratories worldwide has been conducted in parallel on many of the same species. The major allergens were reduced to 21 representative allergens, which were further divided into seven structural classes, each of which contains similar structural components. This study therefore has condensed numerous allergenic sources and major allergens into fewer major representative ones, thus allowing for the use of a smaller number of allergens when conducting comprehensive allergen testing and immunotherapy treatments.

Diagnostic and therapeutic management of eosinophilic oesophagitis in children and adults: results from a Spanish registry of clinical practice.

BACKGROUND: Eosinophilic oesophagitis has emerged as a common cause of oesophageal symptoms. AIMS: To document practice variation in care provided to eosinophilic oesophagitis patients in Spain and to assess adherence to available guidelines. METHODS: A prospective survey-based registry including data from all patients receiving care from gastroenterologists and allergists throughout Spain was developed. RESULTS: Data from 705 patients (82% adults, male:female ratio 4.1:1) were collected from 26 Spanish hospitals. 42.7% received care in teaching hospitals. Adults presented dysphagia and food impaction more frequently; vomiting and weight loss predominated in children (p < 0.01). A mean diagnostic delay of 54.7 and 28.04 months was documented for adults and children, respectively. Normal endoscopic exams were reported in 27.6% and directly related to the experience in managing the disease (p < 0.05). Paediatric patients, non-teaching hospitals and greater experience in managing eosinophilic oesophagitis were associated with increased frequency in eosinophil count reports and with taking gastric and duodenal biopsies (p < 0.001). Initial therapy consisted of topical steroids (61.7% of patients), proton pump inhibitors (52.4%), dietary modifications (51.26%) and endoscopic dilation (7.2%). Referrals to allergy units occurred more frequently in teaching hospitals (p = 0.003) where food restrictions generally followed allergy test results (p < 0.001). CONCLUSIONS: Availability of facilities and the physician's experience constituted the most important factors in explaining differences in patient management.

A professional development model for medical laboratory scientists working in the immunohematology laboratory.

Transfusion medicine, a section of the Department of Laboratory Medicine at The University of Texas MD Anderson Cancer Center is committed to the education and advancement of its health care professionals. It is our belief that giving medical laboratory professionals a path for advancement leads to excellence and increases overall professionalism in the Immunohematology Laboratory. As a result of this strong commitment to excellence and professionalism, the Immunohematology laboratory has instituted a Professional Development Model (PDM) that aims to create Medical Laboratory Scientists (MLS) that are not only more knowledgeable, but are continually striving for excellence. In addition, these MLS are poised for advancement in their careers. The professional development model consists of four levels: Discovery, Application, Maturation, and Expert. The model was formulated to serve as a detailed path to the mastery of all process and methods in the Immunohematology Laboratory. Each level in the professional development model consists of tasks that optimize the laboratory workflow and allow for concurrent training. Completion of a level in the PDM is rewarded with financial incentive and further advancement in the field. The PDM for Medical Laboratory Scientists in the Immunohematology Laboratory fosters personal development, rewards growth and competency, and sets high standards for all services and skills provided. This model is a vital component of the Immunohematology Laboratory and aims to ensure the highest quality of care and standards in their testing. It is because of the success of this model and the robustness of its content that we hope other medical laboratories aim to reach the same level of excellence and professionalism, and adapt this model into their own environment.

The treatment of chronic graft-versus-host disease: consensus recommendations of experts from Germany, Austria, and Switzerland.

BACKGROUND: Chronic graft-versus-host disease (cGVHD) is the commonest complication of allogeneic bone marrow and blood stem-cell transplantation, occurring in 50% of all cases and causing late mortality in as many as 25%. There are now about 10 000 patients with cGVHD in Germany, and their number is growing by about 500 each year. cGVHD is a chronic multisystem disease due to impaired tolerance mechanisms. It affects many organs in variable ways, impairing organ function and lowering quality of life. METHODS: We present consensus recommendations on the treatment of cGVHD that were developed jointly by the German Working Group on Bone Marrow and Blood Stem-Cell Transplantation, the German and Austrian Societies of Hematology and Oncology, the Swiss Blood Stem-Cell Transplantation Group, and the German-Austrian Working Group on Pediatric Stem-Cell Transplantation. All of the recommendations are based on an evaluation of selected publications. RESULTS: Recommendations are given regarding the diagnostic evaluation of cGVHD, first-line treatment (which has a response rate of 30% to 50%), second-line treatment, and topical immunosuppression. Patients with cGVHD should also receive supportive care including anti-infective prophylaxis, vaccinations, hormone replacement, prevention and treatment of osteoporosis, physiotherapy, rehabilitation, and psychosocial assistance. CONCLUSION: Patients with cGVHD need multidisciplinary care under the guidance of the transplantation center. The aim of these recommendations is to standardize the treatment of cGVHD and thereby improve patient care.

Definitions of histocompatibility typing terms.

Histocompatibility testing for stem cell and solid organ transplantation has become increasingly complex as newly discovered HLA alleles are described. HLA typing assignments reported by laboratories are used by physicians and donor registries for matching donors and recipients. To communicate effectively, a common language for histocompatibility terms should be established. In early 2010, representatives from Clinical, Registry, and Histocompatibility organizations joined together as the Harmonization of Histocompatibility Typing Terms Working Group to define a consensual language for laboratories, physicians, and registries to communicate histocompatibility typing information. The Working Group defined terms for HLA typing resolution, HLA matching, and a format for reporting HLA assignments. In addition, definitions of verification typing and extended typing were addressed. The original draft of the Definitions of Histocompatibility Typing Terms was disseminated to colleagues from each organization to gain feedback and create a collaborative document. Commentary gathered during this 90-day review period were discussed and implemented for preparation of this report. Histocompatibility testing continues to evolve; thus, the definitions agreed on today probably will require refinement and perhaps additional terminology in the future.

Allergy prevention.

BACKGROUND: Evidence-based primary prevention of allergic conditions is important in view of their increasing prevalence in Western industrialized countries. METHODS: The Cochrane and Medline databases were searched for relevant scientific publications that appeared from February 2003 to May 2008. Articles in the reference lists of recent reviews were also considered, and experts were directly asked for their opinions. The retrieved publications were screened for relevance by evaluation of the title and abstract, and then by evaluation of the entire text. Each study chosen for inclusion was assigned an evidence grade as well as a grade for study quality relating to its potential for bias (low or high). The revised recommendations were then formally accepted by a consensus of representatives of medical specialist societies and other organizations, including a patient self-help group. RESULTS: The search initially yielded 4556 results out of which 217 articles (4 Cochrane reviews, 14 meta-analyses, 19 randomized clinical trials, 135 cohort studies, and 45 case-control studies) were chosen for inclusion and critical appraisal. No major changes ensued in the existing recommendations to avoid exposure to tobacco smoke, breast-feed for 4 months (or use hypoallergenic formulas), avoid a mould-promoting indoor climate, avoid exposure to furry pets (particularly cats), and vaccinate according to the current recommendations of the Standing Committee on Vaccination of the Robert Koch Institute (Ständige Impfkommission, STIKO). Neither the delayed introduction of solid food nor the avoidance of potent dietary allergens is recommended as a means of primary prevention. New recommendations were issued regarding fish consumption (by the mother while breastfeeding and nursing, and by the infant as solid food), avoidance of overweight, and reduction of exposure to air pollutants. CONCLUSIONS: This updated guideline serves as an aid in giving patients current, evidence-based recommendations for allergy prevention.