Peptide-MHC class I stability is a better predictor than peptide affinity of CTL immunogenicity

Efficient presentation of peptide-MHC class I (pMHC-I) complexes to immune T cells should benefit from a stable peptide-MHC-I interaction. However, it has been difficult to distinguish stability from other requirements for MHC-I binding, for example, affinity. We have recently established a high-throughput assay for pMHC-I stability. Here, we have generated a large database containing stability measurements of pMHC-I complexes, and re-examined a previously reported unbiased analysis of the relative contributions of antigen processing and presentation in defining cytotoxic T lymphocyte (CTL) immunogenicity [Assarsson et al., J. Immunol. 2007. 178: 7890-7901]. Using an affinity-balanced approach, we demonstrated that immunogenic peptides tend to be more stably bound to MHC-I molecules compared with nonimmunogenic peptides. We also developed a bioinformatics method to predict pMHC-I stability, which suggested that 30% of the nonimmunogenic binders hitherto classified as "holes in the T-cell repertoire" can be explained as being unstably bound to MHC-I. Finally, we suggest that nonoptimal anchor residues in position 2 of the peptide are particularly prone to cause unstable interactions with MHC-I. We conclude that the availability of accurate predictors of pMHC-I stability might be helpful in the elucidation of MHC-I restricted antigen presentation, and might be instrumental in future search strategies for MHC-I epitopes.     

Update on research and future directions of the OMERACT MRI inflammatory arthritis group

The OMERACT Magnetic Resonance Imaging (MRI) Task Force has developed and evolved the psoriatic arthritis MRI score (PsAMRIS) over the last few years, and at OMERACT 10, presented longitudinal evaluation by multiple readers, using PsA datasets obtained from extremity MRI magnets. Further evaluation of this score will require more PsA imaging datasets. As well, due to improved image resolution since the development of the original rheumatoid arthritis MRI scoring system (RAMRIS), the Task Force has worked on semiquantitative assessment of joint space narrowing, and developed a reliable method as a potential RAMRIS addendum, although responsiveness will need to be evaluated. One of the strengths of MRI is the ability to detect subclinical synovitis, so the group worked on obtaining low disease activity/clinical remission datasets from a number of international centers and presented cross-sectional findings. Subsequent longitudinal evaluation of this unique resource will be a major continuing focus for the group.     

Embryo selection with artificial intelligence: how to evaluate and compare methods?

Journal of Assisted Reproduction and Genetics - Embryo selection within in vitro fertilization (IVF) is the process of evaluating qualities of fertilized oocytes (embryos) and selecting the best...     

GIP(3<Emphasis Type="Bold">-</Emphasis>30)NH<Subscript>2</Subscript> is an efficacious GIP receptor antagonist in humans: a randomised,double-blinded,placebo-controlled,crossover study

Aims/hypothesis

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone secreted postprandially from enteroendocrine K cells, but despite therapeutically interesting effects, GIP physiology in humans remains incompletely understood. Progress in this field could be facilitated by a suitable GIP receptor antagonist. For the first time in humans, we investigated the antagonistic properties of the naturally occurring GIP(3-30)NH₂ in in vivo and in in vitro receptor studies.

Methods

In transiently transfected COS-7 cells, GIP(3-30)NH₂ was evaluated with homologous receptor binding and receptor activation (cAMP accumulation) studies at the glucagon-like peptide 1 (GLP-1), glucagon-like peptide-2 (GLP-2), glucagon, secretin and growth hormone-releasing hormone (GHRH) receptors. Ten healthy men (eligibility criteria: age 20–30 years, HbA_1c less than 6.5% [48 mmol/mol] and fasting plasma glucose [FPG] less than 7 mmol/l) were included in the clinical study. Data were collected as plasma and serum samples from a cubital vein cannula. As primary outcome, insulin secretion and glucose requirements were evaluated together with in a randomised, four-period, crossover design by infusing GIP(3-30)NH₂ (800 pmol kg^?1 min^?1), GIP (1.5 pmol kg^?1 min^?1), a combination of these or placebo during hyperglycaemic clamp experiments. The content of the infusions were blinded to the study participants and experimental personnel. No study participants dropped out.

Results

GIP(3-30)NH₂ neither bound, stimulated nor antagonised a series of related receptors in vitro. The elimination plasma half-life of GIP(3-30)NH₂ in humans was 7.6 ± 1.4 min. Markedly larger amounts of glucose were required to maintain the clamp during GIP infusion compared with the other days. GIP-induced insulin secretion was reduced by 82% (p < 0.0001) during co-infusion with GIP(3-30)NH₂, and the need for glucose was reduced to placebo levels. There were no effects of GIP(3-30)NH₂ alone or of GIP with or without GIP(3-30)NH₂ on plasma glucagon, GLP-1, somatostatin, triacylglycerols, cholesterol, glycerol or NEFA. GIP(3-30)NH₂ administration was well tolerated and without side effects.

Conclusions/interpretation

We conclude that GIP(3-30)NH₂ is an efficacious and specific GIP receptor antagonist in humans suitable for studies of GIP physiology and pathophysiology.

Trial registration

ClinicalTrials.gov registration no. NCT02747472.

Funding

The study was funded by Gangstedfonden, the European Foundation for the Study of Diabetes, and Aase og Ejnar Danielsens fond.

     

Perceptions of the first family physicians to adopt advanced access in the province of Quebec,Canada

In Quebec, several primary care physicians have made the transition to the advanced access model to address the crisis of limited access to primary care. The objectives are to describe the implementation of the advanced access model, as perceived by the first family physicians; to analyze the factors influencing the implementation of its principles; and to document the physicians' perceptions of its effects on their practice, colleagues and patients. Qualitative methods were used to explore, through semi‐structured interviews, the experiences of 21 family physicians who had made the transition to advanced access. Of the 21 physicians, 16 succeeded in adopting all five advanced access principles to varying degrees. Core implementation issues revolved around the dynamics of collaboration between physicians, nurses and other colleagues. Secretaries' functions, in particular, had to be expanded. Facilitating factors were mainly related to the physicians' leadership and the professional resources available in the organizations. Impediments related to resource availability and team functioning were also encountered. This is the first exploratory study to examine the factors influencing the adoption of the advanced access model conducted with early‐adopter family physicians. The lessons drawn will inform discussions on scaling up to other settings experiencing the same problems. Copyright © 2016 John Wiley & Sons, Ltd.