T cell epitope: Friend or Foe? Immunogenicity of biologics in context

Like vaccines, biologic proteins can be very immunogenic for reasons including route of administration, dose frequency and the underlying antigenicity of the therapeutic protein. Because the impact of immunogenicity can be quite severe, regulatory agencies are developing risk-based guidelines for immunogenicity screening. T cell epitopes are at the root of the immunogenicity issue. Through their presentation to T cells, they activate the process of anti-drug antibody development. Preclinical screening for T cell epitopes can be performed in silico, followed by in vitro and in vivo validation. Importantly, screening for immunogenicity is complicated by the discovery of regulatory T cell epitopes, which suggests that immunogenicity testing must now take regulatory T cells into consideration. In this review, we address the application of computational tools for preclinical immunogenicity assessment, the implication of the discovery of regulatory T cell epitopes, and experimental validation of those assessments.     

Unraveling the mechanisms for heart failure patients' beliefs about compliance

BACKGROUND: Compliance with medication, diet, and monitoring symptoms is a problem in heart failure (HF) patients. Noncompliance can lead to worsening symptoms and is associated with personal beliefs about compliance. To intervene effectively, knowledge of factors related to patients' beliefs about compliance is needed. OBJECTIVES: The aims of this study are to: (1) gain insight into patients' beliefs about compliance; (2) examine the association of demographic variables and depressive symptoms to beliefs; (3) assess compliance with medication, diet, and daily weighing; and (4) examine the association of compliance to patients' beliefs. METHODS: Nine hundred fifty-four HF patients completed questionnaires on beliefs about medication and diet; 297 patients also completed a questionnaire on beliefs about symptom monitoring. Most important barriers and benefits were assessed as well as differences in beliefs between subgroups and the association between compliance and beliefs. RESULTS: The most important barriers were diuresis during the night (57%), the taste of food (51%), and limited ability to go out (33%). A barrier related to failure to weigh daily was forgetfulness (26%). Patients with depressive symptoms and patients with a low level of HF knowledge experienced more barriers to compliance with the HF regimen. Self-reported compliance with medication was almost 99%, compliance with diet 77%, and with daily weighing 33%. CONCLUSIONS AND IMPLICATIONS: In order to improve compliance, it is important that interventions should be directed to those patients who experience more barriers to compliance, such as patients with depressive symptoms and patients with a low level of knowledge on the HF regimen. Improvement of knowledge, therefore, will remain an important issue in HF management programs.     

Autogenous bone grafting for chronic anteroinferior glenoid defects via a complete subscapularis tenotomy approach

Introduction  Open reconstruction of severe anteroinferior chronic glenoid defects via a complete subscapularis (SSC) tenotomy using a tricortical iliac crest bone grafting technique has been reported. The purpose of this study was to evaluate the clinical and radiological results in patients who underwent this procedure and to investigate the influence of the anterior approach on the structure and function of the SSC musculotendinous unit. Materials and methods  Ten patients (two women/eight men, mean age 28.7 years) underwent reconstruction of significant chronic glenoid defects in cases of recurrent shoulder instability with significant glenoid bone loss, using a tricortical autogenous iliac crest in combination with a capsulolabral repair. The patients were followed up clinically (clinical SSC tests and signs, Constant score, Rowe score, Walch-Duplay score, WOSI, MISS), by standard radiographs (true a/p, axillary and glenoid profile view), computed tomography (graft integration, inferior glenoid area) and bilateral magnetic resonance imaging [SSC tendon integrity, cross sectional area, defined muscle diameters and signal intensity analysis (ratio ISP/upper SSC and ISP/lower SSC)]. Results  After a mean follow-up of 37.9 months, the mean Constant score averaged 88.3 points, the Rowe score 89.5 points, the Walch-Duplay score 83.5 points, the MISS 80.6 points and the WOSI 82.6%. No recurrent subluxations or dislocations were observed. Clinical signs for SSC insufficiency were present in 80% of cases. Two patients had grade I and one patient grade II osteoarthritis according to Samilson and Prieto classification. CT imaging revealed a consolidated autograft in all cases with an 18.4% increase of the inferior glenoid area postoperatively (P < 0.05). No tendon ruptures were found. MR imaging revealed muscular atrophy (P < 0.05) and fatty infiltration of the SSC (P > 0.05) muscle compared to the contralateral side. Conclusion  Open reconstruction of anteroinferior chronic glenoid defects via a complete SSC tenotomy using an iliac crest bone grafting technique allows an anatomic reconstruction of the anteroinferior glenoid with good and excellent clinical results. The anterior approach may lead to atrophy and fatty infiltration of the SSC muscle despite an intact tendon. However, this did not affect the results in terms of stability.     

Circulating alloreactive T cells correlate with graft function in longstanding renal transplant recipients

Monitoring for alloreactive memory T cells after organ transplantation may allow individualization of immunosuppression. Two pathways of T cell allorecognition have been implicated in chronic graft dysfunction: Direct (recipient T cells respond to donor peptides presented by donor antigen-presenting cells) and indirect (donor peptides are processed and presented by recipient antigen-presenting cells). Previous studies have assessed these alloresponses only during the first 2 yr after kidney transplantation,so this study correlated the presence of circulating donor-reactive memory/effector T cells, primed by both pathways, in 34 longstanding living-donor renal transplant recipients using the highly sensitive IFN-gamma Elispot assay. Remarkably, 59% of patients had directly primed donor-reactive T cells, and their presence correlated directly with serum creatinine (P = 0.001) and inversely with estimated GFR (P = 0.042). Multivariate analysis revealed that hyporesponsiveness of direct, donor-specific T cells was the only variable that significantly correlated with graft function and that antidonor indirect alloreactivity was the only variable that significantly correlated with proteinuria. Interestingly, when both allorecognition pathways were considered together, patients with undetectable direct alloreactivity had better longterm graft function, independent of allosensitization by the indirect pathway. In conclusion, circulating donor-specific alloreactive T cells primed by both pathways are detectable long after transplantation and are associated with graft injury. Assessment of alloreactive memory/effector T cells might be helpful to tailor individual immunosuppression regimens for transplant recipients in the future.     

Dopaminergic modulation of auditory cortex-dependent memory consolidation through mTOR

Previous studies in the auditory cortex of Mongolian gerbils on discrimination learning of the direction of frequency-modulated tones (FMs) revealed that long-term memory formation involves activation of the dopaminergic system, activity of the protein kinase mammalian target of rapamycin (mTOR), and protein synthesis. This led to the hypothesis that the dopaminergic system might modulate memory formation via regulation of mTOR, which is implicated in translational control. Here, we report that the D1/D5 dopamine receptor agonist SKF-38393 substantially improved gerbils' FM discrimination learning when administered systemically or locally into the auditory cortex shortly before, shortly after, or 1 day before conditioning. Although acquisition performance during initial training was normal, the discrimination of FMs was enhanced during retraining performed hours or days after agonist injection compared with vehicle-injected controls. The D1/D5 receptor antagonist SCH-23390, the mTOR inhibitor rapamycin, and the protein synthesis blocker anisomycin suppressed this effect. By immunohistochemistry, D1 dopamine receptors were identified in the gerbil auditory cortex predominantly in the infragranular layers. Together, these findings suggest that in the gerbil auditory cortex dopaminergic inputs regulate mTOR-mediated, protein synthesis-dependent mechanisms, thus controlling for hours or days the consolidation of memory required for the discrimination of complex auditory stimuli.     

The effect of statins on urinary albumin excretion and glomerular filtration rate: results from both a randomized clinical trial and an observational cohort study.

BACKGROUND: Statins improve cardiovascular outcome, but less is known on the renal outcome. We, therefore, studied the relationship between the use of statins and urinary albumin excretion (UAE) and glomerular filtration rate (GFR) in two settings: a randomized controlled trial (RCT) and an observational cohort study, in which patients were included to study the impact of an elevated UAE on renal and cardiovascular prognosis. METHODS: We used data from the Prevention of REnal and Vascular ENd-stage Disease Intervention trial (PREVEND-IT) and the PREVEND cohort study. The PREVEND-IT subjects (788 with a UAE 15-300 mg/day) received pravastatin 40 mg/day vs placebo and/or fosinopril 20 mg/day vs placebo in a 2x2 factorial-RCT design. Of the 3440 cohort subjects, 469 used statins during the 4-year follow-up period. Multivariate-regression adjusted for confounding factors and the propensity score was used to estimate the relation between statin use and UAE and GFR. RESULTS: In the RCT, pravastatin did not change UAE or GFR, neither in fosinopril yes/no subgroups. In the observational cohort, statin use was associated with a rise in UAE (+12.1%), compared with statin non-use (+3.6%, P<0.001). This rise was most pronounced in those on statins prior to the first screening [+24.8% (95% CI: 11.9-39.2)], those using statins>3 years [+18.5% (7.3-30.8)] and those with >1 or >2 defined daily doses (+15.7 and +17.3%, respectively). These differences remained significant after adjustment for relevant variables and propensity score. The rise in UAE could not be attributed to a higher dose or a specific statin. GFR fell in 4 years in both statin users and non-users (4.6+/-13.5 and 2.4+/-11.2, respectively). The fall in GFR between groups was not different after adjustment (P=0.11). CONCLUSIONS: We conclude from the RCT data that statins do not lower UAE in subjects selected because of an elevated UAE instead of hyperlipidaemia. In the observational cohort study, the use of statins similarly was not associated with a fall in UAE; UAE instead increased. Statin treatment was not associated with a significant change in GFR in these subjects with only modestly impaired GFR.     

Towards mapping phenotypical traits in 18p- syndrome by array-based comparative genomic hybridisation and fluorescent in situ hybridisation

Molecular karyotyping holds the promise of improving genotype-phenotype correlations for frequent chromosome conditions such as the 18p- syndrome. In spite of more than 150 reported cases with deletions in 18p, no reliable phenotype map for the characteristic clinical findings such as mental retardation, post-natal growth retardation and typical facial features has been established yet. Here, we report on four patients with partial monosomy 18p of different sizes owing to unbalanced translocations that were thoroughly characterised clinically and by molecular karyotyping. One patient had a terminal deletion of 1.6 Mb in 18p and a trisomy of 8q24.23-qter as determined by array-based comparative genomic hybridisation and large insert clone fluorescent in situ hybridisation. In two sibs and a fourth patient, cytogenetic and molecular-cytogenetic analyses showed the terminal deletions in 18p (8.0 and 13.84 Mb, respectively) to be accompanied by partial trisomies of 20p. Literature analyses of typical phenotypic features of 18p-, 8q+ and 20p+ syndromes allowed the attribution of clinical findings in our patients to the respective chromosomal aberration. Based on these data, we propose a phenotype map for several clinical features of the 18p- syndrome: Round face was tentatively mapped to the distal 1.6 Mb of 18p; post-natal growth retardation and seizures to the distal 8 Mb and ptosis and short neck to the proximal half of 18p.