Search

The first-in-human clinical trial of the CD28-specific monoclonal antibody (mAb) TGN1412 resulted in a life-threatening cytokine release syndrome. Although TGN1412 was designed as IgG4, known for weak Fc:Fcγ receptor (FcγR) interactions, these interactions contributed to TGN1412-induced T-cell activation. Using cell lines (TFs) expressing human FcγRI, -IIa, -IIb, or -III, we show that TGN1412 and TGN1412 as IgG1 and IgG2 are bound by FcγRs as it can be deduced from literature. However, upon coculture of TGN1412-decorated T cells with TFs or human primary blood cells, we observed that binding capacities by FcγRs do not correlate with the strength of the mediated effector function. FcγRIIa and FcγRIIb, showing no or very minor binding to TGN1412, mediated strongest T cell proliferation, while high-affinity FcγRI, exhibiting strong TGN1412 binding, mediated hardly any T-cell proliferation. These findings are of biological relevance because we show that FcγRI binds TGN1412, thus prevents binding to FcγRIIa or FcγRIIb, and consequently disables T-cell proliferation. In line with this, FcγRI- FcγRII+ but not FcγRI+ FcγRII+ monocytes mediate TGN1412-induced T-cell proliferation. Collectively, by using TGN1412 as example, our results indicate that binding of monomeric IgG subclasses does not predict the FcγR-mediated effector function, which has major implications for the design of therapeutic mAbs.

Human cytomegalovirus (HCMV) is endowed with multiple highly sophisticated immune evasion strategies. This includes the evasion from antibody mediated immune control by counteracting host Fc-gamma receptor (FcγR) mediated immune control mechanisms such as antibody-dependent cellular cytotoxicity (ADCC). We have previously shown that HCMV avoids FcγR activation by concomitant expression of the viral Fc-gamma-binding glycoproteins (vFcγRs) gp34 and gp68. We now show that gp34 and gp68 bind IgG simultaneously at topologically different Fcγ sites and achieve efficient antagonization of host FcγR activation by distinct but synergizing mechanisms. While gp34 enhances immune complex internalization, gp68 acts as inhibitor of host FcγR binding to immune complexes. In doing so, gp68 induces Fcγ accessibility to gp34 and simultaneously limits host FcγR recognition. The synergy of gp34 and gp68 is compelled by the interfering influence of excessive non-immune IgG ligands and highlights conformational changes within the IgG globular chains critical for antibody effector function., eLife digest Human cytomegalovirus is a type of herpes virus that rarely causes symptoms in healthy people but can cause serious complications in unborn babies and in people with compromised immune systems, such as transplant recipients. The virus has found ways to successfully evade the immune system, and once infected, the body retains the virus for life. It deploys an arsenal of proteins that bind to antibodies, specialized proteins the immune system uses to flag virus-infected cells for destruction. This prevents certain cells of the immune system, the natural killer cells, from recognizing and destroying virus-infected cells. These immune-evading proteins are called viral Fc-gamma receptors, or vFcγRs. While it has been previously shown that these receptors are able to evade the immune system, it remained unknown how exactly they prevent natural killer cells from recognizing infected cells. Now, Kolb et al. show that the cytomegalovirus deploys two vFcγRs called gp34 and gp68, which work together to block natural killer cells. The latter reduces the ability of natural killer cells to bind to antibodies on cytomegalovirus-infected cells. This paves the way for gp34 to pull virus proteins from the surface of the infected cell, making them inaccessible to the immune system. Neither protein fully protects virus-infected cells on its own, but together they are highly effective. The experiments reveal further details about how cytomegalovirus uses two defense mechanisms simultaneously to outmaneuver the immune system. Understanding this two-part viral evasion system may help scientists to develop vaccines or new treatments that can protect vulnerable people from diseases caused by the cytomegalovirus.

Lower respiratory tract infections, such as infections caused by influenza A viruses, are a constant threat for public health. Antivirals are indispensable to control disease caused by epidemic as well as pandemic influenza A. We developed a novel anti-influenza A virus approach based on an engineered single-domain antibody (VHH) construct that can selectively recruit innate immune cells to the sites of virus replication. This protective construct comprises two VHHs. One VHH binds with nanomolar affinity to the conserved influenza A matrix protein 2 (M2) ectodomain (M2e). Co-crystal structure analysis revealed that the complementarity determining regions 2 and 3 of this VHH embrace M2e. The second selected VHH specifically binds to the mouse Fc gamma Receptor IV (Fc gamma RIV) and was genetically fused to the M2e-specific VHH, which resulted in a bi-specific VHH-based construct that could be efficiently expressed in Pichia pastoris. In the presence of M2 expressing or influenza A virus-infected target cells, this single domain antibody construct selectively activated the mouse Fc gamma RIV. Moreover, intranasal delivery of this bispecific Fc gamma RIV-engaging VHH construct protected wild type but not Fc gamma RIV-/- mice against challenge with an H3N2 influenza virus. These results provide proof of concept that VHHs directed against a surface exposed viral antigen can be readily armed with effector functions that trigger protective antiviral activity beyond direct virus neutralization.

The constant region of IgG antibodies mediates antiviral activities upon engaging host Fcγ receptors (FcγRs) expressed by a variety of immune cells, such as antibody-dependent cellullar cytotoxcity (ADCC) executed by natural killer (NK)cells. Human cytomegalovirus (HCMV) is unique among viruses by encoding also an array of several Fcγ-binding glycoproteins with cell surface disposition and concomitant incorporation into the virion. Evidence is increasing that the virus-encoded Fcγ receptors differ in their Fcγ binding mode but effectively operate as adversaries of host FcγRs since they are able to prevent IgG-mediated triggering of activating host FcγRs, i.e., FcγRI, FcγRIIA, and FcγRIIIA. Here we discuss virus-encoded FcγRs as the first known HCMV inhibitors of IgG-mediated immunity which could account for the limited efficacy of HCMV hyperimmune globulin in clinical settings. A better understanding of their molecular mode of action opens up new perspectives for improving IgG therapies against HCMV disease. DFG through He 2,526/6–2 European Commission through QLRT-2001–01112 European Commission through MRTN-CT-2005–019248 Helmholtz Association through VISTRIE VH-VI-242 UCR::Vicerrectoría de Docencia::Salud::Facultad de Microbiología

communication skills represent an essential component of clinical competence. In the field of pediatrics, communication between physicians and patients' parents is characterized by particular difficulties. To investigate the effects of a parent-physician communication skills training program on OSCE performance and self-efficacy in a group control design.parallel to their daily work in the outpatient department, intervention-group experienced clinicians in practice (n=14) participated in a communication training with standardized parents. Control-group physicians (n=14) did not receive any training beyond their daily work. Performance was assessed by independent video ratings of an OSCE. Both groups rated their self-efficacy prior to and following training.regarding OSCE performance, the intervention group demonstrated superior skills in building relationships with parents (p.024) and tended to perform better in exploring parents' problems (p.081). The communication training program led to significant improvement in self-efficacy with respect to the specific training objectives in the intervention group (p.046).even in physicians with considerable experience, structured communication training with standardized parents leads to significant improvement in OSCE performance and self-efficacy. PRACTISE IMPLICATIONS: briefness and tight structure make the presented communication training program applicable even for experienced physicians in daily clinical practice.

OBJECTIVE To describe the lymphatic vessel density and to determine the functional and prognostic significance of tumoral lymphatic vessels in upper tract urothelial carcinoma (UTUC). PATIENTS AND METHODS The study included 65 patients who had a radical nephroureterectomy (RNU) for UTUC between 1997 and 2004. All pathological slides were re-evaluated by one reference pathologist and clinical data were reviewed. Lymphatic endothelial cells (LECs) were stained immunohistochemically using D2-40. The lymphatic vessel density (LVD) was described in representative intratumoral (ITLVD), peritumoral (PTLVD) and non-tumoral (NTLVD) areas. Random samples were selected for double-immunostaining with D2-40 and CD-34 (to distinguish blood and lymphatic vessels) and the proliferation marker Ki-67 to detect lymphangiogenesis. The primary outcome measures were disease-specific survival (DSS) and disease recurrence (urothelial and/or distant). RESULTS The median (interquartile range) PTLVD was 4.0 (3.0–6.3), and significantly higher than that for ITLVD, of 0.3 (0–1.7) (P

Peer-assisted learning (PAL) has become a well-accepted teaching method within medical education. However, descriptions of on-ward PAL programmes are rare. We introduced a PAL programme with a focus on clinical competencies on internal medicine wards.To assess the effects of an on-ward PAL programme on self-assessed clinical competencies.A total of 168 medical students were randomly assigned to one of the seven intervention wards or one of the seven control wards. During their 5-week ward-placement, the intervention group (IG; n = 88) received 10 patient-centred tutorials lead by final year tutors: (I) history taking, (II) physical examination, (III) blood withdrawal, (IV) infusion, (V) patient files, (VI and VII) ECG, (VIII-X) chart rounds. The control group (CG; n = 80) did not take part in the PAL programme. Clinical competencies were self-assessed pre- and post-intervention.For five of the ten assessed clinical competencies, increases in self-confidence ratings were significantly higher in the IG as compared to CG.RESULTS provide preliminary evidence to suggest that PAL programmes on internal medicine wards and with final year students as peer tutors may represent a valuable additional tool within medical clerkships. However, the findings must be confirmed and clarified in further research.

In a laboratory experiment, we compare the relative impact of two possible determinants of intuitive evaluative judgments: ease of recognition and total value of prior encounters with a target. Participants encode daily return values of shares on the stock market while watching videotaped ads on the computer screen. This dual-task procedure ensures that participants subsequently lack relevant event memories and thus have to rely on their intuition when evaluating the targets. In the presentation, the share appearing least frequently produced the highest sum of returns. In contrast, the share appearing most frequently produced the lowest sum of returns. Evaluative judgments reveal a preference for the share with the highest sum of returns, although, as evident from recognition latencies, it was the one that was more difficult to recognize. The results provide evidence for the value-account model of implicit attitude formation ( Betsch, Plessner, Schwieren, & Gütig, 2001 ), which predicts that intuitive evaluative judgments reflect the total value of prior encounters.

Background: Learning on the ward as a practice-oriented preparation for the future workplace plays a crucial role in the medical education of future physicians. However, students’ ward internship is partially problematic due to condensed workflows on the ward and the high workload of supervising physicians. For the first time in a German-speaking setting, students’ expectations and concerns about their internship on the ward are examined in a qualitative analysis regarding their internal medicine rotation within clinical medical education. Methods: Of a total of 168 medical students in their 6th semester at the Medical Faculty of Heidelberg, 28 students (m=8, f=20, Ø 23.6 years) took part in focus group interviews 3 to 5 days prior to their internship on the internal medicine ward within their clinical internal medicine rotation. Students were divided into four different focus groups. The protocols were transcribed and a content analysis was conducted based on grounded theory. Results: We gathered a total of 489 relevant individual statements. The students hope for a successful integration within the ward team, reliable and supportive supervisors and supervision in small groups. They expect to face the most common diseases, to train the most important medical skills, to assume full responsibility for their own patients and to acquire their own medical identity. The students fear an insufficient time frame to achieve their aims. They are also concerned they will have too little contact with patients and inadequate supervision. Conclusion: For the development and standardization of effective student internships, the greatest relevance should be attributed to guidance and supervision by professionally trained and well-prepared medical teachers, entailing a significant increase in staff and costs. A structural framework is required in order to transfer the responsibility for the treatment of patients to the students at an early stage in medical education and in a longitudinal manner. The data suggest that the development and establishment of guidelines for medical teachers associated with clearly defined learning objectives for the students’ internships are urgently needed. Based on our findings, we provide first recommendations and suggest possible solutions.

Peer-assisted learning is a common feature of medical education and proves to be highly effective in many areas. So far there have been no reports on on-ward tutorials held by final-year students to promote the clinical competencies of medical undergraduates. The aim of the current investigation was to both evaluate undergraduate and tutor acceptance of a peer-assisted learning programme performed by final-year students and to examine the perception of the role of final-year students within an intervention and a control group.88 medical students (51 female, 37 male; mean age 23.6 years) were assigned to one of seven intervention wards where 10 student-led, patient-centred tutorials were held. 80 medical students (58 female, 22 male; mean age 23.3 years) were assigned to one of seven control wards. Tutorials were held by 14 volunteer final-year student tutors (8 female, 6 male; mean age 26.2 years). Acceptance of the peer-assisted learning programme and ratings of the role of final-year students were evaluated on a six-point Likert scale (ranging from 1 = very good to 6 = unsatisfactory and 1 = completely agree to 6 = completely disagree).Medical undergraduates rated student-led tutorials and tutors rated the introductory course and the complete programme as extremely positive (1.14 +/- 0.36 to 2.34 +/- 1.15). The role of final-year students as role model, teacher, contact person and integrator was rated as being significantly more relevant by students in the intervention group than by those in the control group (p0.02 in each case).Patient-centred, student-led on-ward tutorials designed to promote undergraduate clinical competencies received extremely positive ratings from both medical undergraduates and tutors and enable final-year tutors to assume important roles.

Following the recent amendment to the Medical Education Act in Germany (Approbationsordnung 2002) and the abolition of the preliminary approbation for early residency (AiP), the discussion increasingly focuses on the restructuring of German post-graduate medical training. The training should include well-defined learning objectives and an educational concept with a central emphasis on communication skills training. In the German-speaking countries there has as yet been no publication of a structured training course for the improvement of communication skills in the context of post-graduate education.Jointly designed by the University of Heidelberg's Clinic of Internal Medicine and Clinic of Paediatrics, this study aimed to measure the effect of a training programme for handling problems and difficult situations arising in the communication with parents and patients. 28 paediatric residents took part in a randomised controlled trial using standardized patients and video-feedback (intervention group: N = 14; control group: N = 14). Upon completion of the study, the control group also received training and was subsequently evaluated. The training course consisted of four units, lasting 90 minutes each. Both the acceptance of the training units and the self-evaluation of communication skills in dealing with parents were subject to assessment.The participating residents acknowledged the training course to be an extremely useful tool for improving their communication skills and confidence in dealing with the parents of ill children. A pre-post comparison of self-assessed communication skills revealed a significant increase in the intervention group, but not in the control group.The structured training course presented in the current study proved highly effective and should serve as a model for a compulsory component of a post-graduate training.