Constitutive Expression of CCL22 Is Mediated by T Cell-Derived GM-CSF.

CCL22 is a key mediator of leukocyte trafficking in inflammatory immune responses, allergy, and cancer. It acts by attracting regulatory T cells and Th2 cells via their receptor CCR type 4 (CCR4). Beyond its role in inflammation, CCL22 is constitutively expressed at high levels in lymphoid organs during homeostasis, where it controls immunity by recruiting regulatory T cells to dendritic cells (DCs). In this study, we aimed to identify the mechanisms responsible for constitutive CCL22 expression. We confirmed that CD11c+ DCs are the exclusive producers of CCL22 in secondary lymphatic organs during homeostasis. We show that in vitro both murine splenocytes and human PBMCs secrete CCL22 spontaneously without any further stimulation. Interestingly, isolated DCs alone, however, are unable to produce CCL22, but instead require T cell help. In vitro, only the coculture of DCs with T cells or their supernatants resulted in CCL22 secretion, and we identified T cell-derived GM-CSF as the major inducer of DC-derived CCL22 expression. In vivo, Rag1 -/- mice, which lack functional T cells, have low CCL22 levels in lymphoid organs, and this can be restored by adoptive transfer of wild-type T cells or administration of GM-CSF. Taken together, we uncover T cell-derived GM-CSF as a key inducer of the chemokine CCL22 and thus, to our knowledge, identify a novel role for this cytokine as a central regulator of immunity in lymphatic organs. This knowledge could contribute to the development of new therapeutic interventions in cancer and autoimmunity.

Immunostimulatory RNA blocks suppression by regulatory T cells.

The role of immune suppression by regulatory T (Treg) cells in the maintenance of immune homeostasis is well established. However, little is known about how Treg cell function is inhibited on viral infection to allow the development of a protective immune response. As viral RNA is a crucial mediator for activation of antiviral immunity, we examined the effects of immunostimulatory RNA and infection with RNA viruses on Treg cell function. We show that synthetic RNA oligonucleotides potently inhibit Treg cell-induced suppression in a sequence-dependent manner. This effect is entirely dependent on TLR7 activation of APCs and subsequent IL-6 production. In addition, stimulation with the RNA viruses encephalomyocarditis virus and Sendai virus that specifically activate the RNA-sensing helicases melanoma differentiation-associated gene 5 (MDA-5) and retinoic acid-inducible gene I (RIG-I) also blocks Treg cell function. Interestingly, this effect is seen even in the absence of APCs. Consistent with this, both Treg and T effector cells express RIG-I and MDA-5. Using MDA-5-deficient mice, we demonstrate that the loss of Treg cell function on infection with encephalomyocarditis virus is strictly dependent on MDA-5 expression by Treg cells. Thus, we show in this study for the first time that activation of a RIG-I-like helicase on Treg cells blocks their suppressive function.

Impact of angiotensin-converting enzyme-inhibitors and angiotensin receptor blockers on long-term outcome of catheter ablation for atrial fibrillation.

AIMS: We hypothesized that modulation of the renin-angiotensin-aldosterone system (RAAS) improves success following catheter ablation for atrial fibrillation (AF). METHODS AND RESULTS: We examined a prospective registry of consecutive patients undergoing catheter ablation of paroxysmal or persistent AF between November 2004 and December 2008. Patients were divided based on whether they were taking RAAS modulators at the time of their first procedure and examined on an intention to treat basis. There were 419 patients (222 paroxysmal and 197 persistent AF) who underwent 1.8 ± 0.9 procedures. Median follow-up from the last procedure was 1.7 (range 0.9-5.0) years. There were 142 patients on RAAS modulators; they were older, more likely to suffer from hypertension, diabetes, coronary disease, or left ventricular impairment. Overall, sinus rhythm was maintained in 73.2% of those taking RAAS modulators vs. 77.6% of those taking none (P = 0.304). Multivariate analysis showed no impact of RAAS modulators [hazard ratios (HR): 1.97, CI: 0.56-6.89, P = 0.290] but also no effect of hypertension, ischaemic heart disease, left ventricular impairment, or diabetes that should have confounded results (persistent AF was found to predict failure; HR: 0.34, CI: 0.14-0.84, P = 0.020). Subgroup analysis of patients with risk factors for developing AF (hypertension, coronary artery disease, left ventricular impairment, or diabetes) found no benefit in this context, with sinus rhythm maintained in 73.2% of those taking RAAS modulators compared with 69.9% of those taking none (P = 0.574). CONCLUSION: Modulation of the RAAS does not appear to affect maintenance of sinus rhythm following catheter ablation of AF.

Targeting CpG oligonucleotides to the lymph node by nanoparticles elicits efficient antitumoral immunity.

Viral nucleic acids are recognized by specific pattern-recognition receptors of the Toll-like and RIG-I-like receptor families. Synthetic DNA and RNA oligonucleotides can activate the immune system through these receptors and potentiate Ab and CD8 cytotoxic responses to Ags. Systemic application of immunostimulatory oligonucleotides however also results in a generalized, non-Ag-specific stimulation of the immune system. In this study, we have dissociated the induction of an Ag-specific response from the systemic immune activation generally associated with immunostimulatory oligonucleotides. Delivery of CpG oligodeoxynucleotides that bind TLR9 by cationized gelatin-based nanoparticles potentiates the in vivo generation of an Ag-specific cytotoxic T cell and Ab response. Furthermore, immunization with CpG-loaded nanoparticles induces a protective antitumoral response in a murine model of melanoma. The systemic release of proinflammatory cytokines and widespread immunostimulation associated with free CpG is however completely abolished. In addition, we show that gelatin nanoparticle formulation prevents the destruction of lymphoid follicles mediated by CpG. Nanoparticle-delivered CpG, in contrast to free CpG, are selectively targeted to APCs in the lymph nodes where they mediate local immune stimulation. We describe a novel strategy to target immunostimulatory oligonucleotides to the initiation site of the immune response while at the same time protecting from an indiscriminate and generalized activation of the immune system.

CCL22 controls immunity by promoting regulatory T cell communication with dendritic cells in lymph nodes.

Chemokines have crucial roles in organ development and orchestration of leukocyte migration. The chemokine CCL22 is expressed constitutively at high levels in the lymph node, but the functional significance of this expression is so far unknown. Studying a newly established CCL22-deficient mouse, we demonstrate that CCL22 expression by dendritic cells (DCs) promotes the formation of cell-cell contacts and interaction with regulatory T cells (T reg) through their CCR4 receptor. Vaccination of CCL22-deficient mice led to excessive T cell responses that were also observed when wild-type mice were vaccinated using CCL22-deficient DCs. Tumor-bearing mice with CCL22 deficiency showed prolonged survival upon vaccination, and further, CCL22-deficient mice had increased susceptibility to inflammatory disease. In conclusion, we identify the CCL22-CCR4 axis as an immune checkpoint that is crucial for the control of T cell immunity.

Simulating the physician as healthcare manager: An innovative course to train for the manager role.

INTRODUCTION: During their formal studies medical students acquire extensive medical expertise. However, the medical profession demands additional competencies, such as those involved in efficient resource allocation, business administration, development, organization, and process management in the healthcare system. At present students are not sufficiently prepared for the physician's role as manager. In response, we designed the seminar course, MeCuM-SiGma, to impart basic knowledge about healthcare policy and management to students of medicine. This project report describes our teaching strategies and the initial evaluation of this educational project. PROJECT DESCRIPTION: In this semester-long, seminar course introduced in 2010, medical students gather experience with the competencies mentioned above as well as learn basic management skills. The course is offered each winter semester, and students sign up to attend voluntarily; course coordination and organization is done on a voluntary basis by physicians and employees of the Mentoring Office (MeCuM-Mentor) at the Medical School of the Ludwig Maximilian University (LMU) in Munich, Germany. The course is open to all students enrolled at the two medical schools in Munich. During the first part of this elective, students learn about the basic principles of the German political and healthcare systems in case-based, problem-based tutorials led by trained tutors and in lectures held by experts. In the second part of the course students take on the roles of the University Hospital's executive board of directors and supervisory board to work on an existing hospital project as a group within the scope of a simulation. This phase of the course is accompanied by workshops conducted in cooperation with university-based and off-campus partners that address the procedural learning objectives (teamwork, project management, negotiation strategies, etc.). A suitable, authentic issue currently facing the hospital is selected in advance by the course organizers in coordination with the hospital's executive board. Students then work on this issue in the third and final phase of the course under the supervision of tutors and with assistance from hospital employees. At the end of the course the students formally present the results of their work to the hospital's executive and supervisory boards. RESULTS: The course undergoes written student evaluation, a round of oral feedback, evaluation of the final projects, and feedback from the hospital's executive and supervisory boards. All attendees to date have reported a substantial gain in general knowledge and increased knowledge about the healthcare system, and rate the relevance of the course as being high. The majority felt the content was important for their future practice of medicine. Overall, students evaluated the course very positively [overall rating on a six-point grading scale (1=excellent; 6=unsatisfactory): 1.28 (mean)±0.45 (standard deviation)]. DISCUSSION: The importance of the physician's role as manager in medical organizations and as a guiding force in the healthcare system is neglected in medical degree programs. Our seminar course attempts to address this shortcoming, is the object of great interest and receives positive evaluations from seminar participants, our cooperative partners and the executive and supervisory boards of the University Hospital in Munich.

Characteristics of mentoring relationships formed by medical students and faculty.

BACKGROUND: Little is known about the characteristics of mentoring relationships formed between faculty and medical students. Individual mentoring relationships of clinical medical students at Munich Medical School were characterized quantitatively and qualitatively. METHODS: All students signing up for the mentoring program responded to a questionnaire on their expectations (n = 534). Mentees were asked to give feedback after each of their one-on-one meetings (n = 203). A detailed analysis of the overall mentoring process and its characteristics was performed. For qualitative text analysis, free-text items were analyzed and categorized by two investigators. Quantitative analysis was performed using descriptive statistics and Wilcoxon-test to assess differences in grades between students with and without mentors. RESULTS: High-performing students were significantly more likely to participate in the mentoring program (p<0.001). Topics primarily discussed include the mentee's personal goals (65.5%), career planning (59.6%), and experiences abroad (57.6%). Mentees mostly perceived their mentors as counselors (88.9%), providers of ideas (85.0%), and role models (73.3%). Mentees emphasized the positive impact of the mentoring relationship on career planning (77.2%) and research (75.0%). CONCLUSIONS: Medical students with strong academic performance as defined by their grades are more likely to participate in formal mentoring programs. Mentoring relationships between faculty and medical students are perceived as a mutually satisfying and effective instrument for key issues in medical students' professional development. PRACTICAL IMPLICATIONS: Mentoring relationships are a highly effective means of enhancing the bidirectional flow of information between faculty and medical students. A mentoring program can thus establish a feedback loop enabling the educational institution to swiftly identify and address issues of medical students.

A Novel Large-scale Mentoring Program for Medical Students based on a Quantitative and Qualitative Needs Analysis.

PURPOSE: Mentoring plays an important role in students' performance and career. The authors of this study assessed the need for mentoring among medical students and established a novel large-scale mentoring program at Ludwig-Maximilians-University (LMU) Munich School of Medicine. METHODS: Needs assessment was conducted using a survey distributed to all students at the medical school (n=578 of 4,109 students, return rate 14.1%). In addition, the authors held focus groups with selected medical students (n=24) and faculty physicians (n=22). All students signing up for the individual mentoring completed a survey addressing their expectations (n=534). RESULTS: Needs assessment revealed that 83% of medical students expressed overall satisfaction with the teaching at LMU. In contrast, only 36.5% were satisfied with how the faculty supports their individual professional development and 86% of students voiced a desire for more personal and professional support. When asked to define the role of a mentor, 55.6% "very much" wanted their mentors to act as counselors, arrange contacts for them (36.4%), and provide ideas for professional development (28.1%). Topics that future mentees "very much" wished to discuss included research (56.6%), final year electives (55.8%) and experiences abroad (45.5%). CONCLUSIONS: Based on the strong desire for mentoring among medical students, the authors developed a novel two-tiered system that introduces one-to-one mentoring for students in their clinical years and offers society-based peer mentoring for pre-clinical students. One year after launching the program, more than 300 clinical students had experienced one-to-one mentoring and 1,503 students and physicians were involved in peer mentoring societies.