Control of pathogenic effector T-cell activities in situ by PD-L1 expression on respiratory inflammatory dendritic cells during respiratory syncytial virus infection.

Respiratory syncytial virus (RSV) infection is a leading cause of severe lower respiratory tract illness in young infants, the elderly and immunocompromised individuals. We demonstrate here that the co-inhibitory molecule programmed cell death 1 (PD-1) is selectively upregulated on T cells within the respiratory tract during both murine and human RSV infection. Importantly, the interaction of PD-1 with its ligand PD-L1 is vital to restrict the pro-inflammatory activities of lung effector T cells in situ, thereby inhibiting the development of excessive pulmonary inflammation and injury during RSV infection. We further identify that PD-L1 expression on lung inflammatory dendritic cells is critical to suppress inflammatory T-cell activities, and an interferon-STAT1-IRF1 axis is responsible for increased PD-L1 expression on lung inflammatory dendritic cells. Our findings suggest a potentially critical role of PD-L1 and PD-1 interactions in the lung for controlling host inflammatory responses and disease progression in clinical RSV infection.

Timely immunization subverts the development of peripheral nonresponsiveness and suppresses tumor development in simian virus 40 tumor antigen-transgenic mice.

Tolerance to tumor cell-expressed molecules and selection of cells that evade immune surveillance during tumor progression create effective barriers to immunotherapy. We investigated the cytotoxic T-lymphocyte response to simian virus 40 (SV40) tumor (T/t) antigen in two lineages of transgenic mice bearing the same rat insulin promoter-SV40 T/t antigen (RIP Tag) hybrid gene. RIP1-Tag2 mice, which express Tag as embryos, are tolerant to Tag, whereas RIP1-Tag4 mice, which express the transgene in pancreatic islet beta cells several weeks after birth and develop insulinomas, can be immunized to generate active Tag-specific cytotoxic T lymphocytes as determined by in vitro assays. Indeed, RIP1-Tag4 mice immunized with Tag by SV40 infection prior to the time of endogenous transgene expression also mount an effective in vivo cellular immune response to the Tag-expressing pancreatic beta cells, and Tag-induced tumor growth is significantly delayed (up to 1 year). However, after the transgene is expressed, RIP1-Tag4 mice are unable to mount a tumor-inhibiting response upon immunization, although Tag-specific cytotoxic T cells can still be demonstrated in vitro. Our data suggest that Tag-specific T cells are rendered unresponsive in vivo in RIP1-Tag4 mice and that the establishment of this unresponsiveness to Tag can be prevented by SV40 immunization only before the onset of the transgene expression. In the older, successfully immunized mouse, decreased immune surveillance and selection of cells with down-regulation of major histocompatibility complex class I expression most likely set the stage for insulinoma development.

Career counseling practices in pediatric residency training programs.

Although there has been an emphasis on career satisfaction in pediatrics and on motivators that impact on resident career selection, little attention has been directed toward the career development process in pediatric residency training. This report summarizes the results of a survey conducted of 155 pediatric residency program directors about their counseling practices. Implications of the results and recommendations are discussed to improve this process.

Functional pancreatic beta-cell line from SV40 T-antigen transgenic mouse.

Cell line IgSV195, derived from a pancreatic tumor that arose in an SV40 T-antigen transgenic mouse, retains certain morphological and physiological characteristics of pancreatic beta-cells throughout in vitro and in vivo passage. Insulin secretion is stimulated by exposure of these cells to fetal bovine serum and a combination of 3-isobutyl-1-methylxanthine and glutamine but not by concentrations of glucose in the physiological range. Insulin processing appears to be intact. Neither class I nor class II major histocompatibility complex (MHC) antigens are routinely expressed at the cell surface; however, MHC class I--but not class II--encoded gene products are detected after treatment with recombinant interferon-gamma (IFN-gamma) alone or in combination with tumor necrosis factor. Cytolysis of IgSV195 cells by SV40 T-antigen-specific H-2b-restricted lymphocytes is similarly dependent on IFN-gamma pretreatment. These results emphasize that SV40 T-antigen transgenic mice are likely sources of cell lines that retain their differentiated function in vitro. The IgSV195 cell line provides an accessible model in which to investigate the control of gene expression and function of pancreatic beta-cells.

SV40 T-antigen is a histocompatibility antigen of SV40-transgenic mice.

Although the extensive family of non-H-2 histocompatibility (H) antigens provides a formidable barrier to transplantation, the origin of their encoding genes are unknown. Recent studies have demonstrated both the linkage between H genes and retroviral sequences and the ability of integrated Moloney-murine leukemia virus to encode what is operationally defined as a non-H-2 H antigen. The experiments described in this communication reveal that skin grafts from an SV40 T-antigen transgenic C57BL/6 mouse strain are rejected by coisogenic C57BL/6 recipients with a median survival time of 49 days, which is comparable to those of many previously defined non-H-2 H antigens. The specificity of this response for SV40 T-antigen was demonstrated by the identification of SV40 T-antigen-specific cytolytic T lymphocytes and antibodies in multiply-grafted recipients. Although these cytolytic T lymphocytes could detect SV40 T-antigen on syngeneic SV40-transformed fibroblasts, they neither could be stimulated by splenic lymphocytes from T-antigen transgenics nor could they lyse lymphoblast targets from T-antigen transgenics. These observations suggest a limited tissue distribution of SV40 T-antigen in these transgenics. These results confirm the role of viral genes in the determination of non-H-2 histocompatibility antigens by the strict criteria that such antigens stimulate (1) tissue graft rejection and (2) generation of cytolytic T lymphocytes. Furthermore, they suggest that the SV40 enhancer and promoter region can target expression of SV-40 T-antigen to skin cells of transgenic animals.

Another look at career choice and learning preferences.

The learning styles and preferences of health professionals have been studied increasingly over the past decade, yet few relationships have been found between doctors' career choices and learning styles. One of the problems of relating learning styles to specialty choice is that learning style instruments measure how an individual perceives and processes information in learning situations. This study re-examines doctors' career choices utilizing a learning preference inventory which assesses how one chooses to approach a learning situation. The study results indicate that there are significant differences in doctors' approaches to learning and interacting with others among the different career specialties using a learning preference inventory. This is in contrast to previous research with Kolb's Learning Style Inventory in which learning style was not found to be related to career choice.

The impact of two teaching techniques on physicians' knowledge and performance.

The purpose of the study reported here was to compare two teaching formats, the traditional lecture and the case presentation, to determine which technique is more effective in continuing medical education (CME). Effectiveness was measured by assessing pediatricians' cognitive knowledge utilizing preinstruction and postinstruction multiple-choice tests, the physicians' performances using simulated patients, and the physicians' office records on diagnoses and treatment plans. There were differences between the two teaching techniques in regard to their impact on physicians' knowledge and their performance with patients. Physicians attending case presentation sessions were more likely to increase their cognitive knowledge than physicians attending the lecture sessions, but retention of knowledge was only slightly higher for the case presentation group than the lecture group. More simulated mothers making visits to the offices of pediatricians who had been in the case presentation group reported feeling that the physicians' plans for their children were totally or partially appropriate than did mothers visiting pediatricians from the lecture group. There were few correlations between the physicians' cognitive knowledge and their performances. Based on the findings of the study, recommendations are suggested for use in planning CME.

The impact of two educational techniques on physician knowledge, performance and patient care.

Few studies have examined change in physician performance as a result of participation in CME. In addition, there is no evidence in the literature that traditional didactic instruction is the most effective way to deliver CME. The purpose of our study was to compare two educational processes by which information is conferred (traditional didactic lecture and case study format) to determine their impact on physician cognitive knowledge, performance, and patient care.

Teaching in the clinical setting: factors influencing residents' perceptions, confidence and behaviour.

Because residents are expected to assume a significant share of the teaching responsibilities of peers and students, the authors surveyed first-, second- and third-year paediatric residents at the Children's Hospital National Medical Center in July 1979 to examine those factors influencing their perceptions, confidence and behaviour with regard to teaching. The experimental group received 8 hours of instruction on teaching and learning, which included workshops and feedback sessions. The results indicate that a limited amount of formal instruction in teaching can effect a change in the teaching attitudes and behaviour of residents in addition to their level of confidence and the way in which teachers, students and peers evaluate them.

Giving information for a life-threatening diagnosis. Parents' and oncologists' perceptions.

We surveyed pediatric oncologists throughout the United States and families of children with acute lymphocytic leukemia diagnosed between 1977 and 1980 at Children's Hospital National Medical Center, Washington, DC, to determine what information is perceived by both parents and physicians as essential to convey during the initial presentation of a life-threatening diagnosis. Both groups considered the following topics critical for discussion at the initial conference: diagnosis and prognosis of disease, explanation of disease process, additional tests needed to confirm and/or supplement the diagnosis, immediate therapeutic plan, and the physician's availability. Additionally, both parents and physicians, with minor variations, agreed about the order in which information about the disease should be conveyed. Although acute lymphocytic leukemia was used as a model, this study suggests guidelines that could be utilized to train residents and guide physicians in crisis-counseling techniques in the presentation to parents of a diagnosis of life-threatening illness in their child.

Meeting the need for more formalized education in paediatrics.

The information explosion, the plethora of continuing medical education activities, the complexities and fragmentation of graduate and postgraduate training and the need for cost containment and faculty development all contributed to the decision to create an office of paediatric medical education (OPME) at the Children's Hospital National Medical Center. To plan and prepare strategies for this office, we surveyed all 150 moderate-to-large US paediatric programmes to elicit information about the educational organization of paediatric departments, including administration, staffing, funding, responsibilities, and level of involvement; and the current needs in paediatric medical education. The results suggest that there is a trend towards formalizing education in paediatrics. Thirty-eight per cent (33) of those responding reported OPMEs, with most (86 per cent) of the OPMEs evolving within the last decade and 50 per cent within the last five years. Respondents cited as a priority the need for better organization of medical education to improve the quality of teaching and learning and thus achieve higher quality and more cost-effective health care.

The teaching of crisis counseling skills to pediatric residents: a one-year study.

Pediatric residents should learn to manage family crises such as informing parents that their child has a potentially life-threatening illness. Unfortunately, few training programs prepare residents to counsel parents of a child with cancer. An experiential parent crisis counseling program has been developed at the Children's Hospital National Medical Center in Washington, DC; this program has demonstrated that pediatric residents, with limited instruction, can be taught to give bad news to parents using effective information-giving and interpersonal skills.