An Immunologically Privileged Retinal Antigen Elicits Tolerance: Major Role for Central Selection Mechanisms

Immunologically privileged retinal antigens can serve as targets of experimental autoimmune uveitis (EAU), a model for human uveitis. The tolerance status of susceptible strains, whose target antigen is not expressed in the thymus at detectable levels, is unclear. Here, we address this issue directly by analyzing the consequences of genetic deficiency versus sufficiency of a uveitogenic retinal antigen, interphotoreceptor retinoid-binding protein (IRBP). IRBP-knockout (KO) and wild-type (WT) mice on a highly EAU-susceptible background were challenged with IRBP. The KO mice had greatly elevated responses to IRBP, an altered recognition of IRBP epitopes, and their primed T cells induced exacerbated disease in WT recipients. Ultrasensitive immunohistochemical staining visualized sparse IRBP-positive cells, undetectable by conventional assays, in thymi of WT (but not of KO) mice. IRBP message was PCR amplified from these cells after microdissection. Thymus transplantation between KO and WT hosts demonstrated that this level of expression is functionally relevant and sets the threshold of immune (and autoimmune) reactivity. Namely, KO recipients of WT thymi generated reduced IRBP-specific responses, and WT recipients of KO thymi developed enhanced responses and a highly exacerbated disease. Repertoire culling and thymus-dependent CD25+ T cells were implicated in this effect. Thus, uveitis-susceptible individuals display a detectable and functionally significant tolerance to their target antigen, in which central mechanisms play a prominent role

The neuroscience of social feelings:mechanisms of adaptive social functioning

Social feelings have conceptual and empirical connections with affect and emotion. In this review, we discuss how they relate to cognition, emotion, behavior and well-being. We examine the functional neuroanatomy and neurobiology of social feelings and their role in adaptive social functioning. Existing neuroscience literature is reviewed to identify concepts, methods and challenges that might be addressed by social feelings research. Specific topic areas highlight the influence and modulation of social feelings on interpersonal affiliation, parent-child attachments, moral sentiments, interpersonal stressors, and emotional communication. Brain regions involved in social feelings were confirmed by meta-analysis using the Neurosynth platform for large-scale, automated synthesis of functional magnetic resonance imaging data. Words that relate specifically to social feelings were identfied as potential research variables. Topical inquiries into social media behaviors, loneliness, trauma, and social sensitivity, especially with recent physical distancing for guarding public and personal health, underscored the increasing importance of social feelings for affective and second person neuroscience research with implications for brain development, physical and mental health, and lifelong adaptive functioning

Draft Guidance: Response, Restoration, and Recovery Checklist for Biologically Contaminated Facilities

The Checklist for Facility Response, Restoration, and Recovery presented in this document is principally focused on the Consequence Management Phase of a biothreat agent (i.e., Bacillus anthracis) release at a large facility, such as an airport or subway. Information in this document conforms to the National Response Plan (NRP) (DHS 2004) and the National Incident Management System (NIMS 2004). Under these two guidance documents, the personnel responsible for managing biological response and recovery efforts--that is, the decision-makers--are members of an Incident Command (IC), which is likely to transition to a Unified Command (UC) in the event of a biological warfare agent attack. A UC is used when more than one agency has incident jurisdiction or when incidents cross political jurisdictions. The location for primary, tactical-level command and management is referred to as the Incident Command Post (ICP), as described in the NRP. Thus, regardless of whether an IC or an UC is used, the responsible entities are located at an ICP. Agencies work together through designated members of the UC to establish their designated Incident Commanders at a single ICP and to establish a common set of objectives and strategies and a single Incident Action Plan. Initially during the Crisis Management Phase, the Incident Commander is likely to be the Chief of the fire department that serves the affected facility. As life-safety issues are resolved and the Crisis Management Phase shifts to the Consequence Management Phase, the work of characterization, decontamination, and facility clearance begins. There will likely be a coincident transition in organizational structure as well, and new restoration-focused groups, units, and personnel will be added as restoration needs are anticipated. Depending on the specific facility and type of incident, the responsible individual (Incident Commander or Unified Commander) within the UC during the Consequence Management Phase could be the Facility Manager, the Facility Emergency Operations Manager, or their designee. In an incident involving large-scale biological contamination, the Governor of the state would typically request, and the President of the United States would likely declare, an emergency under the Stafford Act (1974; amended 2002). The Secretary of Homeland Security would likely determine that the event is an Incident of National Significance on the basis of criteria established in Homeland Security Presidential Directive 5 (HSPD-5), ''Management of Domestic Incidents''. Incidents of National Significance are those high-impact events that require a coordinated and effective response by an appropriate combination of Federal, state, local, tribal, private-sector, and nongovernmental entities to save lives, minimize damage, and provide the basis for long-term community recovery and mitigation activities. If facility authorities request outside assistance, or if an emergency is declared under the Stafford Act, then other members of the UC could include local and state agencies as well as Federal agencies, such as the Federal Emergency Management Agency (FEMA) and the U.S. Environmental Protection Agency (USEPA). If an Incident of National Significance is declared, a Principal Federal Official will be appointed by the Department of Homeland Security (DHS) to facilitate Federal support to the UC structure. The following Checklist for Facility Response, Restoration, and Recovery presents the critical steps that would be taken by organizations involved in responding to a biological incident. It is intended for use by key decision-makers in the event that an incident occurs and steps must be taken immediately and systematically. The organizations would follow the Incident Command System (ICS). See Appendix A for more information on the ICS and how the responsible personnel identified in the checklist map into the consequence management organizational structure. The Notification and First-Response Phases are cursorily addressed in the checklist, whereas the main focus is on consequence management actions. The order of actions is generally sequential. However, depending on the specifics of an event and how the response is implemented, actions may be reordered. For example, preparing a Remediation Action Plan (RAP) is identified in the checklist as a critical step of the Remediation Phase. However, it is likely that preparation of the RAP would begin before completing all actions identified in the Characterization Phase. In addition to the actions recommended in the checklist, any emergency response conducted at a major metropolitan facility should comply with notification and response procedures established by the facility, as well as applicable procedures established by the jurisdictional responding agencies

Welcome To The Real World Balancing Practical, Legal, And Educational Issues In Implementing Industrial Sponsored Student Design Experiences

Engineering programs across the U.S. have long recognized the value of incorporating “real- world” active learning experiences into the curriculum. ABET’s EC2000 Criterion 4 further solidified the approach of the many engineering programs that offer a “real-world” team-based senior capstone design experience with its mandate that students be provided a “culminating major design experience which incorporates appropriate engineering standards and multiple realistic constraints1”. While these types of project experiences can be “created” within engineering departments, many programs have found that the most effective “real-world” experience comes from projects that are defined and sponsored by industry. Students participating in these projects have the opportunity for mentoring by industrial project managers and face an increased expectation of results and diligence similar to what they will encounter when they begin their professional careers. In addition to technical and project management experience, these students also gain valuable skills in such things as client development, structuring business relationships, and intellectual property management and rights distribution. At Michigan Technological University, both the Senior Design Program and the more extensive Enterprise Program rely heavily on the supply of these “real-world” project experiences from industry. In this model, the industry sponsor typically provides financial and technical support and becomes a “client” of sorts to the student project team. The financial and technical involvement of external project sponsors introduces a number of related issues such as project deliverables, sponsorship costs, non-disclosure requirements, publication/presentation review, and intellectual property rights. While providing a more holistic experience, the handling of these issues often presents a further challenge of balancing the primary educational mission and scope of the projects against sponsor expectations for value from their investment of effort and financial resources. Furthermore, Michigan Tech views these project experiences to be a potential IP generator through student development of new products and technologies that could then ideally be commercialized through licensing or new business start-ups. How rights to this student generated IP are negotiated then becomes a key factor in allowing for this possibility. For industrially sponsored projects, this results in an analysis, and often negotiation, of reasonable distributions of IP rights and sharing of proceeds from commercialization of that IP. This requires finding an optimum where not only the sponsor is comfortable with the investment of financial and intellectual resources but where the students also have some reasonable opportunity to benefit from the relative value that their independent creativity generates. Furthermore, as observing parties to the negotiation, students can be engaged in discussions with contract personnel on both sides about the relative value of their ideas versus the value of the experience and input that the sponsor is providing. This process can lead to a more sophisticated understanding of the relative value of ideas and the importance of commercial experience and execution than students would otherwise obtain strictly through classroom exercises

Photobiomodulation effects on head and neck squamous cell carcinoma (HNSCC) in an orthotopic animal model

Background: Photobiomodulation (PBM) has shown efficacy in preventing and treating cancer therapy-induced mucositis and dermatitis. However, there is contradictory information regarding the effect of PBM on (pre)malignant cells, which has led to questions regarding the safety of this technique. We address this issue using an orthotopic mouse model (Cal-33) with human squamous cell carcinoma of the oral cavity. Methods: Mice with actively growing orthotopic Cal-33 head and neck carcinoma tumors were divided into 4 groups: control, PBM only, radiation therapy (RT) only, and PBM + RT. We performed three experiments: (1) PBM at 660 nm, 18.4 J/cm2, and 5 RT × 4 Gy doses delivered daily; (2) PBM at 660 nm, 18.4 J/cm2, and 1 × 15 Gy RT; and (3) PBM at 660 nm + 850 nm, 45 mW/cm2, 3.4 J/cm2, and 1 × 15 Gy RT. Mice were weighed daily and tumor volumes were evaluated by IVIS. Survival time was also evaluated. Results: Animals treated with RT survived significantly longer and had significantly smaller tumor volume when compared with the control and PBM-only treatment groups. No significant differences were noted between the RT alone and PBM + RT groups in any of the experiments. Conclusion: Our results suggest that PBM at the utilized parameters does not provide protection to the tumor from the killing effects of RT

Clinical-grade multipotent adult progenitor cells durably control pathogenic T cell responses in human models of transplantation and autoimmunity

Abstract A major goal of immunotherapy remains the control of pathogenic T cell responses that drive autoimmunity and allograft rejection. Adherent progenitor cells, including mesenchymal stromal cells (MSCs) and multipotent adult progenitor cells (MAPCs), represent attractive immunomodulatory cell therapy candidates currently active in clinical trials. MAPCs can be distinguished from MSCs on the basis of cellular phenotype, size, transcriptional profile, and expansion capacity. However, despite their ongoing evaluation in autoimmune and allogeneic solid organ transplantation settings, data supporting the immune regulatory potential of clinical-grade MAPCs are limited. In this study, we used allogeneic islet transplantation as a model indication to assess the ability of clinical-grade MAPCs to control T cell responses that drive immunopathology in human autoimmune disease and allograft rejection. MAPCs suppressed T cell proliferation and Th1 and Th17 cytokine production while increasing secretion of IL-10 and were able to suppress effector functions of bona fide autoreactive T cells from individuals with type 1 diabetes mellitus, including killing of human islets. Furthermore, MAPCs favored the proliferation of regulatory T cells during homeostatic expansion driven by γ-chain cytokines and exerted a durable, yet reversible, control of T cell function. MAPC suppression required licensing and proceeded via IDO-mediated tryptophan catabolism. Therefore, the common immune modulatory characteristics of clinical-grade MAPCs shown in this study suggest that they can be regarded as an alternative source of adult progenitor cells with similar clinical usefulness to MSCs. Taken collectively, these findings may guide the successful deployment of both MSCs and MAPCs for the amelioration of human autoimmunity and allograft rejection.</jats:p