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Abraham Flexner's 1910 report on medical education is widely regarded as a watershed moment in the history of modern medicine in the US and beyond. Most commentators focus on its administrative and managerial impact, despite Flexner dedicating a sizeable portion of his report to a theoretical account of the kind of medicine that he seeks to implement. Close attention to these sections reveals a surprisingly coherent account of medicine that, based on a Deweyan Pragmatist philosophy of science, unites scientific investigator and medical practitioner in a new experimental paradigm of science. Flexner can develop an account that goes beyond a mere epistemic redefinition of medicine, providing the profession with a social, cultural, and ethical identity that avails itself of the extremely wide purview that Dewey granted to modern science. Due to the subsequent narrowing of philosophy of science to a delimited academic subdiscipline, these broad Pragmatist philosophical commitments at the roots of Flexner's scientific medicine remained a largely unexplored intellectual legacy. [ABSTRACT FROM AUTHOR]

Abstract: Increasing numbers of elderly transplant recipients and a growing demand for organs from older donors impose pressing challenges on transplantation medicine. Continuous and complex modifications of the immune system in parallel to aging have a major impact on transplant outcome and organ quality. Both, altered alloimmune responses and increased immunogenicity of organs present risk factors for inferior patient and graft survival. Moreover, a growing body of knowledge on age-dependent modifications of allorecognition and alloimmune responses may require age-adapted immunosuppression and organ allocation. Here, we summarize relevant aspects of immunosenescence and their possible clinical impact on organ transplantation. [Copyright &y& Elsevier]

Background Given their unique capacity for antigen uptake, processing, and presentation, antigen-presenting cells (APCs) are critical for initiating and regulating innate and adaptive immune responses. We have previously shown the role of nicotinamide adenine dinucleotide (NAD+) in T-cell differentiation independently of the cytokine milieu, whereas the precise mechanisms remained unknown. Objective The objective of this study is to further dissect the mechanism of actions of NAD+ and determine the effect of APCs on NAD+-mediated T-cell activation. Methods Isolated dendritic cells and bone marrow–derived mast cells (MCs) were used to characterize the mechanisms of action of NAD+ on CD4+ T-cell fate in vitro. Furthermore, NAD+-mediated CD4+ T-cell differentiation was investigated in vivo by using wild-type C57BL/6, MC−/−, MHC class II−/−, Wiskott-Aldrich syndrome protein (WASP)−/−, 5C.C7 recombination-activating gene 2 (Rag2)−/−, and CD11b-DTR transgenic mice. Finally, we tested the physiologic effect of NAD+ on the systemic immune response in the context of Listeria monocytogenes infection. Results Our in vivo and in vitro findings indicate that after NAD+ administration, MCs exclusively promote CD4+ T-cell differentiation, both in the absence of antigen and independently of major APCs. Moreover, we found that MCs mediated CD4+ T-cell differentiation independently of MHC II and T-cell receptor signaling machinery. More importantly, although treatment with NAD+ resulted in decreased MHC II expression on CD11c+ cells, MC-mediated CD4+ T-cell differentiation rendered mice resistant to administration of lethal doses of L monocytogenes. Conclusions Collectively, our study unravels a novel cellular and molecular pathway that regulates innate and adaptive immunity through MCs exclusively and underscores the therapeutic potential of NAD+ in the context of primary immunodeficiencies and antimicrobial resistance. [ABSTRACT FROM AUTHOR]