Prevention of Diabetes in NOD Mice by Repeated Exposures to a Contact Allergen Inducing a Sub-Clinical Dermatitis

BACKGROUND: Type 1 diabetes is an autoimmune disease, while allergic contact dermatitis although immune mediated, is considered an exposure driven disease that develops due to epicutaneous contact with reactive low-molecular chemicals. The objective of the present study was to experimentally study the effect of contact allergens on the development of diabetes in NOD mice. As the link between contact allergy and diabetes is yet unexplained we also examined the effect of provocation with allergens on Natural Killer T (NKT) cells, since involvement of NKT cells could suggest an innate connection between the two diseases. METHOD: NOD mice 4 weeks of age were exposed, on the ears, to two allergens, p-phenylenediamine and 2,4-dinitrochlorobenzene respectively, to investigate the diabetes development. The mice were followed for a maximum of 32 weeks, and they were either repeatedly exposed to the allergens or only sensitized a week after arrival. The stimulation of NKT cells by the two allergens were additionally studied in C57BL/6 mice. The mice were sensitized and two weeks later provocated with the allergens. The mice were subsequently euthanized at different time points after the provocation. RESULTS: It was found that repeated application of p-phenylenediamine reduced the incidence of diabetes compared to application with water (47% vs. 93%, P = 0.004). Moreover it was shown that in C57BL/6 mice both allergens resulted in a slight increment in the quantity of NKT cells in the liver. Application of the allergens at the same time resulted in an increased number of NKT cells in the draining auricular lymph node, and the increase appeared to be somewhat allergen specific as the accumulation was stronger for p-phenylenediamine. CONCLUSION: The study showed that repeated topical application on the ears with a contact allergen could prevent the development of diabetes in NOD mice. The contact allergens gave a non-visible, sub-clinical dermatitis on the application site. The preventive effect on diabetes may be due to stimulation of peripheral NKT cells, as shown for provocation with p-phenylenediamine in the C57BL/6 mouse. This epicutaneous procedure may lead to new strategies in prevention of type 1 diabetes in humans

Beneficial autoimmunity at body surfaces – immune surveillance and rapid type 2 immunity regulate tissue homeostasis and cancer

Epithelial cells line body surface tissues and provide a physicochemical barrier to the external environment. Frequent microbial and non-microbial challenges such as those imposed by mechanical disruption, injury or exposure to noxious environmental substances including chemicals, carcinogens, ultraviolet-irradiation or toxins cause activation of epithelial cells with release of cytokines and chemokines as well as alterations in the expression of cell surface ligands. Such display of epithelial stress is rapidly sensed by tissue resident immunocytes, which can directly interact with self-moieties on epithelial cells and initiate both local and systemic immune responses. Epithelial cells are thus key drivers of immune surveillance at body surface tissues. However, epithelial cells have a propensity to drive type 2 immunity (rather than type 1) upon non-invasive challenge or stress – a type of immunity whose regulation and function still remain enigmatic. Here we review the induction and possible role of type 2 immunity in epithelial tissues and propose that rapid immune surveillance and type 2 immunity are key regulators of tissue homeostasis and carcinogenesis

A clinically relevant sheep model of orthotopic heart transplantation 24 h after donor brainstem death

BACKGROUND: Heart transplantation (HTx) from brainstem dead (BSD) donors is the gold-standard therapy for severe/end-stage cardiac disease, but is limited by a global donor heart shortage. Consequently, innovative solutions to increase donor heart availability and utilisation are rapidly expanding. Clinically relevant preclinical models are essential for evaluating interventions for human translation, yet few exist that accurately mimic all key HTx components, incorporating injuries beginning in the donor, through to the recipient. To enable future assessment of novel perfusion technologies in our research program, we thus aimed to develop a clinically relevant sheep model of HTx following 24 h of donor BSD. METHODS: BSD donors (vs. sham neurological injury, 4/group) were hemodynamically supported and monitored for 24 h, followed by heart preservation with cold static storage. Bicaval orthotopic HTx was performed in matched recipients, who were weaned from cardiopulmonary bypass (CPB), and monitored for 6 h. Donor and recipient blood were assayed for inflammatory and cardiac injury markers, and cardiac function was assessed using echocardiography. Repeated measurements between the two different groups during the study observation period were assessed by mixed ANOVA for repeated measures. RESULTS: Brainstem death caused an immediate catecholaminergic hemodynamic response (mean arterial pressure, p = 0.09), systemic inflammation (IL-6 - p = 0.025, IL-8 - p = 0.002) and cardiac injury (cardiac troponin I, p = 0.048), requiring vasopressor support (vasopressor dependency index, VDI, p = 0.023), with normalisation of biomarkers and physiology over 24 h. All hearts were weaned from CPB and monitored for 6 h post-HTx, except one (sham) recipient that died 2 h post-HTx. Hemodynamic (VDI - p = 0.592, heart rate - p = 0.747) and metabolic (blood lactate, p = 0.546) parameters post-HTx were comparable between groups, despite the observed physiological perturbations that occurred during donor BSD. All p values denote interaction among groups and time in the ANOVA for repeated measures. CONCLUSIONS: We have successfully developed an ovine HTx model following 24 h of donor BSD. After 6 h of critical care management post-HTx, there were no differences between groups, despite evident hemodynamic perturbations, systemic inflammation, and cardiac injury observed during donor BSD. This preclinical model provides a platform for critical assessment of injury development pre- and post-HTx, and novel therapeutic evaluation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40635-021-00425-4

Shallow marine syn-rift sedimentation: Middle Jurassic Pelion Formation, Jameson Land, East Greenland

The Middle Jurassic Pelion Formation – Fossilbjerget Formation couplet of Jameson Land, East Greenland, is a well-exposed example of the Middle Jurassic inshore–offshore successions characteristic of the rifted seaways in the Northwest European – North Atlantic region. Early Jurassic deposition took place under relatively quiet tectonic conditions following Late Permian – earliest Triassic and Early Triassic rift phases and the Lower Jurassic stratal package shows an overall layer-cake geometry. A long-term extensional phase was initiated in Middle Jurassic (Late Bajocian) time, culminated in the Late Jurassic (Kimmeridgian–Volgian), and petered out in the earliest Cretaceous (Valanginian). The Upper Bajocian – Middle Callovian early-rift succession comprises shallow marine sandstones of the Pelion Formation and correlative offshore siltstones of the Fossilbjerget Formation. Deposition was initiated by southwards progradation of shallow marine sands of the Pelion Formation in the Late Bajocian followed by major backstepping in Bathonian–Callovian times and drowning of the sandy depositional system in the Middle–Late Callovian. Six facies associations are recognised in the Pelion–Fossilbjerget couplet, representing estuarine, shoreface, offshore transition zone and offshore environments. The north–southtrending axis of the Jameson Land Basin had a low inclination, and deposition was sensitive to even small changes in relative sea level which caused the shorelines to advance or retreat over tens to several hundreds of kilometres. Eight composite sequences, termed P1–P8, are recognised and are subdivided into a total of 28 depositional sequences. The duration of the two orders of sequences was about 1–2 Ma and 360,000 years, respectively. The Upper Bajocian P1–2 sequences include the most basinally positioned shallow marine sandstones, deposited during major sealevel lowstands. The lowstands were terminated by significant marine flooding events, during which sandstone deposition was restricted to northern, more proximal parts of the basin. The Upper Bajocian – Middle Bathonian P3–4 sequences show an overall progradational stacking pattern. The sequence boundary at the top of P4 marks a significant shift in stacking pattern, and the Upper Bathonian – Middle Callovian P5–8 sequences show large-scale backstepping, terminating in a widespread condensed succession at the distal, southern end of the basin. The largescale backstepping was governed by combined tectonically-induced subsidence, reflecting increased rates of extension, and eustatic sea-level rise. The depositional trends of the Pelion Formation – Fossilbjerget Formation couplet provide a well-exposed analogue to contemporaneous subsurface deposits which form major hydrocarbon reservoirs on the west Norway shelf, and in the Northern North Sea