A goal in precision medicine is to use patient-derived material to predict disease course and intervention outcomes. Here, we use mechanistic observations in a preclinical animal model to design an ex vivo platform that recreates genetic susceptibility to T-cell–mediated damage. Intestinal graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation. We found that intestinal GVHD in mice deficient in Atg16L1, an autophagy gene that is polymorphic in humans, is reversed by inhibiting necroptosis. We further show that cocultured allogeneic T cells kill Atg16L1-mutant intestinal organoids from mice, which was associated with an aberrant epithelial interferon signature. Using this information, we demonstrate that pharmacologically inhibiting necroptosis or interferon signaling protects human organoids derived from individuals harboring a common ATG16L1 variant from allogeneic T-cell attack. Our study provides a roadmap for applying findings in animal models to individualized therapy that targets affected tissues.
Linear probe measurements are used to assess the severity and extent of attachment loss in chronic periodontitis and to identify, retrospectively, sites of disease activity. The use of the probe for these purposes is based on the implicit assumption that there is a direct and predictable relationship between linear probe measurements of attachment loss and the area of cemental surface which has been denuded of periodontal ligament. The aim of this study was to test this assumption by determining the correlation between loss of attachment as expressed by probe readings, and that expressed as the area of denuded root surface. The areas of denuded root surface of 236 teeth of different morphotype in 41 human dried skulls were determined by a rubber base impression technique and compared with their corresponding probe measurements, made at 10 sites per tooth. Although the majority of correlations between linear and area measurements were statistically significant for some individual morphotypes and categories of bone loss, there was overall, no consistent pattern of correlation between the two parameters. Furthermore, many correlations which were statistically significant had low values of the correlation coefficient: Kendall's T. It was concluded that probe readings are not a very precise measure of attachment loss, particularly with increasing severity destruction. These results cast doubt on the ability of individual linear measurements to represent the true severity of attachment loss, and thus on the precision of loss of attachment charts for retrospectively identifying sites of periodontal disease activity.
SUMMARYPost-exposure protection of rabies-infected mice was observed by proximal application of axonal flow inhibitors, particularly vinblastine, to the local nerve(s). These observations indicate that rabies virus is transported by the axonal flow of the peripheral nerves to the central nervous system, Both a fixed virus (CVS) and a street (sylvatic) virus were used.This model in mice could be used to develop an additional post-exposure local treatment of rabies infection in man, by infiltrating local nerves or ganglions with axonal flow inhibitors, with the advantage that it would not interfere with subsequent vaccination as is the case with the administration of hyperimmune serum or immunoglobulin.
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