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.

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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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The purpose of this study was to demonstrate the presence and anatomical positions of connective tissue progenitor cell populations in the gingival papilla of the rat. Ten male hooded Lister rats aged 4 wk were killed 1 h after flash labelling with tritiated thymidine. Paraffin sections were cut through the molar regions of 19 mandibles parallel to the occlusal plane. Sections immediately apical to the epithelium of the col and just coronal to the crest of the interdental septum (levels 1 and 5) were chosen for autoradiography, as were a further three sections (levels 2, 3 and 4), spaced equidistantly between levels 1 and 5 in a subsample of 10 of these mandibles. Mean labelling indices (LIs) for all 19 specimens were significantly higher within 5 μm of the teeth at levels 1 and 5, and in a zone 15–25 μm from the teeth in level 5. LIs for the subsample of 10 mandibles were also significantly higher within 5 μm of the teeth in levels 3 and 5, and within 15–20 μm in levels 4 and 5. Nuclear densities were highest at all levels within 10 μm of the teeth and at 20 μm (levels 1–3) or 30 Jan (levels 4 and 5) from the teeth. The data are consistent with the existence of ostensible connective tissue progenitor cell populations, one in contact with cementum and junctional epithelium, the other lying in the body of the papilla at its most apical levels, 15–25 μm from the teeth.

Twenty-seven proprietory periodontal dressings were applied to the lower labial segments of 18 subjects showing low levels of gingival inflammation when assessed by the Gingival Index system at the time of application. Specimens of each dressing type were subsequently removed at intervals ranging from 3 h to 5 days. The material adhering to the deep surface of the dressing was examined by light, transmission and scanning electron microscopy and was shown to be a complex heterogeneous structure consisting of large intact epithelial cell sheets and oral bacteria in a proteinaceous matrix. Possible mechanisms which could contribute the epithelial cell and protein components to this structure were discussed. It was concluded that the dressings themselves caused little damage to the normal periodontium but could be associated with increased levels of inflammation at longer time intervals because of bacterial growth. The significance of these findings to current clinical practice is discussed.

The primary substratum for epithelial migration during marsupialization of percutaneous implants is adjacent connective tissue. The purpose of this investigation was to test the hypothesis that if the latter is composed of deep connective tissue or other deep tissue, it will inhibit this process. One-hundred-forty-two smooth-surfaced polyethylene implants of a simple geometric design were implanted in dorsal skin of 6-8-week-old male C57/BL/6 mice such that the stems passed through and deep to the panniculus carnosus (PC), which is a deep tissue. Animals were sacrificed in groups between 1 and 11 weeks, and the implants and surrounding tissue were harvested, embedded in historesin, and 3-microns thick step serial sections prepared. No implants were lost by extrusion and 133 were suitable for examination. Epithelial investment of the devices proceeded deep to PC around only five of the implants over the time course. In the remainder, the mean distance of the advancing epithelial edge from the upper border of the PC was 0.25 mm by 1 week and this did not change significantly thereafter (p = 0.647). Significant extrusion of all devices occurred (p = 0.0001). It was concluded that these results are consistent with the hypothesis that deep connective tissue, such as the fascia surrounding the PC or muscle tissue such as the PC itself, can act as a functional barrier to marsupialization, and that exfoliation of such devices is not an epithelial function.