Novel Mouse Xenograft Models Reveal a Critical Role of CD4+ T Cells in the Proliferation of EBV-Infected T and NK Cells

Epstein-Barr virus (EBV), a ubiquitous B-lymphotropic herpesvirus, ectopically infects T or NK cells to cause severe diseases of unknown pathogenesis, including chronic active EBV infection (CAEBV) and EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH). We developed xenograft models of CAEBV and EBV-HLH by transplanting patients' PBMC to immunodeficient mice of the NOD/Shi-scid/IL-2Rγnull strain. In these models, EBV-infected T, NK, or B cells proliferated systemically and reproduced histological characteristics of the two diseases. Analysis of the TCR repertoire expression revealed that identical predominant EBV-infected T-cell clones proliferated in patients and corresponding mice transplanted with their PBMC. Expression of the EBV nuclear antigen 1 (EBNA1), the latent membrane protein 1 (LMP1), and LMP2, but not EBNA2, in the engrafted cells is consistent with the latency II program of EBV gene expression known in CAEBV. High levels of human cytokines, including IL-8, IFN-γ, and RANTES, were detected in the peripheral blood of the model mice, mirroring hypercytokinemia characteristic to both CAEBV and EBV-HLH. Transplantation of individual immunophenotypic subsets isolated from patients' PBMC as well as that of various combinations of these subsets revealed a critical role of CD4+ T cells in the engraftment of EBV-infected T and NK cells. In accordance with this finding, in vivo depletion of CD4+ T cells by the administration of the OKT4 antibody following transplantation of PBMC prevented the engraftment of EBV-infected T and NK cells. This is the first report of animal models of CAEBV and EBV-HLH that are expected to be useful tools in the development of novel therapeutic strategies for the treatment of the diseases

Nature Immersion in an Extreme Environment: Hiroshima Survivors’ Personal Emergence Following Their Atomic Bomb Experience

Introduction: Nature immersion is defined as multidimensional connecting with earthy materials to generate personal emergence. Personal emergence is an embodied healing force observable via synchronization of bodily rhythms. Research has revealed positive effects of green space for healing. However, little is known about healing of survivors in the space impacted with radioactive nuclear energies. Purpose: To use the theory of nature immersion to guide exploration of the concepts of connecting with earthy materials, personal emergence and space-time expansion in a sample of people who had experienced the catastrophic nature upheaval of the Hiroshima bombings on 6 August 1945. Method: A descriptive exploratory design with directed content analysis was used with existing qualitative data consisting of 29 Hiroshima atomic-bombing survivors’ description of their experience. Results: Self-healing empirically manifested through 23 survivors’ connection with earthy materials. There was synchrony between recuperating natural space and healing of survivors. Conclusions: Synchrony, as a dimension of human connection with nature, transcended the disharmony of bombing upheaval. Although further exploration is necessary, these findings serve as evidence about the essence of healing as related to nature for those in extreme environments

Recombinant measles virus vaccine expressing the Nipah virus glycoprotein protects against lethal Nipah virus challenge.

Nipah virus (NiV) is a member of the genus Henipavirus, which emerged in Malaysia in 1998. In pigs, infection resulted in a predominantly non-lethal respiratory disease; however, infection in humans resulted in over 100 deaths. Nipah virus has continued to re-emerge in Bangladesh and India, and person-to-person transmission appeared in the outbreak. Although a number of NiV vaccine studies have been reported, there are currently no vaccines or treatments licensed for human use. In this study, we have developed a recombinant measles virus (rMV) vaccine expressing NiV envelope glycoproteins (rMV-HL-G and rMV-Ed-G). Vaccinated hamsters were completely protected against NiV challenge, while the mortality of unvaccinated control hamsters was 90%. We trialed our vaccine in a non-human primate model, African green monkeys. Upon intraperitoneal infection with NiV, monkeys showed several clinical signs of disease including severe depression, reduced ability to move and decreased food ingestion and died at 7 days post infection (dpi). Intranasal and oral inoculation induced similar clinical illness in monkeys, evident around 9 dpi, and resulted in a moribund stage around 14 dpi. Two monkeys immunized subcutaneously with rMV-Ed-G showed no clinical illness prior to euthanasia after challenge with NiV. Viral RNA was not detected in any organ samples collected from vaccinated monkeys, and no pathological changes were found upon histopathological examination. From our findings, we propose that rMV-NiV-G is an appropriate NiV vaccine candidate for use in humans

Body weights of Nipah virus-infected monkeys.

<p>Each monkey was inoculated with 10⁸ or 10⁶ TCID₅₀ of NiV <i>via</i> intraperitoneal (A) or intranasal and oral routes (B). Monkeys were examined every 2–3 days, and body weights recorded. Levels were standardized, with the weight at the first day of the experiment set as 1.</p

Pathological findings in organ samples of NiV infected monkeys.

<p>Pathological findings in organ samples of NiV infected monkeys.</p