CD103 Deficiency Prevents Graft-versus-Host Disease but Spares Graft-versus-Tumor Effects Mediated by Alloreactive CD8 T Cells

Graft-versus-host disease (GVHD) remains the main barrier to broader application of allogeneic hematopoietic stem cell transplantation (alloSCT) as a curative therapy for host malignancy. GVHD is mediated by allogeneic T cells directed against histocompatibility antigens expressed by host tissues. Based on previous studies, we postulated that the integrin CD103 is required for CD8-mediated GVHD, but not for graft-versus-tumor effects (GVT).We herein provide evidence in support of this hypothesis. To circumvent the potentially confounding influence of donor CD4 T cells, we developed an alloSCT model in which GVHD mortality is mediated by purified CD8 T cells. In this model, host-reactive CD8 T cells receive CD4 T cell help at the time of initial activation but not in the effector phase in which mature CD8 T effectors migrate into host tissues. We show that donor CD8 T cells from wild-type BALB/c mice primed to host alloantigens induce GVHD pathology and eliminate tumors of host origin in the absence of host CD4 T cells. Importantly, CD103 deficiency dramatically attenuated GVHD mortality, but had no detectable impact on the capacity to eliminate a tumor line of host origin. We provide evidence that CD103 is required for accumulation of donor CD8 T cells in the host intestinal epithelium but not in the tumor or host lymphoid compartments. Consistent with these data, CD103 was preferentially expressed by CD8 T cells infiltrating the host intestinal epithelium but not by those infiltrating the tumor, lamina propria, or lymphoid compartments. We further demonstrate that CD103 expression is not required for classic CD8 effector activities including cytokine production and cytotoxicity.These data indicate that CD103 deficiency inhibits GVHD pathology while sparing anti-tumor effects mediated by CD8 T cells, identifying CD103 blockade as an improved strategy for GVHD prophylaxis

miR-17-5p targets the p300/CBP-associated factor and modulates androgen receptor transcriptional activity in cultured prostate cancer cells

<p>Abstract</p> <p>Background</p> <p>Androgen receptor (AR) signalling is critical to the initiation and progression of prostate cancer (PCa). Transcriptional activity of AR involves chromatin recruitment of co-activators, including the p300/CBP-associated factor (PCAF). Distinct miRNA expression profiles have been identified in PCa cells during the development and progression of the disease. Whether miRNAs regulate PCAF expression in PCa cells to regulate AR transcriptional activity is still unclear.</p> <p>Methods</p> <p>Expression of PCAF was investigated in several PCa cell lines by qRT-PCR, Western blot, and immunocytochemistry. The effects of PCAF expression on AR-regulated transcriptional activity and cell growth in PCa cells were determined by chromatin immunoprecipitation, reporter gene construct analysis, and MTS assay. Targeting of PCAF by miR-17-5p was evaluated using the luciferase reporter assay.</p> <p>Results</p> <p>PCAF was upregulated in several PCa cell lines. Upregulation of PCAF promoted AR transcriptional activation and cell growth in cultured PCa cells. Expression of PCAF in PCa cells was associated with the downregulation of miR-17-5p. Targeting of the 3’-untranslated region of PCAF mRNA by miR-17-5p caused translational suppression and RNA degradation, and, consequently, modulation of AR transcriptional activity in PCa cells.</p> <p>Conclusions</p> <p>PCAF is upregulated in cultured PCa cells, and upregulation of PCAF is associated with the downregulation of miR-17-5p. Targeting of PCAF by miR-17-5p modulates AR transcriptional activity and cell growth in cultured PCa cells.</p

Adapting sheep production to climate change

Apart from contributing to the climate change phenomenon, sheep production sys tem is also sensitive to its adverse impacts. This poses a great challenge for develop ing sheep sector around the world. Currently the economic viability of the sheep production system worldwide is jeopardized due to the devastating effects of cli mate change. Among the multiple climatic stresses faced by sheep, heat stress seems to hugely destabilize production efficiency of the animals. Heat stress jeopardizes the growth, wool, meat and milk production in sheep. Further, climate change leads to several vector borne diseases to sheep by compromising the immune status of the animals. The animal employs several adaptive mechanisms to maintain homeosta sis through behavioural, physiological, neuroendocrine, cellular and molecular responses to cope up to the existing climatic condition. Sheep also significantly contributes to climate change through enteric methane emission and manure man agement. Further, climate change can alter the rumen function and diet digestibility in sheep. Hence, enteric methane mitigation is of paramount importance to prevent both the climate change and dietary energy loss which may pave way for sustaining the economic return from these animals. Further, various other strategies are required to counter the detrimental effects of climate change on sheep production. The management strategies can be categorized as housing management, animal management and monitoring of climate, and these strategies are ultimately targeted to provide suitable microclimate for optimum sheep production. Nutritional inter ventions involving season-specific feeding and micronutrient supplementation may help the animal to sustain its production during adverse environmental conditions. Body condition scoring system developed specifically for sheep may help to opti mize economic return in sheep farms by minimizing the input costs. Finally, suffi cient emphasis must be given to develop appropriate adaptation strategies involving policymakers. These strategies include developing thermotolerant breeds using bio markers, ensured water availability, women empowerment, early warning system and capacity building programmes for all the stakeholders. These efforts may help in augmenting sheep production in the climate change scenario