Characterization Of Intestinal Epithelial Cells In Acute Intestinal Allograft Rejection

Intestinal transplantation (IT) remains highly experimental compared to other solid organ transplants because of poorly defined mechanisms of graft rejection. In this project, the role of luminal bacteria-derived endotoxin and inflammatory cytokines (IL-1, IL-6, TNF-{dollar}\alpha){dollar} in intestinal epithelial damage during acute graft rejection was examined. In a novel mouse model of IT, the acute intestinal rejection was associated with elevated levels of endotoxin, IL-6, and TNF-{dollar}\alpha{dollar} in the peripheral blood. The progressive increase in endotoxin and TNF-{dollar}\alpha{dollar} levels correlated well with the histologic severity of epithelial damage. To further define the role of endotoxin and inflammatory cytokines on intestinal epithelial cells, several epithelial cell lines from the small intestine of BALB/c mice were established by transfection of primary cultured epithelial cells with pMK16 plasmid containing the origin-deficient simian virus 40 (SV40) DNA. One epithelial cell clone (IEC-4.1) stably integrated large T gene of the SV40 virus into the cell genome. IEC-4.1 cells exhibited phenotypic and ultra-structural features of enterocytes. IEC-4.1 cells expressed well-developed microvilli on the cell surface, they formed confluent monolayers and expressed junctional protein zonula occluden-1 (ZO-1) major histocompatibility complex (MHC) class I, and low levels of MHC class II molecules. In vitro studies using IEC-4.1 cells demonstrated that TNF-{dollar}\alpha{dollar} was highly cytotoxic to IEC-4.1 cells. Endotoxin did not affect the growth and viability of IEC-4.1 cells but it potentiated TNF-{dollar}\alpha{dollar}-mediated enterocytotoxicity. We further examined the capacity of IEC-4.1 cells to generate molecules that are capable of promoting immune-mediated injury. In northern blot analysis, IEC-4.1 cells constitutively expressed IL-1{dollar}\alpha{dollar} mRNA. These cells also expressed gene transcripts for IL-6, TGF-{dollar}\beta,{dollar} and adhesion molecules ICAM-1 and VCAM-1 in response to endotoxin or TNF-{dollar}\alpha{dollar} stimulation. Further analysis showed that ICAM-1 and VCAM-1 had different kinetics of cell surface expression following stimulation. The expression of adhesion molecules by IEC-4.1 cells effectively promoted macrophage adhesion to the apical domain of IEC-4.1 cells and this process was also enhanced by endotoxin or TNF-{dollar}\alpha.{dollar};These data suggest that luminal bacteria-derived endotoxin may play an important role in the pathogenesis of intestinal epithelial damage. Intestinal epithelial cells may be actively involved in regulating leukocyte trafficking and leukocyte-epithelial interactions through the expression of inflammatory cytokines and adhesion molecules as well as being a vulnerable target during this process. Strategies to specifically block interactions between epithelial cells and graft-infiltrating cells may help to reduce the risk of graft damage

Nonlinear estimates for traveling wave solutions of reaction diffusion equations

In this paper we will establish nonlinear a priori lower and upper bounds for the solutions to a large class of equations which arise from the study of traveling wave solutions of reaction-diffusion equations, and we will apply our nonlinear bounds to the Lotka-Volterra system of two competing species as examples. The idea used in a series of papers \cite{NBMP-Discrete,JDE-16,CPAA-16,DCDS-B-18,NBMP-n-species,DCDS-A-17} for the establishment of the linear N-barrier maximum principle will also be used in the proof

Study of the cytological features of bone marrow mesenchymal stem cells from patients with neuromyelitis optica.

Neuromyelitis optica (NMO) is a refractory autoimmune inflammatory disease of the central nervous system without an effective cure. Autologous bone marrow‑derived mesenchymal stem cells (BM‑MSCs) are considered to be promising therapeutic agents for this disease due to their potential regenerative, immune regulatory and neurotrophic effects. However, little is known about the cytological features of BM‑MSCs from patients with NMO, which may influence any therapeutic effects. The present study aimed to compare the proliferation, differentiation and senescence of BM‑MSCs from patients with NMO with that of age‑ and sex‑matched healthy subjects. It was revealed that there were no significant differences in terms of cell morphology or differentiation capacities in the BM‑MSCs from the patients with NMO. However, in comparison with healthy controls, BM‑MSCs derived from the Patients with NMO exhibited a decreased proliferation rate, in addition to a decreased expression of several cell cycle‑promoting and proliferation‑associated genes. Furthermore, the cell death rate increased in BM‑MSCs from patients under normal culture conditions and an assessment of the gene expression profile further confirmed that the BM‑MSCs from patients with NMO were more vulnerable to senescence. Platelet‑derived growth factor (PDGF), as a major mitotic stimulatory factor for MSCs and a potent therapeutic cytokine in demyelinating disease, was able to overcome the decreased proliferation rate and increased senescence defects in BM‑MSCs from the patients with NMO. Taken together, the results from the present study have enabled the proposition of the possibility of combining the application of autologous BM‑MSCs and PDGF for refractory and severe patients with NMO in order to elicit improved therapeutic effects, or, at the least, to include PDGF as a necessary and standard growth factor in the current in vitro formula for the culture of NMO patient‑derived BM‑MSCs

Interferon-gamma inducible protein 10 (IP10) induced cisplatin resistance of HCC after liver transplantation through ER stress signaling pathway.

Tumor recurrence remains an obstacle after liver surgery, especially in living donor liver transplantation (LDLT) for patients with hepatocellular carcinoma (HCC). The acute-phase liver graft injury might potentially induce poor response to chemotherapy in recurrent HCC after liver transplantation. We here intended to explore the mechanism and to identify a therapeutic target to overcome such chemoresistance. The associations among graft injury, overexpression of IP10 and multidrug resistant genes were investigated in a rat liver transplantation model, and further validated in clinical cohort. The role of IP10 on HCC cell proliferation and tumor growth under chemotherapy was studied both in vitro and in vivo. The underlying mechanism was revealed by detecting the activation of endoplasmic reticulum (ER) stress signaling pathways. Moreover, the effect of IP10 neutralizing antibody sensitizing cisplatin treatment was further explored. In rat liver transplantation model, significant up-regulation of IP10 associated with multidrug resistant genes was found in small-for-size liver graft. Clinically, high expression of circulating IP10 was significant correlated with tumor recurrence in HCC patients underwent LDLT. Overexpression of IP10 promoted HCC cell proliferation and tumor growth under cisplatin treatment by activation of ATF6/Grp78 signaling. IP10 neutralizing antibody sensitized cisplatin treatment in nude mice. The overexpression of IP10, which induced by liver graft injury, may lead to cisplatin resistance via ATF6/Grp78 ER stress signaling pathway. IP10 neutralizing antibody could be a potential adjuvant therapy to sensitize cisplatin treatment