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Introduction of IHS in Immunology



FROM IMMUNOLOGY TO STEM CELLS, SEARCHING FOR NEW STRATEGIES TO TREAT HUMAN DISEASE

The Institute of Health Sciences (IHS), the first non-profit research organization in China devoted to translational medical research, was established in 2002 as a joint venture between the Shanghai Institutes for Biological Sciences of the Chinese Academy of Sciences and the Shanghai Jiao Tong University School of Medicine. Such unique collaboration allows IHS to bridge the expertise in basic biological research of the Chinese Academy of Sciences and the superior clinical resources of the Medical School. IHS focuses on immune regulation and critical diseases, stem cell research and applications, and cancer prevention and novel therapies. On the cutting edge of these research areas, IHS investigators are integrating expertise in immunology, genetics, epigenetics, cancer and stem cells to find better strategies to combat critical diseases that affect humanity.

Immune Regulation and Critical Diseases
IHS has a strong immunology research team devoted to understanding the role of autoreactive T cells and inflammatory cytokines in autoimmunity, transplant rejection, and cancer immunity. In a study of the IL-17 cytokine family, the Institute recently demonstrated that IL-17RE is a functional receptor for IL-17C, and regulates early innate immunity against intestinal pathogens. The IHS researchers also unraveled a novel mechanism through which IL-17 induces proinflammatory cytokine expression in stroma by the down-regulation of miR-23b during systemic lupus erythematosus (Zhu et al., Nat Med 2012). Furthermore, an essential function of β-arrestin 2 has been identified as an inhibitory signal for natural killer cells, which regulates the susceptibility of host to viral infection(Yu et al., Nat Immunol 2008). IHS researchers also have found a key role for osteopontin in CD8+ T cell-mediated graft-versus-host disease.

Uncontrolled growth of the intestinal bacteria enteropathogenic E. coli (EPEC) is a leading cause of children death in developing countries. Using proteasome analysis, investigators here discovered that these bacteria avoid immune clearance by expressing ITIM (immunological inhibitory motif)-bearing proteins. Collectively, the institute is now harnessing these critical discoveries to find better therapies for immunological disorders.

Stem Cell Research and Application
IHS research on stem cells extends from stemness maintenance, differentiation induction, to immune regulation of stem cells. Investigators at IHS have successfully established stem cell lines including embryonic stem cell (ESCs), tissue stem cells and induced pluripotent stem cells (iPSCs). Among seven human ESC line established, three have been generated under xenogenic-free conditions. Through a transposon-mediated mutagenesis approach, scientists at IHS discovered that calcineurin-NFAT signaling is both necessary and sufficient to switch ESCs from an undifferentiated state to lineage-specific cells (Li et al., Cell Stem Cell 2011). They also found that different exosomes have distinct roles in the growth and differentiation of stem cells. To meet the prerequisites for stem cell use in regenerative medicine, the production of de novo progenitors and tissue cells from pluripotent stem cells is also a focus in IHS. Investigators here have established robust protocols to differentiate mouse, rat, and human ESCs and iPSCs into functional cardiomyocytes, cardiac cell progenitors and neural progenitors.

Stem cell immunology is another unique expertise of IHS, To study the interactions between tissue stem cells and immune responses, scientists in the institute found that neural progenitor cells derived from ESCs exert their therapeutic effect on experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, by secreting cytokine LIF (Cao et al., Immunity 2011). Moreover, it was found that inflammatory cytokines induce tissue stem cells to express large amounts of immune regulators (iNOS and IDO), chemokines, adhesion molecules and growth factors. The concerted action of chemokines and immune regulators mediates the exceptionally powerful immune suppressive effect of tissue stem cells. Tissue stem cells are currently being investigated for their therapeutic potential for liver cirrhosis. IHS scientists are attempting to effectively differentiate stem cells for therapeutic purposes and eliminate their tumorigenicity. The goals are to develop stem cell-based therapies for autoimmune diseases, myocardial infarction, diabetes, Parkinson’s disease, and bone defects.

Cancer Prevention and Novel Therapies
While prostate, breast, and colon (PBC) cancers are common in western countries, cancers of stomach, esophageal, and liver are more prevalent in China. To search for genes and gene networks that are responsible for liver carcinoma, IHS researchers have performed large-scale genomic screening. They are also seeking the molecular mechanisms underlying the recent increases of PBC cancer incidents in China. In addition, IHS researchers have demonstrated that metadherin, a gene responsible for both drug-resistance and metastasis, is frequently amplified in PBC cancers. Metadherin is currently being explored as a therapeutic target for PBC cancers. To search for the genetic cause of acute myeloid leukemia, a research team at IHS found loss of expression of the alpha-catenin tumor suppressor in hematopoietic stem cells provides a growth advantage that contributes to human myelodysplastic and acute myeloid leukemia with del(5q) (Liu et.al., Nature Med, 2007).

Mesenchymal stem cells (MSC) are well-known for their functions in tissue repair and immune suppression, but their role in tumor progression is unknown. IHS investigators discovered a relay between bone marrow MSCs and tumor-resident MSCs, such that the bone-marrow MSCs produce cytokine TNF-alpha which induce CCR2 expression in tumor-resident MSCs to recruit monocyte and macrophage during tumor growth. Elucidating the role of MSCs in cancer cell metastasis will lead to new targets for the tumor cell microenvironment for cancer therapies.

Perspectives
In its short 10-year history, the IHS has become well-positioned to carry out its mission of translating basic science into medicine. In addition to its 27 existing laboratories, about 20 new laboratories in translational medical research will be established for the next 5 years. Closely collaborating teams will form around specific diseases to conduct sophisticated research with the highest ethical and professional standards. The IHS has already published 279 first-author papers in high-impact peer-reviewed journals (9 in Nature, Science or Cell Series), and more exciting publications are anticipated. With an established training record of more than 150 PhD’s, and improvements in the education landscape in China and the world, IHS is looking forward to providing an unparalleled learning environment for graduate students, postdoctoral fellows, and young physicians. Many international collaborations have been formed between IHS and well established research institutions (i.e. Toronto University Health Network, Child Health Institute of New Jersey, MCR Toxicology Unit) and pharmaceutical companies (i.e. Johnson & Johnson, GSK). With the Chinese government’s commitment to research and development, the Institute of Health Sciences is sure to make significant contributions to the improvement of human health.

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