Day 1 :
Medical College of Georgia-Augusta University, USA
Keynote: The regulation of indoleamine 2, 3 dioxygenase and its role in a porcine model of acute kidney allograft rejection
Time : 10:00-10:45
Stanley Nahman joined the Faculty at Ohio State University College of Medicine after completing his fellowship at the same institution in 1987. In 2004, he became Director of Nephrology division of University of Florida Jacksonville. In 2010, he joined Nephrology division at Medical College of Georgia, where he has directed the Department of Medicine Translational Research Program since 2013, leads a USRDS data mining group, and is PI of a basic research lab studying the tolerogenic properties of enzyme IDO. In 2017, he became Co-chair of American Society of Nephrology in-training exam question writing group.
In kidney transplantation acute rejection is the most common cause of late allograft loss. Changes in indoleamine 2, 3 dioxygenase (IDO) activity, which catabolizes the degradation of tryptophan to kynurenine, may predict rejection. However, when used therapeutically, IDO is immunosuppressive in rodent kidney transplantation. Thus, the increase in IDO activity observed in acute allograft rejection is insufficient to prevent rejection. To address this question, we assessed the regulation of IDO and its role in acute rejection in a porcine model of kidney transplant. In tissue samples form rejecting kidney allografts we showed a 13 fold increase in IDO gene transcription, and 20 fold increase in IDO enzyme activity when compared to autotransplanted kidneys. Allografts also demonstrated an over 4-fold increase in tissue IFN-, with marked increases in TNF-, TNF- and IL1-. Rejecting allografts also showed down regulation of kynurenine 3-monooxygenase (KMO) gene transcription and protein levels. KMO generates the immunosuppressive kynurenine 3-hydroxykynurenine (3-HK) from kynurenine. The results of these studies demonstrate a clear association between rejection and increased allograft IDO expression, likely driven in part by IFN- and facilitated by other cytokines of the allogeneic response. Moreover, the loss of downstream enzymatic activity in the IDO metabolic pathway may suggest novel mechanisms for the perpetuation of rejection in the early transplant period.
Emory University, USA
Keynote: Muscle-derived miR-26a mediate cardiac fibrosis through exosome in chronic kidney disease mice
Time : 10:45-11:30
Dr. Xiaonan Wang gained his MD in 1982 from Peking Union Medical College, Beijing, China. She finished her post-doc training in 1991 in the University of Colorado HSC, Denver, CO and in 1997 in Emory University, Atlanta, GA, USA. Currently, Dr. Wang is an Assistant Professor of Renal Division, Department of medicine. She has published 50 papers in peer review journal. Since 1997, Dr. Wang has focused on investigation of the molecular/cellular mechanisms that lead to protein malnutrition in, diabetes, chronic kidney disease and aging in order to develop therapeutic strategies for treatment.
Dr. Wang uses transgenic mice, virus (adenovirus, adeno-associated virus (AAV) and lentivirus) mediated gene transfer and cell culture systems to test her hypotheses.
Uremic cardiomyopathy and muscle atrophy contribute to CKD-induced morbidity and mortality. Exosomes, natural carriers of many signal molecules including microRNA (miR), mediate organ-to-organ communication. We hypothesized that miR-26 would benefit both CKD-induced muscle wasting and cardiomyopathy through exosome-mediated muscle-heart crosstalk. We used an engineered exosome vector, which contains an exosomal membrane protein gene Lamp2b fused with muscle specific surface peptide for targeting delivery. Exosome encapsulated miR-26a precursor RNA (Exo/miR26) were injected into the tibialis anterior (TA) muscle of CKD mice (5/6 subtotal nephrectomy) for 10 weeks. miR-26a was decreased in skeletal muscle and heart of CKD mice. Uremic serum enhanced secretion of miR-26a exosomes in cultured C2C12 skeletal and H9C2 cardiac muscle cells. The intervention of Exo/miR26a increased the expression of miR-26a in skeletal muscle and heart, as well as increased muscle cross-section area and decreased CKD-induced up-regulation of atrogin-1 and MuRF1. Curiously, cardiac fibrosis lesion was partially depressed, and FoxO1, α-SMA, connect tissue growth factor (CTGF), fibronectin and collagen1α were decreased in CKD mice with intramuscular injection of Exo/miR-26a. Echocardiography showed that the percentage of ejection fraction was increased in CKD mice treated with Exo/miR26a. Using fluorescence dye labeled Exo/miR26a; we found that the fluorescence intensity in heart was correlated with skeletal muscle, examined by linear regression. We found that miR-26a directly inhibits FoxO1 and CTGF, which provided mechanism for inhibition of muscle atrophy and cardiac fibrosis by Exo/miR26a. Overexpression of miR-26a in muscle prevents CKD-induced muscle loss and attenuates cardiac fibrosis via exosome-mediated muscle-heart crosstalk.
UCB Celltech, UK
Keynote: Biomarkers of tolerance in kidney transplantation: When predicting tolerance adjustment for confounding factors is imperative
Time : 11:50-12:30
Maria Hernandez-Fuentes studied Medicine at Universidad Complutense and then completed PhD in Immunology at Universidad de Alcalá, both in Madrid, Spain. She then moved to the UK, Imperial College London, working on alloimmune responses. In 2005, the research group moved to King’s College London and since then she led the biomarker research group of the MRC Centre for Transplantation. She has a long standing interest in understanding and quantifying alloimmune responses and immune monitoring in kidney transplantation; particularly looking at obtaining evidence of tolerance.
We and others have previously described signatures of tolerance in kidney transplantation showing differential-expression of B-cell related genes and relative expansions of B-cell subsets. However, in all of these studies, the index groups namely the tolerant recipients were not receiving immunosuppressive (IS) treatment unlike the rest of the comparator groups. The work will demonstrate that the expression of the previously reported signature was biased by IS regimens, which also influenced transitional B-cells. We have defined and validated a new gene-expression signature that was independent of drug effects and also differentiated tolerant patients from healthy controls and have validated this signature in a number of cohorts. We will demonstrate how adjustment for IS-drug intake does not obliterate the contribution of genes to tolerance, when this exists; but it does indeed remove the effects ascribable to pharmacological immunosuppression and, thus, reveals underlying tolerance characteristics. Consequently, we would argue that IS regimens do affect the expression of many genes (although not all) and require adequate investigation. When IS are, indeed, altering the expression of signature genes, investigators should adjust for IS-drug intake. Only a similar approach will make the conduct of pilot clinical trials for IS-minimization safe, and hence allow critical improvements in kidney post-transplant management.