Significance and suppression of redundant IL17 responses in acute allograft rejection by bioinformatics based drug repositioning of fenofibrate.

Despite advanced immunosuppression, redundancy in the molecular diversity of acute rejection (AR) often results in incomplete resolution of the injury response. We present a bioinformatics based approach for identification of these redundant molecular pathways in AR and a drug repositioning approach to suppress these using FDA approved drugs currently available for non-transplant indications. Two independent microarray data-sets from human renal allograft biopsies (n = 101) from patients on majorly Th1/IFN-y immune response targeted immunosuppression, with and without AR, were profiled. Using gene-set analysis across 3305 biological pathways, significant enrichment was found for the IL17 pathway in AR in both data-sets. Recent evidence suggests IL17 pathway as an important escape mechanism when Th1/IFN-y mediated responses are suppressed. As current immunosuppressions do not specifically target the IL17 axis, 7200 molecular compounds were interrogated for FDA approved drugs with specific inhibition of this axis. A combined IL17/IFN-y suppressive role was predicted for the antilipidemic drug Fenofibrate. To assess the immunregulatory action of Fenofibrate, we conducted in-vitro treatment of anti-CD3/CD28 stimulated human peripheral blood cells (PBMC), and, as predicted, Fenofibrate reduced IL17 and IFN-γ gene expression in stimulated PMBC. In-vivo Fenofibrate treatment of an experimental rodent model of cardiac AR reduced infiltration of total leukocytes, reduced expression of IL17/IFN-y and their pathway related genes in allografts and recipients' spleens, and extended graft survival by 21 days (p<0.007). In conclusion, this study provides important proof of concept that meta-analyses of genomic data and drug databases can provide new insights into the redundancy of the rejection response and presents an economic methodology to reposition FDA approved drugs in organ transplantation

Resultados tempranos y a medio plazo de la reparación quirúrgica endovascular y abierta del aneurisma del arco aórtico no disecado

OBJECTIVES: With the introduction of endovascular stent graft technology, a variety of surgical options are available for patients with aortic aneurysms. We sought to evaluate early-term and mid-term outcomes of patients undergoing endovascular and open surgical repair for non-dissected aortic arch aneurysm. METHODS: Overall, 200 patients underwent treatment for isolated non-dissected aortic arch aneurysm between January 2008 and February 2016: 133 patients had open surgery and 67, endovascular repair. Early-term and mid-term outcomes were compared. RESULTS: Seventy percent (n?=?47) needing endovascular repair underwent fenestrated stent graft and 30% (n?=?20) underwent the debranched technique. Patients in the open surgery group were younger (71 vs 75 years, P?<?0.001) and had a lower prevalence of ischaemic heart disease (11% vs 35%, P?<?0.001). Intensive care unit stay (1 vs 3 days, P?<?0.001), hospital stay (11 vs 17 days, P?<?0.001) and surgical time (208 vs 390?min, P?<?0.001) were lower in the endovascular repair group than in the open surgery group. There were 3 in-hospital deaths each in the open surgery and endovascular groups (2% vs 5%, respectively, P?=?0.40). Mid-term survival (P?<?0.001) and freedom from reintervention (P?=?0.009) were better in the open surgery than in the endovascular repair group. No aneurysm-related deaths were observed. The propensity-matched comparison (n?=?58) demonstrated that survival was better in the open surgery group (P?=?0.011); no significant difference was seen in the reintervention rate (P?=?0.28). CONCLUSIONS: Close follow-up for re-intervention may reduce the risk for aneurysm-related deaths and provide acceptable outcomes in patients undergoing endovascular repair

Resultados tempranos y a medio plazo de la reparación quirúrgica endovascular y abierta del aneurisma del arco aórtico no disecado

OBJECTIVES: With the introduction of endovascular stent graft technology, a variety of surgical options are available for patients with aortic aneurysms. We sought to evaluate early-term and mid-term outcomes of patients undergoing endovascular and open surgical repair for non-dissected aortic arch aneurysm. METHODS: Overall, 200 patients underwent treatment for isolated non-dissected aortic arch aneurysm between January 2008 and February 2016: 133 patients had open surgery and 67, endovascular repair. Early-term and mid-term outcomes were compared. RESULTS: Seventy percent (n?=?47) needing endovascular repair underwent fenestrated stent graft and 30% (n?=?20) underwent the debranched technique. Patients in the open surgery group were younger (71 vs 75 years, P?<?0.001) and had a lower prevalence of ischaemic heart disease (11% vs 35%, P?<?0.001). Intensive care unit stay (1 vs 3 days, P?<?0.001), hospital stay (11 vs 17 days, P?<?0.001) and surgical time (208 vs 390?min, P?<?0.001) were lower in the endovascular repair group than in the open surgery group. There were 3 in-hospital deaths each in the open surgery and endovascular groups (2% vs 5%, respectively, P?=?0.40). Mid-term survival (P?<?0.001) and freedom from reintervention (P?=?0.009) were better in the open surgery than in the endovascular repair group. No aneurysm-related deaths were observed. The propensity-matched comparison (n?=?58) demonstrated that survival was better in the open surgery group (P?=?0.011); no significant difference was seen in the reintervention rate (P?=?0.28). CONCLUSIONS: Close follow-up for re-intervention may reduce the risk for aneurysm-related deaths and provide acceptable outcomes in patients undergoing endovascular repair

Significance and Suppression of Redundant IL17 Responses in Acute Allograft Rejection by Bioinformatics Based Drug Repositioning of Fenofibrate

<div><p>Despite advanced immunosuppression, redundancy in the molecular diversity of acute rejection (AR) often results in incomplete resolution of the injury response. We present a bioinformatics based approach for identification of these redundant molecular pathways in AR and a drug repositioning approach to suppress these using FDA approved drugs currently available for non-transplant indications. Two independent microarray data-sets from human renal allograft biopsies (n = 101) from patients on majorly Th1/IFN-y immune response targeted immunosuppression, with and without AR, were profiled. Using gene-set analysis across 3305 biological pathways, significant enrichment was found for the IL17 pathway in AR in both data-sets. Recent evidence suggests IL17 pathway as an important escape mechanism when Th1/IFN-y mediated responses are suppressed. As current immunosuppressions do not specifically target the IL17 axis, 7200 molecular compounds were interrogated for FDA approved drugs with specific inhibition of this axis. A combined IL17/IFN-y suppressive role was predicted for the antilipidemic drug Fenofibrate. To assess the immunregulatory action of Fenofibrate, we conducted <i>in-vitro</i> treatment of anti-CD3/CD28 stimulated human peripheral blood cells (PBMC), and, as predicted, Fenofibrate reduced IL17 and IFN-γ gene expression in stimulated PMBC. <i>In-vivo</i> Fenofibrate treatment of an experimental rodent model of cardiac AR reduced infiltration of total leukocytes, reduced expression of IL17/IFN-y and their pathway related genes in allografts and recipients’ spleens, and extended graft survival by 21 days (p<0.007). In conclusion, this study provides important proof of concept that meta-analyses of genomic data and drug databases can provide new insights into the redundancy of the rejection response and presents an economic methodology to reposition FDA approved drugs in organ transplantation.</p> </div

Study Design.

<p>Whole genome microarrays from 66 pre- and post-transplant kidney graft biopsies and from 35 post-transplant kidney graft biopsies were analyzed for rejection specific injury pathways using 3 computational databases comprising 3305 independent gene-sets. AR specific IL17 pathway (FDR = 0.3, p = 0.011) and activated IL17⁺ T-helper cells cell (FDR = 0.5; p = 0.008) gene-sets were aligned to a database of 7200 compounds with proven interactions with the input genes (MetaCore™, GeneGo, Thomson Reuters) resulting in the identification of Fenofibrate for drug repositioning in AR. Efficacy of Fenofibrate was tested in vitro using human PBMC and in vivo in mouse total allo-mismatch cardiac rejection for anti-inflammatory and for its potency to prolong graft survival.</p