A PHASE 1, RANDOMIZED, DOUBLE-BLIND, SPONSOR OPEN, PLACEBO CONTROLLED, DOSE ESCALATING STUDY TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF SINGLE INTRAVENOUS AND MULTIPLE SUBCUTANEOUS AND INTRAVENOUS DOSES OF PF-07261271 IN HEALTHY PARTICIPANTS

The purpose of this clinical trial is to learn about the safety and effects of the study medicine PF-07261271 for the potential treatment of Inflammatory Bowel Disease.

Start Date17 Oct 2022

Sponsor / Collaborator

Pfizer Inc.

100 Clinical Results associated with VEGI x IL-12p40

100 Translational Medicine associated with VEGI x IL-12p40

0 Patents (Medical) associated with VEGI x IL-12p40

Literatures (Medical) associated with VEGI x IL-12p40

10 Nov 2022·Human Molecular GeneticsQ2 · BIOLOGY

Identification of shared loci associated with both Crohn’s disease and leprosy in East Asians

Q2 · BIOLOGY

Article

Author: Park, Dohoon ; Jung, Seulgi ; Ye, Byong Duk ; Han, Buhm ; Yang, Suk-Kyun ; Liu, Jianjun ; Lee, Ho-Su ; Song, Kyuyoung ; Kim, Yongjae ; Baek, Jiwon ; Sun, Yonghu ; Liu, Hong ; Zhang, Furen ; Park, Sang Hyoung ; Hwang, Sung Wook

AbstractGenome-wide association studies (GWAS) of Crohn’s disease (CD) in European and leprosy in Chinese population have shown that CD and leprosy share genetic risk loci. As these shared loci were identified through cross-comparisons across different ethnic populations, we hypothesized that meta-analysis of GWAS on CD and leprosy in East Asian populations would increase power to identify additional shared loci. We performed a cross-disease meta-analysis of GWAS data from CD (1621 cases and 4419 controls) and leprosy (2901 cases 3801 controls) followed by replication in additional datasets comprising 738 CD cases and 488 controls and 842 leprosy cases and 925 controls. We identified one novel locus at 7p22.3, rs77992257 in intron 2 of ADAP1, shared between CD and leprosy with genome-wide significance (P = 3.80 × 10−11) and confirmed 10 previously established loci in both diseases: IL23R, IL18RAP, IL12B, RIPK2, TNFSF15, ZNF365-EGR2, CCDC88B, LACC1, IL27, NOD2. Phenotype variance explained by the polygenic risk scores derived from Chinese leprosy data explained up to 5.28% of variance of Korean CD, supporting similar genetic structures between the two diseases. Although CD and leprosy shared a substantial number of genetic susceptibility loci in East Asians, the majority of shared susceptibility loci showed allelic effects in the opposite direction. Investigation of the genetic correlation using cross-trait linkage disequilibrium score regression also showed a negative genetic correlation between CD and leprosy (rg [SE] = −0.40[0.13], P = 2.6 × 10−3). These observations implicate the possibility that CD might be caused by hyper-sensitive reactions toward pathogenic stimuli.

01 Dec 2020·Life SciencesQ3 · MEDICINE

TL1A primed dendritic cells activation exacerbated chronic murine colitis

Q3 · MEDICINE

Article

Author: Zhang, Xiaolan ; Song, Jia ; Zhang, Hong ; Shih, David Q ; Han, Fei ; Targan, Stephan R ; Yang, Mingyue ; Wang, Dong ; Jia, Wenxiu

AIMSTumor necrosis factor-like ligand 1A (TL1A) has been proved to activate adaptive immunity in inflammatory bowel disease (IBD). However, its role in the regulation of intestinal dendritic cells (DCs) has not been fully characterized. This study aims to investigate the modulation of TL1A in DCs activation in murine colitis.MATERIALS AND METHODSMyeloid TL1A-Transgenic C57BL/6 mice and wild-type (WT) mice were administrated with dextran sulfate sodium (DSS) to explore the effects of TL1A in murine colitis. Bone marrow-derived DCs (BMDCs) were isolated to detect the ability of antigen phagocytosis and presentation. The expression of nuclear factor-κB (NF-κB) pathway and chemokines receptors (CCRs) was assessed by real-time PCR and Western blot.KEY FINDINGSMyeloid cells with constitutive TL1A expression developed worsened murine colitis with exacerbated T_H1/T_H17 cytokine responses. Intestinal DCs from TL1A transgenic mice expressed high levels of costimulatory molecules (CD80 and CD86) with increased pro-inflammatory cytokines of IL-1β, TNF-α and IL-12/23 p40. Mechanistic studies showed that TL1A enhanced the phagocytotic ability of BMDCs. Moreover, TL1A enhanced the capacity of antigen process and presentation in BMDCs. Besides, TL1A induced the phosphorylation of NF-κB(p65) and IκBα. Meanwhile, higher expression of CCR2, CCR5, CCR7, and CX3CR1 was observed both in vivo and in vitro.SIGNIFICANCETL1A exacerbated DSS-induced chronic experimental colitis, probably through activation and migration of dendritic cells, and therefore increasing the secretion of pro-inflammatory cytokines.

01 Jan 2020·Developmental & Comparative ImmunologyQ2 · BIOLOGY

MicroRNA gga-miR-10a-mediated transcriptional regulation of the immune genes in necrotic enteritis afflicted chickens

Q2 · BIOLOGY

Article

Author: Hong, Yeong Ho ; Truong, Anh Duc ; Lillehoj, Hyun S ; Ban, Jihye ; Lee, Kyungbaek ; Pham, Thu Thao ; Hong, Yeojin ; Lee, Jiae

miRNAs are involved in both adaptive and innate immune systems of host animals; and play important roles in many immune-related pathways. The systemic biological roles of gga-miR-10a-5p chicken microRNA on immune response were investigated in two necrotic enteritis (NE) induced chicken lines, Marek's disease (MD) resistant (line 6.3) and susceptible (line 7.2). We determined the expression patterns of gga-miR-10a in the intestinal mucosal layer of chickens upon NE induction, and identified the target genes (MyD88, and SKP1) related to the host immune response to pathogens. We found that gga-miR-10a expression in the intestinal mucosal layer of MD-resistant chicken line 6.3 gga-miR-10a was significantly down-regulated (p < 0.01) during NE. Overexpression analysis of gga-miR-10a and reporter gene analysis using a wild- or mutant-type MyD88 3' untranslated region (3' UTR)-luciferase construct in chicken macrophage cell line HD11 and chicken fibroblast cell line OU2 showed that gga-miR-10a acted as a direct translational repressor of MyD88 by targeting the 3' UTR of this gene. Furthermore, miR-10a indirectly negatively influenced the expression of signaling molecules related to the MyD88-dependent pathway, including TRAF6, TAK1, and NF-κB1 at both transcriptional and translational levels. Downstream of the MyD88-dependent pathway, several proinflammatory cytokines such as IL-1β, IFN-γ, IL-12p40, TNFSF15, and LITAF were down-regulated by overexpression of gga-miR-10a. These results suggest that gga-miR-10a is an important regulator of the Toll-like receptor signaling pathway. The findings of this study improve our understanding of the biological functions of miR-10a and the mechanisms underlying the TLR signaling pathway upon NE afflicted chickens, as well improving the overall understanding of the immune system function in domestic animals.

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