title: Enhanced Innate Inflammation Induced by Anti-BTLA Antibody in Dual Insult Model of Hemorrhagic Shock/Sepsis.
abstract: Sepsis following hemorrhagic shock is a common clinical condition, in which innate immune system suffers from severe suppression. B and T lymphocyte attenuator (BTLA) is an immune-regulatory coinhibitory receptor expressed not only on adaptive, but also on innate immune cells. Our previous data showed that BTLA gene deficient mice were protected from septic mortality when compared with wild-type control C57BL/6 mice. Here, we extended our study by treating C57BL/6 mice with an anti-BTLA monoclonal antibody (clone 6A6; reported to have the ability to neutralize or agonize/potentiate BTLA signaling) in a mouse model of hemorrhagic shock (Hem) followed by sepsis induced by cecal ligation and puncture (CLP); positing initially that if BTLA engagement was neutralized, like gene deficiency, an anti-BTLA mAb would have the similar effects on the inflammatory response/morbidity in these mice after such insults. Here, we report that BTLA expression is elevated on innate immune cells after Hem/CLP. However, anti-BTLA antibody treatment increased cytokine (TNF-α, IL-12, IL-10)/chemokine (KC, MIP-2, MCP-1) levels and inflammatory cells (neutrophils, macrophages, dendritic cells) recruitment in the peritoneal cavity, which in turn aggravated organ injury and elevated these animals' mortality in Hem/CLP. When compared with the protective effects of our previous study using BTLA gene deficient mice in a model of lethal septic challenge, we further confirmed BTLA's contribution to enhanced innate cell recruitment, elevated IL-10 levels, and reduced survival, and that engagement of antibody with BTLA potentiates/exacerbates the pathophysiology in Hem/sepsis.
authors.affiliation: *Department of Emergency Internal Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China †Division of Surgical Research, Department of Surgery, Rhode Island Hospital, The Alpert School of Medicine at Brown University ‡Pathobiology Graduate Program, Division of Biology and Medicine, Brown University, Providence, Rhode Island.
authors.forename: Tingting
authors.initials: T
authors.lastname: Cheng
authors.forename: Jianwen
authors.initials: J
authors.lastname: Bai
authors.forename: Chun-Shiang
authors.initials: CS
authors.lastname: Chung
authors.forename: Yaping
authors.initials: Y
authors.lastname: Chen
authors.forename: Bethany M
authors.initials: BM
authors.lastname: Biron
authors.forename: Alfred
authors.initials: A
authors.lastname: Ayala
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D058491:Bacterial Load / Q000276:immunology; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D007113:Immunity, Innate; D007249:Inflammation / Q000209:etiology / Q000276:immunology* / Q000382:microbiology; D007962:Leukocytes / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008297:Male; D008810:Mice, Inbred C57BL; D010529:Peritoneal Cavity / Q000166:cytology; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology*; D018805:Sepsis / Q000209:etiology / Q000276:immunology* / Q000382:microbiology; D012771:Shock, Hemorrhagic / Q000150:complications / Q000276:immunology* / Q000382:microbiology
chemical_list: D000911:Antibodies, Monoclonal; C488868:BTLA protein, mouse; D018925:Chemokines; D016207:Cytokines; D008070:Lipopolysaccharides; D011971:Receptors, Immunologic