Roles of programmed death-1 (PD-1)/PD-1 ligands pathway in the development of murine acute myocarditis caused by coxsackievirus B3

Abstract

Objective: This study was designed to investigate the roles of programmed death-1 (PD-1) and PD-1ligands (PD-L) in the development of murine acute myocarditis caused by Coxsackievirus B3. PD-1/PD-L belong to the CD28/B7 superfamily, and the PD-1/PD-L pathway is known to transduce a negative immunoregulatory signal that antagonizes the T-cell receptor-CD28 signal and inhibits T-cell activation. Methods: We first analyzed the expression of PD-L1/PD-L2 on cardiac myocytes in vivo and in vitro. Second, we examined the effects of in vivo treatment with an anti-PD-1, PD-L1, or PD-L2 monoclonal antibodies on the development of myocardial inflammation in C3H/He mice infected with Coxsackievirus B3. Third, to investigate the effects of anti-PD-1 monoclonal antibody treatment on the activation of the infiltrating cells, we examined the expression of interleukin (IL)-2, interferon (IFN)-γ, CD40 ligand (CD40L), Fas ligand (FasL), and perforin as activation markers in mouse hearts by a semiquantitative PCR method. Results: PD-L1 was markedly induced on cardiac myocytes with acute myocarditis. In vivo anti-PD-1 or -PD-L1 blocking monoclonal antibody treatment increased the myocardial inflammation whereas anti-PD-1 stimulating monoclonal antibody treatment decreased the myocardial inflammation, and anti-PD-L2 monoclonal antibody treatment had no effect. Anti-PD-1 monoclonal antibody treatment significantly increased the expression of IFN-γ, FasL, CD40L, perforin, and Coxsackievirus B3 genomes in myocardial tissue. Conclusion: Our findings strongly suggest that the PD-1/PD-L1 pathway played a pivotal role in suppressing myocardial inflammation and raise the possibility of immunotherapy by stimulating the PD-1/PD-L1 pathway to prevent myocardial damage in viral myocarditis.

Programmed cell death 1 (PD‐1) and its ligand PD‐L1 are required for allograft tolerance

“…Similarly, no agonistic anti-CTLA-4 mAb are yet described, although transgenic NOD mice expressing a single-chain, membrane-bound anti-CTLA-4 antibody on B cells show protection against development of autoimmune diabetes [21]. By contrast, agonist mAb to PD-1 and fusion proteins, such as PD-L1.Ig, have proven effective in disease models by increasing inhibitory signals within activated T cells [12,22]. The current studies suggest that PD-1 signaling serves to curtail T cell alloactivation, proliferation and cytokine production, and promotes anergy following costimulation blockade.…”

Programmed Death-1 Pathway in Host Tissues Ameliorates Th17/Th1-Mediated Experimental Chronic Graft-versus-Host Disease

“…Anti-mouse PD-1 agonistic mAb (PIM2) for in vivo experiments was prepared as described previously, and 200 mg was administered i.v. on days 14, 17, 20, 23, and 26 after BMT (28). Recipients were administered Am80 (1.0 mg/kg body weight; Nippon Shinyaku) or vehicle solution orally daily from day 0.…”

PD-1 Protects against Inflammation and Myocyte Damage in T Cell-Mediated Myocarditis

“…Despite a significant body of work devoted to the pathogenesis of myocarditis in various models, relatively little work has been done on the roles of the B7/CD28 family of molecules that likely regulate the activation of pathogenic T cell responses in these models (24, 25). One group has previously studied the effects of blocking PD-1 and PD-L1 in coxsackievirus-induced myocarditis in mice (24).…”

“…One group has previously studied the effects of blocking PD-1 and PD-L1 in coxsackievirus-induced myocarditis in mice (24). Additionally PD-L1 or PD-1 deficiency has been implicated in causing spontaneous myocarditis in MRL mice (26, 27).…”