Thursday July 05, 2018 from 09:45 to 11:00
Anti-TIRC7 Antibody Treatment Prevents Rejection of Mice Cardiac Allografts while Immune Competency to Viral and Bacterial Antigens Remain Normal
Stefan G Tullius1, Yusuke Kumamoto2, Rolf M Zinkernagel3, Nalân Utku4.
1Department of Medicine, Transplant surgery , Brigham and Women`s Hospital, Boston, MA, United States; 2Department of Surgery, Kitasato University School of Medicine, Kanagawa, Japan; 3Institute for Experimental Immunology, University Hospital, Zürich, Switzerland; 4Institut for Medical Immunology, Charite, Berlin, Germany
Introduction: T cell immune response c-DNA (TIRC7) is expressed in activated lymphocytes binding to its ligand HLA-class II protein in response to alloantigens. Notably, TIRC7 is mainly induced in activated lymphocytes at the site of the inflammation. Thus, unlike other immunosuppressive agents, treatment with an anti-TIRC7 does not interfere with an overall immune competency. Here, anti-TIRC7 antibody (mAb) treatment was compared with Cyclosporin A (CyA) treatment in a mouse cardiac transplant model. As currenty used therapeutics to prevent rejection act unspecifically with severe side effects including infections, we tested the overall immue competency in the presence of anti-TIRC7 mAb treatment and challanged mice with infectious antigens.
Method: Fully vascularized heterotopic allogeneic heart transplants were performed across a full-mismatch barrier (C57BL/10 into CBA). Recipients mice received anti-TIRC7 mAb (40mg/kg, day 0-7) and compared to treatments with CyA (10mg/kg for either 7 or 14 days or an untreated control n=5-7/group.
In an additional experiment, two experimental model systems for viral infections - non-cytopathic lymphocytic choriomeningitis virus (LCMV) and acutely cytopathic vesicular stomatitis virus (VSV) in addition to Listeria monocytogenes (LM) infections were used to analyse fundamentally different types of antiviral and bacterial antibody responses in the presence or absence of anti-TIRC7 mAb. LCMV responses were examined after injecting 200pfu LCMV into the footpad of B6 mice and response was assessed by CTL assays. VSV triggers the production of IFN-I in mice leading to augmentation of specific B cell responses. IgG and IgM titer against VSV was analyzed up to 20d post infection. Listeria monocytogenes (LM) provides a means for introducing antigens into the class I pathway of antigen presentation and induces CD4 response. 1000cfu LM was injected i.v and LM-titers were assessed in spleen and liver (n=4/experiment).
Results: Mean cardiac allograft survival in anti-TIRC7 mAb treated mice was 52 days with some grafts working > 140 days, in sharp contrast to CyA treated mice and controls with a mean graft function of 8days. Morphology of allografts showed diminished lymphocyte infiltration in anti-TIRC7 mAb treated allografts. Mice cleared the LCMV infection within 15 d. Anti-VSV IgG and IgM antibody titers were highest at 15 d post infection. Mice liver and spleen infected with LM were protected in anti-TIRC7 mAb treated mice as assessed at day 4 post infection.
Conclusion: Ligation of TIRC7 regulates immune activation at the site of inflammation while the function of peripheral blood lymphocytes remains normal. Mice treated with anti-TIRC7 mAb mounted normal immune responses to infections. Thus, targeting TIRC7 may provide a novel therapeutic approach to specifically modulate alloimmune responses.