PB0143 - Induced B cell tolerance in Hemophilia A mice is destroyed by infections

Sunday, June 25, 2023

18:30 – 19:30 ET

Room: Exhibition

Co-Author(s)

BJ

Blanca Jurado-Mestre

PhD Student
Institute of Molecular Medicine and Experimental Immunology (IMMEI), University Clinic Bonn
Bonn, Nordrhein-Westfalen, Germany
AA

Amina Abdelmageed

PhD Student
Institute of Molecular Medicine and Experimental Immunology (IMMEI), University Clinic Bonn
Bonn, Nordrhein-Westfalen, Germany
VK

Vadim Kotov

Technician
Institute of Molecular Medicine and Experimental Immunology (IMMEI), University Clinic Bonn
Bonn, Nordrhein-Westfalen, Germany
TA

Thilo Albert

Dr. rer. nat.
Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn
Bonn, Nordrhein-Westfalen, Germany
Johannes Oldenburg, MD (he/him/his)

Professor, Chairman and Director
University Clinic Bonn AöR, Institute of Experimental Haematology and Transfusion Medicine, Bonn, Germany
Bonn, Nordrhein-Westfalen, Germany
CK

Christian Kurts

Director
Institute of Molecular Medicine and Experimental Immunology (IMMEI), University Clinic Bonn
Bonn, Nordrhein-Westfalen, Germany

Presenting Author(s)

Janine Becker-Gotot, Dr rer nat (she/her/hers)

Junior Group Leader
Institute of Molecular Medicine and Experimental Immunology (IMMEI), University Clinic Bonn
Bonn, Nordrhein-Westfalen, Germany

Background: Hemophilia A (HemA) is the most common inherited bleeding disorder, caused by a deficiency in coagulation factor VIII (FVIII). Upon replacement therapy, up to 30% of patients develop inhibitory antibodies (inhibitors), rendering it ineffective. Inhibitor eradication can be accomplished via immune tolerance induction (ITI) therapy which is successful in about 70% of patients.
Recently, antigen-specific induced regulatory T cells (iTregs) expressing PD-L1 were identified as the cell population responsible for mediating suppression. However, the impact of environmental risk factors, like viral or bacterial infections, on tolerance stability remains under debate.

Aims: The aim of this study is to identify potential effects of different infection models on tolerance stability in Hemophilia A mice in an ITI setting and the underlying molecular mechanisms.

Methods: In order to exploit the impact of infections on the FVIII-specific B cell response, 2 UI/mouse of rhFVIII were intravenously injected into HemA mice twice a week for 3 weeks. Afterward, ITI-treated mice were additionally infected with influenza A or S. aureus on day 21. Splenocytes were harvested and analyzed by flow cytometry or by RT-PCR at different time points after infection. Furthermore, blood was tested for inhibitor abundance. Mann-Whitney test was used to determine statistical significance.

Results: Immune tolerance against FVIII, which is established during ITI, is disrupted upon viral or bacterial infection. In detail, FVIII-specific B cells were re-activated, indicated by an abrogated PD-1 and an increased CD80 expression, which in consequence, enhanced the survival of inhibitor-forming B cells. In line, tolerance breakdown is associated with a loss of circulating active FVIII.

Conclusion(s): Here, we propose that ITI, which re-engages the PD-1-mediated tolerance against FVIII, is abolished upon parallel infection, and should be stopped to avoid B cell activation.