Page 167 - Haematologica August 2018

Coagulation & Its Disorders
Dexamethasone promotes durable factor VIII-specific tolerance in hemophilia A mice via thymic mechanisms
Maria T. Georgescu,1 Paul C. Moorehead,2,3 Alice S. van Velzen,4 Kate Nesbitt,1 Birgit M. Reipert,5 Katharina N. Steinitz,5 Maria Schuster,5 Christine Hough1 and David Lillicrap1
1Department of Pathology and Molecular Medicine, Queen’s University, Kingston, ON, Canada; 2Janeway Children’s Health and Rehabilitation Centre, St. John’s, NL, Canada; 3Faculty of Medicine, Memorial University, St. John’s, NL, Canada; 4Department of Pediatric Hematology, Immunology and Infectious Diseases, Emma Children’s Hospital, Amsterdam, the Netherlands and 5Baxalta Innovations GmbH, Vienna, Austria
ABSTRACT
The development of inhibitory antibodies to factor VIII is the most serious complication of replacement therapy in hemophilia A. Activation of the innate immune system during exposure to this protein contributes to inhibitor development. However, avoidance of factor VIII exposure during innate immune system activation by external stimuli (e.g., vaccines) has not been consistently shown to prevent inhibitors. We hypothesized that dexamethasone, a drug with potent anti-inflammatory effects, could prevent inhibitors by promoting immunologic tolerance to factor VIII in hemophilia A mice. Transient dexamethasone treatment during ainitial factor VIII exposure reduced the incidence of anti-factor VIII immunoglobulin G in both a convention- al hemophilia A mouse model (E16KO, 77% vs. 100%, P=0.048) and a hemophilia A mouse model with a humanized major histocompatibility complex type II transgene (E17KO/hMHC, 6% vs. 33%, P=0.0048). More importantly, among E17KO/hMHC mice that did not develop anti- factor VIII immunoglobulin G after initial exposure, dexamethasone- treated mice were less likely to develop a response after re-exposure six (7% vs. 52%, P=0.005) and 16 weeks later (7% vs. 50%, P=0.097). Similar results were obtained even when factor VIII re-exposure occurred in the context of lipopolysaccharide (30% vs. 100%, P=0.069). The abil- ity of these mice to develop immunoglobulin G to human von Willebrand factor, a structurally unrelated antigen, remained unaffected by treatment. Transient dexamethasone administration therefore pro- motes antigen-specific immunologic tolerance to factor VIII. This effect is associated with an increase in the percentage of thymic regulatory T cells (12.06% vs. 4.73%, P<0.001) and changes in the thymic messenger ribonucleic acid transcription profile.
Introduction
Neutralizing antibodies (inhibitors) against factor VIII (FVIII) develop in approxi- mately 30% of treated severe hemophilia A (HA) patients, remaining the major com- plication of therapy in this disease.1 The gold standard for eliminating inhibitors, immune tolerance induction (ITI), is difficult to administer, incompletely effective2 and expensive.3 Strategies for preventing inhibitors are therefore needed. The risk of developing inhibitors is not completely predicted by known patient-related genetic risk factors (e.g., f8 genotype,4 polymorphisms in Il10, Ctla4, Tnfa, major histocom- patibility complex class II [MHCII]5), suggesting that inhibitor risk is modifiable.
Inhibitors are high-affinity immunoglobulin (Ig) G antibodies that are the result of cognate interactions between FVIII-specific B cells and follicular T helper cells (Tfhs). Tfhs are derived from naïve CD4+ T cells following interactions with mature dendritic cells (DCs).6 In contrast, the interaction of naïve CD4+ T cells
Ferrata Storti Foundation
Haematologica 2018 Volume 103(8):1403-1413
Correspondence:
david.lillicrap@queensu.ca
Received: January 30, 2018. Accepted: April 19, 2018. Pre-published: April 19, 2018.
doi:10.3324/haematol.2018.189852
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/8/1403
©2018 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
haematologica | 2018; 103(8)
1403
ARTICLE