Animal models of inhibitors

Reipert, Birgit M.; Arruda, Valder R.; Lillicrap, David

doi:10.1111/j.1365-2516.2010.02293.x

Cited by 15 publications

(12 citation statements)

References 53 publications

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“…Animal models can provide this complex immunologic environment, but here it is important to realize that human FVIII infused in knockout mice or rats, is a xenoprotein with a homology of only 51% compared to rat FVIII [59]. Novel transgenic mouse models with human MHC II expression are generated to study inhibitor development and tolerance [60,61].…”

Section: Preclinical Datamentioning

confidence: 99%

An update on the ‘danger theory’ in inhibitor development in hemophilia A

Schep

Boes

Schutgens

et al. 2019

Expert Review of Hematology

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Introduction: Nowadays, one of the most serious treatment complications in hemophilia A is the formation of neutralizing antibodies against coagulation factor VIII (FVIII). These so-called inhibitors develop in about 30% of all patients with severe hemophilia A. Once formed, inhibitors reduce FVIII efficacy in blood coagulation, which has a negative impact on patients' health and quality of life and significantly increases hemophilia A treatment costs. The pathophysiology of inhibitor development is a complex and multi-causal process, in which both genetic factors as well as environmental factors participate. So-called 'danger signals' are considered contributors to inhibitor formation, and can be triggered by surgery, joint bleeds or infections. A pro-inflammatory tissue micro-environment is thereby established, which is characterized by the upregulation of costimulatory molecules on antigen-presenting cells (APCs), that can facilitate the alloimmunization to FVIII and thereby inhibitor formation. Here, the authors will discuss evidence from (pre)clinical studies about this theory in hemophilia A. Areas covered: In this review, the current knowledge regarding the 'danger theory' with regard to inhibitor development in hemophilia A is summarized. Expert opinion: Danger signals might contribute to inhibitor development; however, the evidence is scarce and not conclusive. Future studies, like multinational registries, are warranted but challenging. ARTICLE HISTORY

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Section: Preclinical Datamentioning

confidence: 99%

An update on the ‘danger theory’ in inhibitor development in hemophilia A

Schep

Boes

Schutgens

et al. 2019

Expert Review of Hematology

View full text Add to dashboard Cite

show abstract

“…However, to date, all potentially important immunological mechanisms of tolerance have been studied in animals [43,[45][46][47][48]51]; advances in mouse, dog and non-human primate models were recently reviewed [52]. Several such observations have been or are being corroborated through the in vitro study of haemophilic inhibitor plasma [43,44,[48][49][50].…”

Section: Immune Tolerance Induction In Hemophilia 217mentioning

confidence: 99%

Immune tolerance induction in haemophilia: evidence and the way forward

Michele

2011

Journal of Thrombosis and Haemostasis

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To cite this article: Di Michele DM. Immune tolerance induction in haemophilia: evidence and the way forward. J Thromb Haemost 2011; 9 (Suppl. 1): 216-225.Summary. Given the inhibitor-associated morbidity resulting from limited effective treatment options, antibody eradication is the ultimate goal of inhibitor management. The only clinically proven strategy for achieving antigen-specific tolerance to factor VIII is immune tolerance induction (ITI). First reported over 30 years ago, much of our current knowledge about ITI in haemophilia A and B was derived from small cohort studies and retrospective national and international ITI registries. More recently, prospective randomised ITI trials have been designed and initiated to answer outstanding questions related to the optimisation of current therapeutic strategy in haemophilia A. However, due to the low incidence of inhibitor development in haemophilia B compared to haemophilia A, there are few comparable data from which to develop a useful evidence-based approach to the prevention and eradication of FIX inhibitors. The lack of an effective strategy is particularly problematic given the even greater morbidity associated with the almost unique occurrence of allergic and anaphylactic reactions that often herald FIX antibody development, and further complicates attempts to eradicate FIX inhibitors. Ultimately, successful inhibitor prevention and eradication strategies for both diseases will emerge from the clinical translation of our evolving knowledge of immune stimulation and tolerance. This paper will discuss our current understanding of immune tolerance outcome and outcome predictors for haemophilia A and B; it will also review the current consensus recommendations for ITI, as well as the emerging scientific body of immunological knowledge that may significantly impact the therapeutic and preventative strategies of the future.

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“…Novel transgenic mouse models are generated to study inhibitor development and tolerance . In the first model, expression of mouse MHC class II molecules is replaced by human MHC II in order to study the antigen presentation of human FVIII.…”

Section: Rodent Models To Study the ‘Danger Theory’mentioning

confidence: 99%

First preclinical support for the ‘danger theory’ in inhibitor development

2016

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Development of an antibody response directed against the administered clotting factor is the most important treatment-related complication in haemophilia. These antibodies are called inhibitors when besides binding to the factor VIII/IX (FVIII/FIX) molecule, its functionality is also neutralized. Inhibitors usually develop within the first 50 exposure days (EDs) to treatment, with reported frequencies of 25-30% in previously untreated patients (PUPs) with severe haemophilia A, and 5-7% in PUPs with severe haemophilia B [1,2]. Although much more rarely, inhibitors can also develop in previously treated patients.Various factors are associated with inhibitor development: gene mutation, family history, race or ethnicity, immunological varieties and therapy-associated factors (intensity, age at first treatment, type of concentrate used) [3][4][5]. Knowledge of the mechanisms underlying inhibitor development is important to adapt treatment strategies in order to prevent its occurrence.In this issue of Haemophilia, L€ ovgren et al. describe the influence of joint bleeds on the antibody response towards recombinant human FVIII in their recently developed haemophilia A rat model. Following the hypothesis that presence of 'danger signals' induces a faster inhibitor response with higher inhibitor levels in rats treated on-demand after a joint bleeding, this study offers new insights on the role of inflammation in inhibitor development.

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Animal models of inhibitors

Abstract: Summary. Antibody responses to clotting factor concentrates remain a major treatment limitation. In conjucation with ongoing clinical studies, the pathogenesis and potential treatment of clotting factor immune responses is being evaluated in a variety of animal models.

Cited by 15 publications

References 53 publications

An update on the ‘danger theory’ in inhibitor development in hemophilia A

An update on the ‘danger theory’ in inhibitor development in hemophilia A

Immune tolerance induction in haemophilia: evidence and the way forward

First preclinical support for the ‘danger theory’ in inhibitor development

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