Immune-monitoring of haemophilia A patients undergoing ITI
Despite clinical experience with the different protocols of ITI, little is known about the immunological mechanisms that cause the downregulation of FVIII-specific immune responses and the induction of long-lasting immune tolerance against FVIII. S. Lacroix-Desmazes will monitor and analyze the modifications of the immune system and the inflammatory status of the patient during the course of ITI.
Hypothesis:
Some clinically relevant immune markers (IMs) might help to predict the positive or negative outcome of the ITI.
The FVIII-inhibitor plasma may be able to affect the differentiation and maturation state of dendritic cells from healthy blood donors.
Method:
Both, cells and plasma collected during the course of ITI therapy will be required to study the IMs in haemophilia A patients with inhibitors. Depending on the amount of blood collected, the IMs will be studied with the following priority:
- IM1: Different subpopulations of circulating T cells
- IM2: Number, maturation state and endocytotic capacity of different antigen-presenting cells
- IM3: Circulating cells that have endocytosed FVIII
- IM4: Number of FVIII-specific B cells
- IM5: Will be studied in any case
Also, quantitative measurements of different interleukins involved in the immune response including INF-γ, TGF-β1 and TNF-α in plasma will be done.
Literature overview:
- Ananyeva NM et al. Inhibitors in haemophilia A: mechanisms of inhibition, management and persepectives. Blood Coagul Fibrinolysis 2004; 15(2): 109-24.
- Lacroix-Desmazes S et al. Dynamics of factor VIII interactions determine its immunologic fate in haemophilia A. Blood 2008; 12(2): 240-49.
- Wroblewska A et al. Dangerous liaisons: how the immune system deals with factor VIII. J Thromb Haemost 2013; 11(1): 47-55.
- Navarrete AM et al. Endocytic receptor for pro-coagulant factor VIII: relevance to inhibitor formation. Thromb Haemost 2010; 104(6): 1093-98.
- Chaves DG et al. A shift towards a T cell cytokine deficiency along with an antiinflammatory/regulatory microenvironment may enable the synthesis of anti-FVIII inhibitors in haemophilia A patients. Clin Exp Immunol 2010; 162(3): 425-37.