The ability of conventional ITI protocols involving high-dose FVI

The ability of conventional ITI protocols involving high-dose FVIII infusion to reduce inhibitor titres may relate

to inhibiting the re-stimulation Selleck FK506 of FVIII-specific memory B cells and their differentiation into antibody-secreting plasma cells. In vitro and in vivo experiments in a mouse model of haemophilia A indicated that inhibition of memory B cell responses correlated with FVIII dose (Fig. 11) and that inhibition was irreversible at an FVIII dose of 20 μg mL−1 [37]. Elimination of B cells with rituximab is a feasible approach to inhibitor eradication but is not a permanent solution in all patients. Although long-term inhibitor eradication has been reported in patients following successful ablation of B cell with rituximab, it is expected that most patients will experience inhibitor relapse after B-cell repopulation [43]. Application of anti-idiotypic antibodies presents another means of interfering with the B-cell-mediated immune response. In recent experiments, mice were infused with an inhibitory monoclonal antibody against FVIII (GMA8021; Green Mountain Antibodies, Burlington, VT, USA). Addition of a highly specific anti-idiotype (JkH5) blocked the effects of GMA8021in a concentration-dependent fashion such that FVIII residual activity increased in line with higher concentrations of JkH5. Is it possible go even further

and translate these findings into clinical applications? Currently, collaborations with investigators from several Y-27632 cost major ITI studies including the International ITI Study and RES.I.ST allow the analysis of epitopes and IgG subclasses. The aim is to correlate molecular biology data with clinical outcomes and ITI course to increase understanding of the immune response, establish relevant biomarkers and improve prognosis for the patient. The success of ITI therapy depends largely on the inhibitor titre at the start of treatment. Other possible factors include genetic risk, type of concentrate (recombinant or plasma-derived), presence of danger signals (e.g. infections, surgery, immunizations etc). Data are also accumulating

which point to the influence of antibody signature on ITI course and success. Antibody epitopes have been shown to affect the reactivity of a patient’s plasma with different FVIII concentrates Astemizole in vitro [21-23, 25] as well as influence the course and success of ITI therapy [21, 24, 44, 45]. Van Helden and coworkers characterized the domain specificity of FVIII inhibitors in 11 patients with haemophilia receiving ITI [45]. In five patients, the relative contribution of anti-light chain or A2 inhibitors changed during the course of treatment. Antibodies directed towards the A2 domain of FVIII were observed in more patients who failed ITI, whereas antibodies exclusively directed towards the light chain were seen predominantly in patients who achieved successful tolerization.

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