62B. M. Reipert et al.Figure 5. Relation of neutralizing anti-FVIII antibodies (Bethesda titer) and total anti-FVIII antibodies (ELISA titer) in hemophilicE-17 mice after treatment with FVIII together with or without anti-CD40 ligand antibody. 200 mg anti-mouse CD40 ligand antibodyMR1 were given intravenously 24 hours before treatment with FVIII as described in Reipert et al. 29 Each point representsvalues for an individual mouse. Mice received the treatments as indicated at weekly intervals. 200 ng FVIII (80 U/kg) weregiven per dose. All analyses were done as described. 29 From Reipert et al. 29 with permission.treated with infusions of FVIII concentrates.Depending on the type of gene mutation, theFVIII in these concentrates might be recognized bythe patient’s immune system as a foreign proteinor an altered self-protein. In addition, othergenetic factors such as the HLA haplotype arebelieved to influence the anti-FVIII immuneresponse. Considering this heterogeneous situation,obviously no single animal model canaccommodate all the different aspects of the anti-FVIII immune response in patients.Therefore, we have to be aware that each animalmodel that we use, and will use in the future,to search for new approaches for inducing toleranceto FVIII has its advantages and its limitations.Furthermore, it must not be forgotten thatexperimental studies in animal models can onlyprovide new ideas, proof of concepts and strategiesfor therapeutic approaches and it is the clinicaltrial that will always be the ultimate tool forleading to therapeutic advances.AcknowledgmentsWe are grateful to Howard M. Reisner for his criticalreview and Elise Langdon-Neuner for editingthe manuscript.References1. Schwaab R, Brackmann HH, Meyer C, Seehafer J,Kirchgesser M, Haack A, et al. Haemophilia A: Mutationtype determines risk of inhibitor formation. ThrombHaemost 1995;74:1402-6.2. Tuddenham EGD, McVey JH. The genetic basis ofinhibitor development in hemophilia A. Haemophilia1998;4:543-5.3. Fakharzadeh SS, Kazazian HH. Correlation between factorVIII genotype and inhibitor development in hemophiliaA. Sem Thromb Hemost 2000;26:167-71.4. McGinniss MJ, Kazazian HH, Hoyer LW, Bi L, Inaba H,Antonarakis SE. Spectrum of mutations in CRM-positiveand CRM-reduced hemophilia A. Genomics 1993;15:392-8.5. Vergnolle N, Wallace JL, Bunnett NW, Hollenberg MD.Protease-activated receptors in inflammation, neuronalsignalling and pain. Trends Pharmacol Sci 2001; 22:146-52.6. Camerer E, Huang W, Coughlin SR. Tissue factor- andfactor X-dependent activation of PAR2 by factor VIIa.Proc Natl Acad Sci USA 2000;97:5255-60.7. Asokananthan N, Graham PT, Fink J, Knight DA,Bakker AJ, McWilliam AS et al. Activation of proteaseactivatedreceptor (PAR)-1, PAR-2, and PAR-4 stimulatesIL-6, IL-8, and prostaglandin E2 release fromhuman respiratory epithelial cells. J Immunol 2002;168:3577-85.8. Bi L, Lawler AM, Antonarakis SE, High KA, Gearhart JD,Kazazian Jr HH. Targeted disruption of the mouse factorVIII gene produces a model of haemophilia A. Nathaematologica vol. 88(supplement n. 12):september <strong>2003</strong>
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