2003; baxter - Supplements - Haematologica

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58B. M. Reipert et al.BFigure 2. Long-term persistence of anti-FVIII antibody-secreting cells in spleen and bone marrow and of anti-FVIII antibodies inblood plasma of hemophilic E-17 mice after treatment with human FVIII. From Hausl et al. (17) with permission. Figure 2b: Kineticof anti-FVIII antibody titers in blood of hemophilic mice after one, two, three or four doses of FVIII as well as 5, 10, 14 and22 weeks after the fourth dose of FVIII. Anti-FVIII antibody titers were analyzed by ELISA as described in Hausl et al. (17). Eachpoint represents the result obtained from an individual mouse. Three mice were analyzed per time point.not find any anti-FVIII antibody response afterintravenous application of human FVIII in normalmice, but detected anti-FVIII antibodies afterintraperitoneal application. This antibodyresponse was dependent on the induction ofFVIII-specific T cells. Jarvin et al. 35 and Levin etal. 36 used normal rats and immunized them withhuman FVIII in adjuvant. This treatment scheduleresulted in the induction of an anti-FVIIIimmune response that was characterized by neutralizingantibodies that recognized some of theepitopes that were also found in patients withFVIII inhibitors. The application route thatinduced the anti-FVIII immune response in thesestudies cannot, however, be compared to that forFVIII in patients. Furthermore, treating normalmice and rats with mouse or rat FVIII should notinduce any immune response at all because themurine proteins represent a self protein. Analyticalcomparison of the amino-acid sequence ofmurine and human FVIII has shown that thehomology in the functionally important A and Cdomains is 84-93%, but only 42-70% in thenonfunctional B domain and the acidic regions. 14Therefore, anti-FVIII antibodies developedagainst human FVIII can be expected to be directedpredominantly against the more divergentregions and, accordingly, not to reflect the wholerepertoire of possible antibody responses thatwould be seen in FVIII knockout mice.Another major disadvantage is the lack of ableeding syndrome in normal mice. As mentionedabove the cross-talk between the immunesystem and the coagulation system might beimportant for regulating the immune response toFVIII and should, therefore, be considered in ananimal model.Nevertheless, recent experimental study usingnormal mice should be mentioned. Chao andWalsh reported the loss of neutralizing anti-FVIIIantibodies in normal C57BL/6 mice after sustainedexpression of human FVIII. 37 Antibodieshaematologica vol. 88(supplement n. 12):september <strong>2003</strong>
IV International Workshop on Immune Tolerance in Hemophilia59Figure 3. Representative Elispots showing the frequency of anti-FVIII antibody-secreting cells (total IgG) as well as the IgGsubclassdistribution of anti-FVIII antibody-secreting cells (IgG1, IgG2a, IgG2b, IgG3) in bone marrow and spleen of hemophilicmice after four intravenous doses of 200 ng FVIII (80 U/kg). Serial dilutions of cell samples were incubated with FVIII immobilizedto the solid phase of PVDF-bottomed Multiscreen-IP filtration plates. Each spot represents an individual anti-FVIII antibody-secretingcell. Analyses of antibody-secreting cells were done as described. 17 From Hausl et al. 17 with permission.haematologica vol. 88(supplement n. 12):september <strong>2003</strong>
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Index of authorsAhmad, R.U., 56Albe
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