Haematologica 2000;85:supplement to no. 10 - Supplements ...

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Immune Tolerance and the Treatment of Hemophilacs with an Inhibitor 13 ISTH Florence. Thromb Haemost 1997; Suppl:162. 28. Gruppo R, Chen H, Schroth P, Bray GL. Safety and immunogenicity of recombinant factor VIII (Recombinate) in previously untreated patients (PUPs). A 7.3 year update. WFH The Hague. Haemophilia 1998; 4:228. 29. Addiego JE, Kasper C, Abildgaard C, et al. Increased frequency of inhibitors in African American hemophilia A patients. ASH Nashville. Blood 1994; (Suppl):239. 30. Development of factor VIII antibody in haemophilic monozygotic twins. European Study Group of Factor VIII Antibody. Scand J Haematol 1979; 23:64-8. DISCUSSION 2. Risk factors for inhibitor development Oldenburg, J. Schwaab, R (Bonn) ALEDORT: Thank you for that very extensive discussion and provocative commentary Dr. Hoyer. I would like to call on you to comment on HLAs. This is an issue you have brought to the literature before and been very interested in, and then I’d like to ask Dr. Di Michele to comment on the inflammatory issue because it’s something she has been very interested in and concerned about. Dr. Hoyer could you start HOYER: I’m afraid I can’t add very much to that very nice discussion of HLA. I think that the bottom line is that it seems that there is some relation, but it is certainly not the dominant factor and this is certainly consistent with all of the earlier studies concerning smaller groups of patients; certainly the Intron-22 Inversion Population is the one to study. It’s been studied and the answer was maybe. ALEDORT: Dr. Di Michele do you want to comment on your interest and concern I would just like to add another factor in looking at surrounding environmental differences in people developing inhibitors and those not. It is not uncommon for the surgical setting in which it’s either the surgery itself or large quantities of antigen but I would add that there is certainly some evidence that a patient having surgery is more likely to develop an inhibitor than one not having surgery. Dr. Di Michele could we have a comment from you DI MICHELE: I don’t think I can say it any better than Dr. Oldenburg and you when you made your comment. I think it’s something that we have all observed clinically, particularly in pediatric patients in whom we’ve watched inhibitortiters wax and wane in association with any inflammatory stimulus, usually illness. I just want to add that we are going to look at this issue and Dr. Hay will comment on this a little more when he talks about the International Immune Tolerance Study Protocol. We are also interested in the question of inflammatory responses on success of immune tolerance for exactly those reasons and all of those inflammatory stimuli that you mentioned will be carefully recorded in the International Immunetolerance Study Protocol to try to assess their impact on outcome. RYPERT: I think the problem with the assessment is the risk of these HLA alleles is that we don’t know anything about T-cell epitopes. I think there were three haplotypes in MC class II. Have you ever looked at any data base with these particular haplotypes which might be particularly likely to bind certain peptides within the FVIII molecule that could be T-cell epitopes OLDENBURG: No, we have not done this and it’s a problem that the haplotypes that are common in the inhibitor patients are also common in the normal population and so it’s difficult to differentiate from the background. RYPERT: What about patients that form autoantibodies against FVIII; would you find the same HLA types OLDENBURG: This a very rare occurrence and we are at present gathering samples of this group. We have about twenty-five and we are trying to increase the number in order to look at this point. These were two subsets of groups with a control group of forty patients and inhibitor was intron 22 inversion of thirty patients and I think we need at least this size to get an answer to this question. LILLICRAP: I wanted you to comment on this ten per cent of patients in which you looked for mutations and didn’t find them. First of all you put this down to a lack of sensitivity in the methodology which it may well be, but do you have a sense of whether these might be cryptic splice sites within introns Is it possible that some of these mutations may be elsewhere and not at factor VIII And then whether you’ve got enough numbers to say whether that ten percent of individuals have a higher or lower incidence of inhibitor formation OLDENBURG: This is a very interesting question. We have looked at about 107 patients at the Haemophilia Centre in Bonn and we found that the fact that we don’t find the mutation is connected with the risk factor of about 1.7 for developing an inhibitor which was in the same range as for intron 22 inversion. We are using the DGGE method which looks at the melting behavior of DNA and for the B-domain done by Haematologica vol. 85(supplement to n. 10):October 2000
14 J. Oldenburg et al. Dr. Schwaab who uses chemical-mismatch cleavage. We think that most of the sensitivity is due to the method we have been using; this is for two reasons: we have looked at a subset of patients in which we were unable to find the mutation with DGGE by another method based on HPLC and we were able to find some mutation in two thirds of these patients. I think this number can be increased. LUSHER: Dr. Oldenburg this intriguing question of the inflammatory reaction and how much that adds to inhibitor development when we look at small children with severe hemophilia they all have bleeding episodes, childhood diseases and most of them have vaccinations and so we need to ask if it is a matter of degree and severity of these things or how do you envisage this is affecting the development of an inhibitor OLDENBURG: I think this is really difficult to answer and we can speculate that it is when such immune system challenge occurs in relation with the administration of factor VIII: when it is administered very close to an immune system challenge of another type it may be of higher significance in terms of inhibitor formation but this is only speculation. I think the answer will come from the immune tolerance studies to induce new tolerance status because all the factors I pointed out, as Dr. Aledort already mentioned, are of the same importance for the outcome and duration of immune tolerance therapy. SAINT REMY: My comment regards your comments about inflammation and its role in the generation of inhibitors. It’s probably no coincidence that the majority of inhibitors pertain to the IgG 4 subtype because the subclass of IgG 4 is driven by interferon and the main cytokine which is produced during inflammation is indeed interferon. HOYER: That is a very important point and I think that one of the things that is coming from the sequential clinical studies is increased gathering of information that may be able to clarify these studies. We just don’t have enough data on the incidence of bleeding, size of bleeding and treatment. I think your point that maybe not all bleeding episodes are the same in that a large bleed may be different from a smaller one in terms of its risk for inhibitor development is a very good point. One thing I’d like to add to your comments about gene therapy and treatment regards the fact that your data were for factor IX. We have a very small amount of information that is consistent with the opposite effect; that is, in the hemophiliac mouse you can very easily induce with plasma factor VIII or with recombinant factor VIII an immune response by intravenous injection but on the other hand in the adenovirus derived gene therapy studies inhibitor formation was not been seen. In this case it would appear to be the opposite but it’s a different factor and a different model and so I don’t know if they can be generalized. Haematologica vol. 85(supplement to n. 10):October 2000
Page 1 and 2: Haematologica established in 1920 e
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76 H-H. Brackmann et al. Table 1a.
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