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Immune Tolerance and the Treatment of Hemophilacs with an Inhibitor 105 Figure 1. The anti-FVIII activity, evaluated in a chromogenic assay, of purified anti-FVIII Abs from SCID mice reconstituted with cells from healthy donors. Similar results were obtained with the anti-FVIII Ab fractions from the source donors. 12 SCID mice and anti-CD40 ligand Anti-FVIII antibodies can only be produced when efficient help is provided by specific T-cells. This help includes 2 signals besides the production of cytokines. The first signal is the presentation of a FVIII peptide to the TCR in the frame of MHC class II molecules. In the absence of a second signal, the B-T cell interaction results in anergy rather than activation. The second signal is constituted by interaction of antigen-nonspecific, accessory molecules, complementary structures on the membrane surface. One important accessory molecule interaction is the binding of CD40L on T-cells to CD40. CD40L is transiently expressed (2 to 24 hours) on helper (CD4 + ) T-lymphocytes following early activation (usually mediated through the TCR). 14-16 The molecule plays an early and important role in the interaction of these activated T-lymphocytes with cells expressing CD40. CD40-bearing cells include B-ymphocytes, vascular endothelial cells, macrophages, dendritic cells, various epithelial cell types, and fibroblasts, inter alia. Administration of an antibody blocking the CD40L-CD40 interaction during immunization with protein antigens can specifically block the antibody response to that antigen in a mouse model. 17 Total serum Ig and antibody responses to proteins administered outside of the window of CD40L blockade are not affected. Preclinical studies in a variety of autoimmune disease models have shown that blockade of this pathway with antibodies to CD40L can substantially reduce symptoms of disease and, in some cases, reduce mortality. 18-21 The antibodies have also been used to induce long-term graft acceptance in allogeneically mismatched transplant settings. 22-24 The impressive activity of anti- CD40L antibody therapy in a variety of both antibody-and cell-mediated autoimmune diseases, and in organ transplantation, suggests that blockade of the CD40L-CD40 interaction will be therapeutically useful in human disease. This is why we have evaluated this CD40L- CD40 interaction to block the anti-FVIII humoral response in SCID mice reconstituted with cells of a hemophilia A patient with inhibitors. Preliminary experiments showed an important decrease in the anti-FVIII antibody production in reconstituted mice injected with FVIII and anti-CD40L antibody when compared to control group. SCID-FVIII-knock-out mice Direct detection of natural specific antibodies in mouse serum is not possible, whereas antibodies made by mice reconstituted with cells of hemophilia patient with a high inhibitor titer can be detected. There are several possible reasons for this phenomenon. Anti-FVIII antibodies could be neutralized by anti-idiotypic antibodies produced in reconstituted mice or the specific anti-FVIII antibody concentration could be too low to be detectable in plasma. Attempts to detect anti-idiotypic activity in mice serum were unsuccessful, using a method described previously for the characterization of anti-idiotypic antibodies specific for anti-FVIII antibodies made by healthy donors. This suggest that the time period during which mice were followed was too short. The fact that specific antibodies are undetectable in mouse plasma may be related to the close homology between murine and human FVIII, 25 suggesting that anti-FVIII antibodies produced in SCID mice could bind to FVIII and thereby render the anti-FVIII antibodies undetectable in the plasma. To avoid such a problem, we have created SCID-FVIII-knock-out mice by cross-breeding the two species, creating a model in which we will be able to explore the different conditions under which anti-FVIII antibodies are produced. Data obtained with SCID mice and preliminary data generated by the SCID-FVIII-knockout mice indicate that such models are appropriate to study the regulation of tolerance against self antigens in normal subjects and could be extended to diseases such as acquired hemophilia in which unresponsiveness to self has been lost. These models are also suitable for the pre-clinical evaluation of immune therapies such as immunomodulation (e.g. by administration of anti-CD40L antibodies) or immune regulation, which includes the evaluation of idio- Haematologica vol. 85(supplement to n. 10):October 2000
106 J.G. Gilles et al. typic interactions after passive administration of monoclonal or polyclonal anti-idiotypic antibodies, or after active therapy (immunization with monoclonal or polyclonal anti-FVIII antibodies, peptides or cDNA). REFERENCES 1. Briët E, Rosendaal Fr, Kreuz W, et al. A meta-analysis based on eight long-term follow-up studies concerning inhibitors associated with crude or intermediate purity FVIII products. Thromb Haemost 1994; 72: 162-4. 2. Bray G, Gomperts E, Courter S, et al. A multi-center study of recombinant FVIII (recombinate): safety, efficacy and inhibitor risk in previously untreated patients with hemophilia A. Blood 1994; 83:2428-35. 3. Kessler CM. An introduction to FVIII inhibitors: the detection and quantitation. Am J Med 1991; 91: 1S- 5S. 4. Brackmann H, Etzel F, Hoffmann P, et al. The successful treatment of acquired inhibitors against FVIII. Thromb Haemost 1977; 38:269-71. 5. Nilsson I, Berntorp E, Zettervall O. Induction of tolerance in patients with hemophilia and antibodies to FVIII by combined treatment with intravenous IgG, cyclophosphamide and FVIII. N Engl J Med 1988; 318: 947-51. 6. Sultan Y, Kazatchkine M, Maisonneuve P, et al. Antiidiotypic suppression of auto-antibodies to FVIII (antihemophilic factor) by high dose intravenous gammaglobulin. Lancet 1984; 2:765-8. 7. Gilles JG, Jacquemin M, Saint-Remy JM. Factor VIII inhibitors. Thromb Haemost 1997; 78:641-6. 8. Bosma GC, Custer RP, Bosma MJ. A severe combined immunodeficiency mutation in the mouse. Nature 1983; 301:527-30. 9. Araki R, Fujimori A, Hamatani K, et al. Nonsense mutation at Tyr-4046 in the DNA-dependent protein kinase catalytic subunit of severe combined immune deficiency mice. Proc Natl Acad Sci USA 1997; 94: 2438-43. 10. Mosier DE, Gulizia RJ, Baird SM, Wilson DB. Transfer of a functional human immune system to mice with severe combined immunodeficiency. Nature 1988; 335:256-9. 11. Avrameas S, Guilbert B, Dighiero G. Natural antibodies against tubulin, actin, myoglobin, thyroglobulin, fetuin, albumin and transferrin are present in normal human sera and monoclonal immunoglobulins from multiple myeloma and Waldenström's macroglobulinemia may express similar antibody specificities. Ann Immunol (Inst Pasteur) 1981; 132C:231. 12. Gilles JG, Saint-Remy JM. Healthy subjects produce both antifactor VIII and specific anti-idiotypic antibodies. J Clin Invest 1994; 94:1496-505. 13. Gilles JG, Desqueper B, Lenk H, Vermeylen J, Saint- Remy JM. Neutralising anti-idiotypic antibodies to factor VIII inhibitors following desensitization in patients with hemophilia A. J Clin Invest 1996; 97:1382-8. 14. Cassamayor-Palleja M, Khan M, MacLennan ICM. A subset of CD4+ memory T cells contains preformed CD40 ligand that is rapidly but transiently expressed on their surface after activation through the T-cell receptor complex. J Exp Med 1995; 181:1293-301. 15. Durie FH, Foy TM, Masters SR, et al. The role of CD40 in the regulation of humoral and cell-mediated immunity. Immunol Today 1994; 15:406-12. 16. Laman JD, Claassen E, Noelle RJ. Functions of CD40 and its ligand, gp39 (CD40L). Crit Rev Immunol 1996; 16:59-108. 17. Foy TM, Shepherd DM, Durie FH, et al. In vivo CD40- gp39 interactions are essential for thymus-dependent humor immunity. II. Prolonged suppression of the humoral immune response by an antibody to the ligand for CD40, gp39. J Exp Med 1993; 178:1567-75. 18. Gerritse K, Laman JD, Noelle RJ, et al. CD40-CD40 ligand interactions in experimental allergic encephalomyelitis and multiple sclerosis. Proc Natl Acad Sci USA 1996; 93:2499-504. 19. Grewal IS, Foellmer HG, Grewal KD, et al. Requirement for CD40 ligand costimulation induction, T-cell activation, and experimental allergic encephalomyelitis. Science 1996; 273:1864-7. 20. Mohan C, Shi Y, Laman JD, et al. Interaction between CD40 and its ligand gp39 in the development of murine lupus nephritis. J Immunol 1995; 154:1470- 80. 21. Durie FH, Fava RA, Foy TM, et al. Prevention of collagen-induced arthritis with an antibody to gp39, the ligand for CD40. Science 1993; 261:1328-30. 22. Blazar BR, Taylor PA, Panoskaltsis-Mortari A, et al. Blockade of CD40 ligand-CD40 interaction impairs CD4+ T-cell-mediated alloreactivity by inhibiting mature donor T cell expansion and function after bone marrow transplantation. J Immunol 1997; 158:29-39. 23. Larsen CP, Elwood ET, Alexander DZ, et al. Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways. Nature 1997; 381:434-8. 24. Parker DC, Greiner DL, Phillips NE, et al. Survival of mouse pancreatic islet allografts in recipients treated with allogeneic small lymphocytes and antibody to CD40 ligand. Proc Natl Acad Sci USA 1995; 92:9560- 4. 25. Elder B, Lakich D, Gitschier J. Sequence of the murine factor VIII cDNA. Genomics 1993; 16:374-9. DISCUSSION 18 Animal models to explore tolerance induction to factor VIII J.G.Gilles, B. Vanzieleghem, J.M. Saint Remy (Leuven, Belgium) HOYER: Do you know whether or not humans spontaneously develop any antibodies against CD40 or antibodies against CTL4 GILLES: No, we don’t know. KAZATCHKINE: But we do know, at least in the case of IGIV. You can affinity verify the presence of those antibodies from intravenous immunoglobulin so they are present in low amounts. EWENSTEIN: I would like to ask you about the administration regimen for the anti CD40 ligand and antigen. You mentioned co-administration. GILLES: Yes and we observed that this is certainly a dose-dependent immune response. We have to be very careful with the concentration of the anti-CD40 antibody ligand that we use. If Haematologica vol. 85(supplement to n. 10):October 2000
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Acknowledgments We wish to thank th
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18 J. Ingerslev sion monitoring dem
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20 J. Ingerslev REFERENCES 1. Hay C
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30 P. Lollar titer and an anti-porc
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