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Thromb Haemost 1999; 82(02): 509-515
DOI: 10.1055/s-0037-1615873
Research Article
Schattauer GmbH

CD4+ T Cell Response to Factor VIII in Hemophilia A, Acquired Hemophilia, and Healthy Subjects

M.T. Reding
1   Department of Biochemistry, Molecular Biology and Biophysics, and Department of Medicine, University of Minnesota, Minneapolis/St. Paul, MN, USA
,
H. Wu
1   Department of Biochemistry, Molecular Biology and Biophysics, and Department of Medicine, University of Minnesota, Minneapolis/St. Paul, MN, USA
,
M. Krampf
1   Department of Biochemistry, Molecular Biology and Biophysics, and Department of Medicine, University of Minnesota, Minneapolis/St. Paul, MN, USA
,
D.K. Okita
1   Department of Biochemistry, Molecular Biology and Biophysics, and Department of Medicine, University of Minnesota, Minneapolis/St. Paul, MN, USA
,
B.M. Diethelm-Okita
1   Department of Biochemistry, Molecular Biology and Biophysics, and Department of Medicine, University of Minnesota, Minneapolis/St. Paul, MN, USA
,
N.S. Key
1   Department of Biochemistry, Molecular Biology and Biophysics, and Department of Medicine, University of Minnesota, Minneapolis/St. Paul, MN, USA
,
B.M. Conti-Fine   *
1   Department of Biochemistry, Molecular Biology and Biophysics, and Department of Medicine, University of Minnesota, Minneapolis/St. Paul, MN, USA
› Author Affiliations
Further Information

Publication History

Publication Date:
09 December 2017 (online)

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Introduction

In spite of the significant advances in the treatment of hemophilia over the last 30 years, the development of antibodies that neutralize the procoagulant activity of factor VIII (factor VIII inhibitors) remains a serious complication of treatment with factor VIII products. Recent prospective studies of previously untreated patients with severe hemophilia have reported the incidence of inhibitor development to be approximately 20% to 25%.1-11 Factor VIII inhibitors may also develop in individuals without congenital factor VIII deficiency. Acquired autoimmune hemophilia occurs with an incidence of 0.2 to 1.0 per 1,000,000 per year in the general population.12,13 In both congenital and acquired hemophilia, anti-factor VIII antibody inhibitors are significant contributors to the morbidity and mortality of those affected. As such, these cases present difficult therapeutic challenges.

Much work over the last decade has focused on defining the epitopes on factor VIII to which inhibitor antibodies bind. While this work has clarified some of the mechanisms by which inhibitors neutralize the procoagulant function of factor VIII, our knowledge of the factor VIII-specific CD4+ T helper cells, whose activation is crucial for the synthesis of factor VIII inhibitors, remains quite limited. This review will, first, discuss how a better understanding of the cellular mechanisms involved in the immune response to factor VIII may lead to improved methods of long-term inhibitor suppression and, perhaps, even prevention of inhibitor development. Lastly, this review will describe the work in our laboratory that has begun to characterize the CD4+ T cell response to factor VIII in patients with hemophilia and in normal subjects.

* Previously known as B.M. Conti-Tronconi


 

  • References

  • 1 Aledort L. Inhibitors in hemophilia patients: current status and management. Am J Hematol 1994; 47: 208-217.
    CrossrefPubMedGoogle Scholar
  • 2 Kreuz W, Becker S, Lenz E, Martinez-Saguer I, Escuriola-Ettingshausen C, Funk M, Ehrenforth S, Auerswald G, Kornhuber B. Factor VIII inhibitors in patients with hemophilia A: epidemiology of inhibitor development and induction of immune tolerance for factor VIII. Semin Thromb Hemost 1995; 21 (04) 382-389.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Hoyer LW. The incidence of factor VIII inhibitors in patients with severe hemophilia A. Adv Exp Med Biol 1995; 386: 35-45.
    PubMedGoogle Scholar
  • 4 Kreuz W, Escuriola-Ettingshausen C, Martinez-Saguer I, Gungor T, Kornhuber B. Epidemiology of inhibitors in haemophilia A. Vox Sang 1996; 70 (Suppl. 01) 2-8.
    CrossrefPubMedGoogle Scholar
  • 5 Lusher JM, Arkin S, Abildgaard CF, Schwartz RS. the Kogenate® Previously Untreated Patient Study Group. Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. N Engl J Med 1993; 328: 453-459.
    CrossrefPubMedGoogle Scholar
  • 6 De Biasi R, Rocino A, Papa ML, Salerno E, Mastrullo L, De Blasi D. Incidence of factor VIII inhibitor development in hemophilia A patients treated with less pure plasma derived concentrates. Thromb Haemost 1994; 71: 544-547.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Addiego J, Kasper C, Abildgaard C, Hilgartner M, Lusher J, Glader B, Aledort L. Frequency of inhibitor development in hemophiliacs treated with low purity factor VIII. Lancet 1993; 342: 462-464.
    CrossrefPubMedGoogle Scholar
  • 8 Ehrenforth S, Kreuz W, Scharrer I, Linde R, Funk M, Gungor T, Krackhardt B, Kornhuber B. Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet 1992; 339: 594-598.
    CrossrefPubMedGoogle Scholar
  • 9 Bray GL, Liu-Maruya S, Courter S, High K, Gomperts E. the Recombinate® Study Group. Experience with recombinant factor VIII (Recombinate®) in previously untreated patients (PUPs) with severe hemophilia A. Blood 1992; 80 (Suppl. 01) 229a.
    PubMedGoogle Scholar
  • 10 Ljung R, Petrini P, Lindgren A, Tengborn L, Nilsson I. Factor VIII and factor IX inhibitors in haemophiliacs. Lancet 1992; 339: 1550.
    CrossrefPubMedGoogle Scholar
  • 11 Lusher JM. Viral safety and inhibitor development associated with monoclonal antibody-purified F VIII C. Ann Hematol 1991; 63: 138-141.
    CrossrefPubMedGoogle Scholar
  • 12 Shulman NR, Hirschman RJ. Acquired hemophilia. Trans Assoc Am Physicians 1969; 82: 388-397.
    PubMedGoogle Scholar
  • 13 Cohen AJ, Kessler CM. Acquired inhibitors. Baillieres Clin Haematol 1996; 9 (02) 331-354.
    CrossrefPubMedGoogle Scholar
  • 14 Vehar GA, Keyt B, Eaton D, Rodriguez H, O’Brien DP, Rotblat F, Oppermann H, Keck R, Wood WI, Harkins RN, Tuddenham EGD, Lawn RM, Capon DJ. Structure of human factor VIII. Nature 1984; 312: 337-342.
    CrossrefPubMedGoogle Scholar
  • 15 Lollar P. Structure and function of factor VIII. Adv Exp Med Biol 1995; 386: 3-17.
    PubMedGoogle Scholar
  • 16 Moussalli M, Pipe SW, Nichols WC, Ginsburg D, Hauri H-P, Kaufman RJ. Mistargeting of the lectin ERGIC-53 to the endoplasmic reticulum impairs the secretion of coagulation factors V and VIII. Blood 1998; 92 (Suppl. 01) 474a.
    PubMedGoogle Scholar
  • 17 Lusher JM, Spira J, Magill M. A four-year update of safety and efficacy of a second generation B-domain deleted factor VIII (R-VIII SQ) in previously untreated hemophilia A patients. Blood 1998; 92 (Suppl. 01) 555a.
    PubMedGoogle Scholar
  • 18 Naylor J, Banke A, Hassock S, Green Glennelli G. Characteristic mRNA abnormality found in half the patients with severe hemophilia A is due to large gene inverstions. Hum Mol Genet 1993; 2: 1773-1779.
    CrossrefPubMedGoogle Scholar
  • 19 Rossiter JP, Young M, Kimberland ML, Hutter P, Ketterling RP, Gitschier J, Horst J, Morris MA, Schaid DJ, de Moerloose P. et al. Factor VIII gene inversions causing severe hemophilia A originate almost exclusively in male germ cells. Hum Mol Genet 1994; 3 (07) 1035-1039.
    CrossrefPubMedGoogle Scholar
  • 20 Antonarakis S, Kazazian Jr H, Tuddenham E. Molecular etiology of factor VIII deficiency in hemophilia A. Hum Mutat 1995; 6: 1-22.
    CrossrefPubMedGoogle Scholar
  • 21 McGinniss MJ, Kazazian Jr HH, Hoyer LW, Bi L, Inaba H, Antonarrakis SE. Spectrum of mutations in CRM-positive and CRM-reduced hemophilia A. Genomics 1993; 15: 392-398.
    CrossrefPubMedGoogle Scholar
  • 22 McMillan CW, Shapiro SS, Whitehurst D, Hoyer LW, Rao AV, Lazerson J. The natural history of factor VIII:C inhibitors in patients with hemophilia A: A national cooperative study. II. Observations on the initial development of factor VIII:C inhibitors. Blood 1988; 71: 344.
    PubMedGoogle Scholar
  • 23 Tuddenham EGD, McVey JH. The genetic basis of inhibitor development in hemophilia A. Haemophilia 1998; 4: 543-545.
    CrossrefPubMedGoogle Scholar
  • 24 Jacquemin MG, Saint-Remy JMR. Factor VIII immunogenicity. Haemophilia 1998; 4: 552-557.
    CrossrefPubMedGoogle Scholar
  • 25 Gilles JGG, Jacquemin MG, Saint-Remy JMR. Factor VIII inhibitors. Thromb Haemost 1997; 78 (01) 641-646.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Hoyer LW, Scandella D. Factor VIII inhibitors: structure and function in autoantibody and hemophilia A patients. Semin Hematol 1994; 31 (02) (Suppl. 04) 1-5.
    PubMedGoogle Scholar
  • 27 Castaldi PA, Penny R. A macroglobulin with inhibitory activity against coagulation factor VIII. Blood 1970; 35: 370-376.
    PubMedGoogle Scholar
  • 28 McKelvey EM, Kwaan HC. An IgM circulating anticoagulant with factor VIII inhibitory activity. Ann Intern Med 1972; 77: 571-575.
    CrossrefPubMedGoogle Scholar
  • 29 Glueck HI, Hong R. A circulating anticoagulant in IgA multiple myeloma: its modification by penicillin. J Clin Invest 1965; 44: 1866-1881.
    CrossrefPubMedGoogle Scholar
  • 30 Gralnick HR, Flaum MA, Kessler CM, Zimbler H, Coller BS. IgA inhibitor to factor VIII/von Willebrand factor. Br J Haematol 1985; 59: 149-158.
    CrossrefPubMedGoogle Scholar
  • 31 Nilsson IM, Berntorp E, Zettervall O, Dahlback B. Noncoagulation inhibitory factor VIII antibodies after induction of tolerance to factor VIII in hemophilia A patients. Blood 1990; 75 (02) 378-383.
    PubMedGoogle Scholar
  • 32 Gilles JGG, Arnout J, Vermylen J, Saint-Remy J-MR. Anti-factor VIII antibodies of hemophiliac patients are frequently directed towards nonfunctional determinants and do not exhibit isotypic restriction. Blood 1993; 82 (08) 2452-2461.
    PubMedGoogle Scholar
  • 33 Scandella D, Gilbert GE, Shima M, Nakai H, Eagleson C, Felch M, Prescott R, Rajalakshmi KJ, Hoyer LW, Saenko E. Some factor VIII inhibitor antibodies recognize a common epitope corresponding to C2 domain amino acids 2248 through 2312, which overlap a phospholipid-binding site. Blood 1995; 86 (05) 1811-1819.
    PubMedGoogle Scholar
  • 34 Shima M, Nakai H, Scandella D, Tanaka I, Sawamoto Y, Kamisue S, Morichika S, Murakami T, Yoshioka A. Common inhibitory effects of human anti-C2 domain inhibitor alloantibodies on factor VIII binding to von Willebrand factor. Br J Haematol 1995; 91: 714-721.
    CrossrefPubMedGoogle Scholar
  • 35 Healey JF, Lubin IM, Nakai H, Saenko E, Hoyer LW, Scandella D, Lollar P. Residues 484-508 contain a major determinant of the inhibitory epitope in the A2 domain of human factor VIII. J Biol Chem 1995; 270 (24) 14,505-14,509.
    CrossrefPubMedGoogle Scholar
  • 36 Zhong D, Saenko EL, Shima M, Felch M, Scandella D. Some human inhibitor antibodies interfere with factor VIII binding to factor IX. Blood 1998; 92 (01) 136-142.
    PubMedGoogle Scholar
  • 37 Prescott R, Nakai H, Saenko E, Scharrer I, Nilsson IM, Humphries JE, Hurst D, Bray G, Scandella D. the Recombinate® and Kogenate® Study Groups. The inhibitor anti body response is more complex in hemophilia A patients than in most nonhemophiliacs with factor VIII autoantibodies. Blood 1997; 89 (10) 3663-3671.
    PubMedGoogle Scholar
  • 38 Batlle J, Gomez E, Rendal E, Torea J, Loures E, Couselo M, Vila P, Sedano C, Tusell X, Magallon M, Quintana M, Gonzalez-Boullosa R, Lopez-Fernandez MF. Antibodies to factor VIII in plasma of patients with hemophilia A and normal subjects. Ann Hematol 1996; 72: 321-326.
    CrossrefPubMedGoogle Scholar
  • 39 Algiman M, Dietrich G, Nydegger UE, Boieldieu D, Sultan Y, Kazatchkine MD. Natural antibodies to factor VIII (antihemophilic factor) in healthy individuals. Proc Natl Acad Sci USA 1992; 89: 3795-3799.
    CrossrefPubMedGoogle Scholar
  • 40 Gilles JG, Saint-Remy J-MR. Healthy subjects produce both anti-factor VIII and specific anti-idiotypic antibodies. J Clin Invest 1994; 94: 1496-1505.
    CrossrefPubMedGoogle Scholar
  • 41 Avrameas S. Natural autoantibodies: from ‘horror autotoxicus’ to ‘gnothi seauton.’. Immunol Today 1991; 12 (05) 154-158.
    PubMedGoogle Scholar
  • 42 Morel-Kopp MC, Tchernia G, Lambert T, Verdy E, Schlegel N, Dreyfus M, Chateauvieux L, Kaplan C. Autoantibodies directed against the platelet GP complex Ib-IX in normal individuals. Blood 1992; 80 (Suppl. 01) 49a.
    PubMedGoogle Scholar
  • 43 Moiola L, Karachunski P, Protti M, Howard J, Conti-Tronconi BM. Epitopes on the ß subunit of muscle acetylcholine receptor recognized by CD4+ cells of myasthenia patients and healthy subjects. J Clin Invest 1994; 93: 1020-1028.
    CrossrefPubMedGoogle Scholar
  • 44 Kellerman S, McCormick D, Freeman S, Morris J, Conti-Fine BM. TSH receptor sequences recognized by CD4+ cells in Graves’ disease patients and in healthy controls. J Autoimmun 1995; 8: 685-698.
    CrossrefPubMedGoogle Scholar
  • 45 Burns J, Rosenzweig A, Zweiman B, Lisak RP. Isolation of myelin basic protein-reactive T-cell lines from normal human blood. Cell Immunol 1983; 81: 435-440.
    CrossrefPubMedGoogle Scholar
  • 46 Pette M, Fujita K, Wilkinson D, Altmann DM, Trowsdale J, Giegerich G, Hinkkanen A, Epplen JT, Kappos L, Wekerle H. Myelin autoreactivity in multiple sclerosis: Recognition of myelin basic protein in the context of HLA-DR2 products by T lymphocytes of multiple sclerosis patients and healthy donors. Proc Natl Acad Sci USA 1990; 87: 7968-7972.
    CrossrefPubMedGoogle Scholar
  • 47 Ota K, Matusi M, Milford EL, Mackin GA, Weiner HL, Hafler DA. T-cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis. Nature 1990; 346: 183-187.
    CrossrefPubMedGoogle Scholar
  • 48 Kuwana M, Medsger Jr TA, Wright TM. T cell proliferative response induced by DNA topoisomerase I in patients with systemic sclerosis and healthy donors. J Clin Invest 1995; 96: 586-596.
    CrossrefPubMedGoogle Scholar
  • 49 Ito Y, Nieda M, Uchigata Y, Nishimura M, Tokunaga K, Kuwata S, Obata F, Tadokoro K, Hirata Y, Omori Y, Juji T. Recognition of human insulin in the context of HLA-DRB1*0406 products by T cells of insulin autoimmune syndrome patients and healthy donors. J Immunol 1993; 151: 5770-5776.
    PubMedGoogle Scholar
  • 50 Hoffman RW, Takeda Y, Sharp GC, Lee DR, Hill DL, Kaneoka H, Caldwell CW. Human T cell clones reactive against U-small nuclear ribonucleoprotein autoantigens from connective tissue disease patients and healthy individuals. J Immunol 1993; 151: 6460-6469.
    PubMedGoogle Scholar
  • 51 Singer ST, Addiego Jr JE, Reason DC, Lucas AH. T lymphocyte proliferative responses induced by recombinant factor VIII in hemophilia A patients with inhibitors. Thromb Haemost 1996; 76 (01) 17-22.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 52 Germain RH, Margulies DM. The biochemistry and cell biology of antigen processing and presentation. Ann Rev Immunol 1993; 11: 403-450.
    CrossrefPubMedGoogle Scholar
  • 53 Abbas AK, Lichtman AH, Pober JS. T lymphocyte antigen recognition and activation. In: Abbas AK, Lichtman AH, Pober JS. eds. Cellular and Molecular Immunology. W.B. Saunders; Philadelphia: 1997: 138-170.
    Google Scholar
  • 54 Lenschow DJ, Walunas TL, Bluestone JA. CD28/B7 system of T cell costimulation. Ann Rev Immunol 1996; 14: 233-258.
    CrossrefPubMedGoogle Scholar
  • 55 Bray GL, Kroner BL, Arkin S, Aledort LW, Hilgartner MW, Etster ME, Ragni MV, Goedert JJ. Loss of high-responder inhibitors in patients with severe hemophilia A and human immunodeficiency virus type 1 infection: A report from the multicenter hemophilia cohort study. Am J Hematol 1993; 42: 375-379.
    CrossrefPubMedGoogle Scholar
  • 56 Madhok R, Smith J, Jenkins A, Lowe GDO. T cell sensitization to factor VIII in hemophilia A?. Br J Haematol 1991; 79: 235-238.
    CrossrefPubMedGoogle Scholar
  • 57 Qian AJ, Collins M, Hoyer LW. Prevention of factor VIII inhibitors in murine hemophilia. Blood 1998; 92 (Suppl. 01) 709a.
    PubMedGoogle Scholar
  • 58 Abbas A, Murphy K, Sher A. Functional diversity of helper T lymphocytes. Nature 1996; 383: 787-793.
    CrossrefPubMedGoogle Scholar
  • 59 Romagnani S. The Th1/Th2 paradigm. Immunol Today 1997; 18: 263-266.
    PubMedGoogle Scholar
  • 60 Weigle WO, Romball CG. CD4+ T-cell subsets and cytokines involved in peripheral tolerance. Immunol Today 1997; 18: 533-538.
    CrossrefPubMedGoogle Scholar
  • 61 Qian A, Scott D, Hoyer L. T cell response to human factor VIII in murine hemophilia. Blood 1997; 90: 599a.
    PubMedGoogle Scholar
  • 62 Chen Y, Inobe J, Marks R, Gonnella P, Kuchroo V, Weiner H. Peripheral deletion of antigen-reactive T cells in oral tolerance. Nature 1995; 376: 177-180.
    CrossrefPubMedGoogle Scholar
  • 63 Sloane-Lancaster J, Evavold B, Allen P. Th2 cells clonal anergy as a consequence of partial activation. J Exp Med 1994; 180: 1195-1205.
    CrossrefPubMedGoogle Scholar
  • 64 Kappler J, Roehm N, Marrack P. T cell tolerance by clonal elimination in the thymus. Cell 1987; 49: 273-280.
    CrossrefPubMedGoogle Scholar
  • 65 Schwartz R. Acquisition of Immunological self-tolerance. Cell 1989; 57: 1073-1081.
    CrossrefPubMedGoogle Scholar
  • 66 Matzinger P. Tolerance, danger, and the extended family. Ann Rev Immunol 1994; 12: 991-1045.
    CrossrefPubMedGoogle Scholar
  • 67 Nossal G. Choices following antigen entry: antibody formation or immunologic tolerance?. Ann Rev Immunol 1995; 13: 1-27.
    PubMedGoogle Scholar
  • 68 Weiner H, Friedman A, Miller A, Khoury SJ, Al-Sabbagh A, Santos L, Sayegh M, Nussenblatt RB, Trenthan DE, Hafler AD. Oral tolerance: immunologic mechanisms and treatment of animal and human organ-specific autoimmune diseases by oral administration of autoantigens. Ann Rev Immunol 1994; 12: 809-837.
    CrossrefPubMedGoogle Scholar
  • 69 Chen Y, Inobe J, Kuchroo V, Baron J, Janeway CJ, Weiner H. Oral tolerance in myelin basic protein T-cell receptor transgenic mice: suppression of autoimmune encephalomyelitis and dose-dependent induction of regulatory cells. Proc Natl Acad Sci USA 1996; 93: 388-391.
    CrossrefPubMedGoogle Scholar
  • 70 Friedman A, Weiner HL. Induction of anergy or active suppression following oral tolerance is determined by antigen dosage. Proc Natl Acad Sci USA 1994; 91: 6688-6692.
    CrossrefPubMedGoogle Scholar
  • 71 Gregerson D, Obritsch W, Donoso L. Oral tolerance in experimental autoimmune uveoretinitis. Distinct mechanisms of resistance are induced by low dose vs. high dose feeding protocols. J Immunol 1993; 151: 5751-5761.
    PubMedGoogle Scholar
  • 72 Critchfield JM, Racke MK, Zuniga-Pflucker JC, Cannella B, Rainse CS, Goverman J, Lenardo M. T cell deletion in high antigen dose therapy of autoimmune encephalomyelitis. Science 1994; 263: 1139-1143.
    CrossrefPubMedGoogle Scholar
  • 73 Vardhachary AS, Perdow SN, Hu C, Ramanarayanan M, Salgame P. Differential ability of T cell subsets to undergo activation-induced cell death. Proc Natl Acad Sci USA 1997; 94: 5778-5783.
    CrossrefPubMedGoogle Scholar
  • 74 Zhang X, Brunner T, Carter L, Dutton RW, Rogers P, Bradley L, Sato T, Reed JD, Green D, Swain SL. Unequal death in T helper cell (Th)1 and Th2 effectors: Th1, but not Th2, effectors undergo rapid Fas/FasL-mediated apoptosis. J Exp Med 1997; 185: 1837-1849.
    CrossrefPubMedGoogle Scholar
  • 75 Panina-Bordignon P, Tan A, Termijtelen A, Demotz S, Corradin G, Lanzavecchia A. Universally immunogenic T cell epitopes: promiscuous binding to human MHC class II and promiscuous recognition by T cells. Eur J Immunol 1989; 19: 2237-2242.
    CrossrefPubMedGoogle Scholar
  • 76 Ho PC, Mutch DA, Winkel KD, Saul AJ, Jones GL, Doran TJ, Rzepczyk CM. Identification of two promiscuous T cell epitopes from tetanus toxin. Eur J Immunol 1990; 20: 477-483.
    CrossrefPubMedGoogle Scholar
  • 77 Reece JC, Geysen HM, Rodda SJ. Mapping the major human T helper epitopes of tetanus toxin. The emerging picture. J Immunol 1993; 151: 6175-6184.
    PubMedGoogle Scholar
  • 78 Protti MP, Manfredi AA, Horton BM, Bellone M, Conti-Tronconi BM. Myasthenia Gravis: recognition of a human autoantigen at the molecular level. Immunol Today 1993; 14: 363-368.
    CrossrefPubMedGoogle Scholar
  • 79 Raju R, Navaneethan D, Okita DK, Diethelm-Okita B, McCormick D, Conti-Fine BM. Epitopes for human CD4+ T cells on diphtheria toxin: structural features of sequence segments forming epitopes recognized by most subjects. Eur J Immunol 1995; 25: 3207-3214.
    CrossrefPubMedGoogle Scholar
  • 80 Diethelm B, Raju R, Okita DK, Conti-Fine BM. Epitope repertoire of human CD4+ T cells on tetanus toxoid: identification of immunodominant sequence segments. J Infect Dis 1997; 175: 382-391.
    CrossrefPubMedGoogle Scholar
  • 81 Karachunski P, Ostlie N, Okita D, Conti-Fine BM. Protection from experimental myasthenia gravis in C57Bl/6 mice by sniffing of synthetic CD4+ T cells epitopes. J Clin Invest 1997; 100: 3027-3035.
    CrossrefPubMedGoogle Scholar
  • 82 Karachunski PI, Ostlie NS, Okita DK, Garman R, Conti-Fine BM. Subcutaneous administration of T-epitope sequences of the acetylcholine receptor prevents experimental myasthenia gravis. J Neuroimmunol 1999; 93: 108-121.
    CrossrefPubMedGoogle Scholar
  • 83 Rudensky AY, Preston-Hurburt P, Hong SC, Barlow A, Janeway Jr CA. Sequence analysis of peptide bound to MHC class II molecules. Nature 1991; 353: 622-627.
    CrossrefPubMedGoogle Scholar
  • 84 Hunt DF, Michel H, Dickison TA, Shabanowitz J, Cox AL, Sakaguchi K, Appella E, Grey HM, Sette A. Peptides presented to the immune system by the murine class II major histocompatibility complex molecule I-Ad . Science 1992; 256: 1817-1820.
    CrossrefPubMedGoogle Scholar
  • 85 Stern LJ, Brown JH, Jardetzky TS, Gorga JC, Urban RG, Strominger JL, Wiley DC. Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide. Nature 1994; 368: 215-221.
    CrossrefPubMedGoogle Scholar
  • 86 Chicz RM, Urban RG, Gorga JC, Vignali DAA, Lane WS, Strominger JL. Specificity and promiscuity among naturally processed peptides bound to HLA-DR alleles. J Exp Med 1993; 178: 27-47.
    CrossrefPubMedGoogle Scholar
  • 87 Fisher GH, Rosenberg FJ, Straus SE, Dale JK, Middleton LR, Lin RY, Strober W, Lenardo MJ, Puck JM. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell 1995; 81 (06) 935-946.
    CrossrefPubMedGoogle Scholar
  • 88 Rieux-Laucat F, Le Deist F, Hivroz C, Roberts IR, Debatin KM, Fisher A, de Villartay JP. Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science 1995; 268: 1347-1349.
    CrossrefPubMedGoogle Scholar
  • 89 Johnson JG, Jenkins MK. The role of anergy in peripheral T cell unresponsiveness. Life Sci 1994; 55: 1767-1780.
    CrossrefPubMedGoogle Scholar
  • 90 Schwartz RH. Models of T cell anergy: is there a common molecular mechanism?. J Exp Med 1996; 184: 1-8.
    CrossrefPubMedGoogle Scholar