Immune Implications of Gene Therapy for Hemophilia

Similar to any novel treatment strategy for hemophilia, gene therapy faces the question of the risk of formation of inhibitory antibodies to the therapeutic factor VIII or factor IX protein. Activation of CD4⁺ or CD8⁺ T cells could lead to antibody formation or cytotoxic T lymphocyte responses to transgene-expressing cells. Preclinical studies in animal models of hemophilia A and B with different mutations in the dysfunctional gene shed light on the risk for such immune responses and point toward strategies to avoid immune activation or even promote tolerance induction. The impacts of variables such as choice and design of gene transfer vector, underlying gene mutation, route of vector administration, and transient immune suppression are discussed. Maintenance of immunological hyporesponsiveness to the therapeutic gene product is critical for successful gene therapy. Recent studies provide evidence for tolerance induction to coagulation factor antigens by viral hepatic or neonatal in vivo gene transfer, by in utero gene delivery, and by oral or nasal administration of protein or peptides.

KEYWORDS

Immune response - inhibitor - T cell - B cell - cytotoxic T lymphocyte

REFERENCES

• 1 Gianelli F, Green P M. The molecular basis of hemophilia A and B. In: Lee CA Clinical Haematology: Haemophilia. Vol. 9 London, UK; Bailliere Tindall 1996: 211-228
• 2 Fijnvandraat K, Bril W S, Voorberg J. Immunobiology of inhibitor development in hemophilia A.  Semin Thromb Hemost. 2003;  29 61-68
• 3 Astermark J. Treatment of the bleeding inhibitor patient.  Semin Thromb Hemost. 2003;  29 77-86
• 4 Mariani G, Siragusa S, Kroner B L. Immune tolerance induction in hemophilia A: a review.  Semin Thromb Hemost. 2003;  29 69-76
• 5 Monnahan P E, White G C. Hemophilia gene therapy.  Update Curr Opin Hematol. 2002;  9 430-436
• 6 Fields P A, Kowalczyk D W, Arruda V R et al.. Choice of vector determines T cell subsets involved in immune responses against the secreted transgene product factor IX.  Mol Ther. 2000;  1 225-235
• 7 Brown B D, Lillicrap D. Dangerous liaisons: the role of “danger” signals in the immune response to gene therapy.  Blood. 2002;  100 1133-1140
• 8 Jooss K, Yang Y, Fisher K J, Wilson J M. Transduction of dendritic cells by DNA viral vectors directs the immune response to transgene products in muscle fibers.  J Virol. 1998;  72 4212-4223
• 9 Yang Y, Xiang Z, Ertl H C, Wilson J M. Upregulation of class I major histocompatibility complex antigens by interferon gamma is necessary for T-cell-mediated elimination of recombinant adenovirus-infected hepatocytes in vivo.  Proc Natl Acad Sci USA. 1995;  92 7257-7261
• 10 Weiner H L. Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells.  Immunol Rev. 2001;  182 207-214
• 11 Roncarolo M G, Bacchetta R, Bordignon C, Narula S, Levings M K. Type 1 T regulatory cells.  Immunol Rev. 2001;  182 68-79
• 12 Liu Y J. Dendritic cell subsets and lineages, and their functions in innate and adaptive immunity.  Cell. 2001;  106 259-262
• 13 Mellman I, Steinman R M. Dendritic cells: specialized and regulated antigen processing machines.  Cell. 2001;  106 255-258
• 14 Gallucci S, Lolkema M, Matzinger P. Natural adjuvants: endogenous activators of dendritic cells.  Nat Med. 1999;  5 1249-1255
• 15 Schnell M A, Zhang Y, Tazelaar J et al.. Activation of innate immunity in nonhuman primates following intraportal administration of adenoviral vectors.  Mol Ther. 2001;  3 708-722
• 16 Zhang Y, Chirmule N, Gao G P et al. Acute cytokine response to systemic adenoviral vectors in mice is mediated by dendritic cells and macrophages.  Mol Ther. 2001;  3 697-707
• 17 Liu Q, Zaiss A K, Colarusso P et al.. The role of capsid-endothelial interactions in the innate immune response to adenovirus vectors.  Hum Gene Ther. 2003;  14 627-643
• 18 Muruve D A, Barnes M J, Stillman I E, Libermann T A. Adenoviral gene therapy leads to rapid induction of multiple chemokines and acute neutrophil-dependent hepatic injury in vivo. .  Hum Gene Ther. 1999;  10 965-976
• 19 Tao N, Gao G P, Parr M et al.. Sequestration of adenoviral vector by Kupffer cells leads to a nonlinear dose response of transduction in liver.  Mol Ther. 2001;  3 28-35
• 20 Fields P A, Armstrong E, Hagstrom J N et al.. Intravenous administration of an E1/E3-deleted adenoviral vector induces tolerance to factor IX in C57BL/6 mice.  Gene Ther. 2001;  8 354-361
• 21 Brown B D, Shi C X, Rawle F E et al.. Factors influencing therapeutic efficacy and the host immune response to helper-dependent adenoviral gene therapy in hemophilia A mice.  J Thromb Haemost. 2004;  2 111-118
• 22 Gallo-Penn A M, Shirley P S, Andrews J L et al.. Systemic delivery of an adenoviral vector encoding canine factor VIII results in short-term phenotypic correction, inhibitor development, and biphasic liver toxicity in hemophilia A dogs.  Blood. 2001;  97 107-113
• 23 VandenDriessche T, Schiedner G, Thorrez L et al.. Induction of long-term immune tolerance for neo-antigens following gene therapy with high capacity adenoviral vectors by transient elimination of Kupffer cells.  Mol Ther. 2003;  7 S193 (abst)
• 24 Sarukhan A, Camugli S, Gjata B, von Boehmer H, Danos O, Jooss K. Successful interference with cellular immune responses to immunogenic proteins encoded by recombinant viral vectors.  J Virol. 2001;  75 269-277
• 25 VandenDriessche T, Thorrez L, Naldini L et al.. Lentiviral vectors containing the human immunodeficiency virus type-1 central polypurine tract can efficiently transduce nondividing hepatocytes and antigen-presenting cells in vivo.  Blood. 2002;  100 813-822
• 26 Pfeifer A, Kessler T, Yang M et al.. Transduction of liver cells by lentiviral vectors: analysis in living animals by fluorescence imaging.  Mol Ther. 2001;  3 319-322
• 27 De Geest B R, Van Linthout S A, Collen D. Humoral immune response in mice against a circulating antigen induced by adenoviral transfer is strictly dependent on expression in antigen-presenting cells.  Blood. 2003;  101 2551-2556
• 28 Pastore L, Morral N, Zhou H et al.. Use of a liver-specific promoter reduces immune response to the transgene in adenoviral vectors.  Hum Gene Ther. 1999;  10 1773-1781
• 29 Kafri T, Morgan D, Krahl T, Sarvetnick N, Sherman L, Verma I. Cellular immune response to adenoviral vector infected cells does not require de novo viral gene expression: implications for gene therapy.  Proc Natl Acad Sci USA. 1998;  95 11377-11382
• 30 Zaiss A K, Liu Q, Bowen G P, Wong N C, Bartlett J S, Muruve D A. Differential activation of innate immune responses by adenovirus and adeno-associated virus vectors.  J Virol. 2002;  76 4580-4590
• 31 Fisher K J, Jooss K, Alston J et al.. Recombinant adeno-associated virus for muscle directed gene therapy.  Nat Med. 1997;  3 306-312
• 32 Sarkar R, Xiao W, Kazazian H H. A single adeno-associated virus (AAV)-murine factor VIII vector partially corrects the hemophilia A phenotype.  J Thromb Haemost. 2003;  1 220-226
• 33 Sarkar R, Gao G P, Chirmule N, Tazelaar J, Kazazian Jr H H. Partial correction of murine hemophilia A with neo-antigenic murine factor VIII.  Hum Gene Ther. 2000;  11 881-894
• 34 Scallan C D, Lillicrap D, Jiang H et al.. Sustained phenotypic correction of canine hemophilia A using an adeno-associated viral vector.  Blood. 2003;  102 2031-2037
• 35 Balague C, Zhou J M, Dai Y F et al.. Sustained high-level expression of full-length human factor VIII and restoration of clotting activity in hemophilic mice using a minimal adenovirus vector.  Blood. 2000;  95 820-828
• 36 Ehrhardt A, Mikkelsen J G, Meuse L, Pham T, Kay M A. A new adenoviral helper-dependent vector results in long-term therapeutic levels of human coagulation factor IX at low doses in vivo.  Nat Biotechnol. 2002;  20 999-1005
• 37 Chuah M KL, Scheidner G, Thorrez L et al.. Therapeutic factor VIII levels and negligible toxicity in mouse and dog models of hemophilia A following gene therapy with high-capacity adenoviral vectors.  Blood. 2003;  101 1734-1743
• 38 Fields P A, Arruda V R, Armstrong E et al.. Risk and prevention of anti-factor IX formation in AAV-mediated gene transfer in the context of a large deletion of F9.  Mol Ther. 2001;  4 201-210
• 39 Lin H F, Maeda N, Smithies O, Straight D L, Stafford D W. A coagulation factor IX-deficient mouse model for human hemophilia B.  Blood. 1997;  90 3962-3966
• 40 Herzog R W, Mount J D, Arruda V R, High K A, Lothrop Jr C D, Fields P A. Muscle-directed gene transfer and transient immune suppression result in sustained partial correction of canine hemophilia B caused by a null mutation.  Mol Ther. 2001;  4 192-200
• 41 Mauser A E, Whitney K M, Lothrop Jr C D. A deletion mutation causes hemophilia B in Lhasa apso dogs.  Blood. 1996;  88 3451-3455
• 42 Herzog R W, High K A. AAV-mediated gene transfer of factor IX for treatment of hemophilia B by gene therapy.  Thromb Haemost. 1999;  82 540-546
• 43 Evans J P, Brinkhous K M, Brayer G D, Reisner H M, High K A. Canine hemophilia B resulting from a point mutation with unusual consequences.  Proc Natl Acad Sci USA. 1989;  86 10095-10099
• 44 Manno C S, Chew A J, Hutchinson S et al.. A phase I safety study in patients with severe hemophilia B using adeno-associated viral (AAV) vector to deliver the gene for human factor IX to skeletal muscle.  Blood. 2003;  101 2963-2972
• 45 High K A. Factor IX: molecular structure, epitopes, and mutations associated with inhibitor formation. In: Aledort LM, Hoyer LW, Lusher JM, Reisner HM, White GC Advances in Experimental Medicine and Biology. Vol. 386 New York; Plenum Press 1995: 79-86
• 46 Goodeve A C, Peake I R. The molecular basis of hemophilia A: genotype-phenotype relationships and inhibitor development.  Semin Thromb Hemost. 2003;  29 23-30
• 47 Ljung R, Petrini P, Tengborn L, Sjorin E. Haemophilia B mutations in Sweden: a population-based study of mutational heterogeneity.  Br J Haematol. 2001;  113 81-86
• 48 Bi L, Lawler A M, Antonarakis S E, High K A, Gearhart J D, Kazazian H H. Targeted disruption of the mouse factor VIII gene: a model for hemophilia A.  Nat Genet. 1995;  10 119-121
• 49 Lozier J N, Dutra A, Pak E et al.. The Chapel Hill hemophilia A dog colony exhibits a factor VIII gene inversion.  Proc Natl Acad Sci USA. 2002;  99 12991-12996
• 50 Hough C, Kamisue S, Cameron C et al.. Aberrant splicing and premature termination of transcription of the FVIII gene as a cause of severe canine hemophilia A: similarities with the intron 22 inversion mutation in human hemophilia.  Thromb Haemost. 2002;  87 659-665
• 51 Nathwani A C, Davidoff A, Hanawa H, Zhou J, Vanin E F, Nienhuis A W. Factors influencing in vivo transduction by recombinant adeno-associated viral vectors expressing the human factor IX cDNA.  Blood. 2001;  97 1258-1265
• 52 Mount J D, Herzog R W, Tillson D M et al.. Sustained phenotypic correction of hemophilia B dogs with a factor IX null mutation by liver-directed gene therapy.  Blood. 2002;  99 2670-2676
• 53 Mingozzi F, Liu Y L, Dobrzynski E et al.. Induction of immune tolerance to coagulation factor IX antigen by in vivo hepatic gene transfer.  J Clin Invest. 2003;  111 1347-1356
• 54 Snyder R O, Miao C, Meuse L et al.. Correction of hemophilia B in canine and murine models using recombinant adeno-associated viral vectors.  Nat Med. 1999;  5 64-70
• 55 Lozier J N, Donahue R E, Donahue B A et al.. AAV-mediated expression of human factor IX in rhesus macaques.  Mol Ther. 2000;  1 S289 (abst)
• 56 Mizukami H, Mimuro J, Ogura T et al.. Muscle-mediated human factor IX expression in Cynomolgus monkey using AAV serotype-derived vectors.  Mol Ther. 2003;  7 S81 (abst)
• 57 Nathwani A C, Davidoff A M, Hanawa H et al.. Sustained high-level expression of human factor IX (hFIX) after liver-targeted delivery of recombinant adeno-associated virus encoding the hFIX gene in rhesus macaques.  Blood. 2002;  100 1662-1669
• 58 Kootstra N A, Matsumura R, Verma I M. Efficient production of human FVIII in hemophilic mice using lentiviral vectors.  Mol Ther. 2003;  7 623-631
• 59 Herzog R W, Fields P A, Arruda V R et al.. Influence of vector dose on factor IX-specific T and B cell responses in muscle-directed gene therapy.  Hum Gene Ther. 2002;  13 1281-1291
• 60 Arruda V R, Schuettrumpf J, Herzog R W et al.. Safety and efficacy of factor IX gene transfer to skeletal muscle in murine and canine hemophilia B models by adeno-associated viral vector serotype 1.  Blood. 2004;  103 85-92
• 61 Chao H, Monahan P E, Liu Y, Samulski R J, Walsh C E. Sustained and complete phenotype correction of hemophilia B mice following intramuscular injection of AAV1 serotype vectors.  Mol Ther. 2001;  4 217-222
• 62 Qian J, Collins M, Sharpe A H, Hoyer L W. Prevention and treatment of factor VIII inhibitors in murine hemophilia A.  Blood. 2000;  95 1324-1329
• 63 Rossi G, Sarkar J, Scandella D. Long-term induction of immune tolerance after blockade of CD40-CD40L interaction in a mouse model of hemophilia A.  Blood. 2001;  97 2750-2757
• 64 Mayumi H, Umesue M, Nomoto K. Cyclophosphamide-induced immunological tolerance: an overview.  Immunobiology. 1996;  195 129-139
• 65 Arruda V R, Stedman H, Nichols T C et al.. Sustained correction of hemophilia B phenotype following intravascular delivery of AAV vector to skeletal muscle.  Mol Ther. 2002;  5 S157
• 66 Zhang J, Wong F, Gao C, Xu L, Ponder K P. CTLA4-Ig and cyclophosphamide can inhibit an antibody response to human factor X in BALB/c mice after retroviaral vector-mediated gene therapy.  Mol Ther. 2002;  5 S82-S83
• 67 Walter J, You Q, Hagstrom J N, Sands M, High K A. Successful expression of human factor IX following repeat administration of adenoviral vector in mice.  Proc Natl Acad Sci USA. 1996;  93 3056-3061
• 68 Xu L, Gao C, Sands M S et al.. Neonatal or hepatocyte growth factor-potentiated adult gene therapy with a retroviral vector results in therapeutic levels of canine factor IX for hemophilia B.  Blood. 2003;  101 3924-3932
• 69 Zhang J, Xu L, Haskins M E, Parker Ponder K. Neonatal gene transfer with a retroviral vector results in tolerance to human factor IX in mice and dogs.  Blood. 2004;  103 143-151
• 70 VandenDriessche T, Vanslembrouck V, Goovaerts I et al.. Long-term expression of human coagulation factor VIII and correction of hemophilia A after in vivo retroviral gene transfer in factor VIII- deficient mice.  Proc Natl Acad Sci USA. 1999;  96 10379-10384
• 71 Ponder K P. Should gene therapy be used for newborns with hemophilia?.  Mol Ther. 2003;  7 7-8
• 72 Anderson M S, Venanzi E S, Klein L et al.. Projection of an immunological self shadow within the thymus by the aire protein.  Science. 2002;  298 1395-1401
• 73 Waddington S N, Buckley S M, Nivsarkar M et al.. In utero gene transfer of human factor IX to fetal mice can induce postnatal tolerance of the exogenous clotting factor.  Blood. 2003;  101 1359-1366
• 74 Bagley J, Tian C, Sachs D H, Iacomini J. Induction of T-cell tolerance to an MHC class I alloantigen by gene therapy.  Blood. 2002;  99 4394-4399
• 75 Bagley J, Wu Y, Sachs D H, Iacomini J. Defining the requirements for peptide recognition in gene therapy-induced T cell tolerance.  J Immunol. 2000;  165 4842-4847
• 76 Kang E-S, Iacomini J. Induction of central deletional T cell tolerance by gene therapy.  J Immunol. 2002;  169 1930-1935
• 77 Tian C, Bagley J, Iacomini J. Expression of antigen on mature lymphocytes is required to induce T cell tolerance by gene therapy: induction of central deletional T cell tolerance by gene therapy.  J Immunol. 2002;  169 3771-3776
• 78 Heim D A, Hanazono Y, Giri N et al.. Introduction of a xenogeneic gene via hematopoietic stem cells leads to specific tolerance in a rhesus monkey model.  Mol Ther. 2000;  1 533-544
• 79 Evans G L, Morgan R A. Genetic induction of immune tolerance to human clotting factor VIII in a mouse model for hemophilia A.  Proc Natl Acad Sci USA. 1998;  95 5734-5739
• 80 Fry J W, Morris P J, Wood K J. Adenoviral transfer of a single donor-specific MHC class I gene to recipient bone marrow cells can induce specific immunological unresponsiveness in vivo.  Gene Ther. 2002;  9 220-226
• 81 Wong W, Billing J S, Stranford S A et al.. Retroviral transfer of donor MHC class I or MHC class II genes into recipient bone marrow cells can induce operational tolerance to alloantigens in vivo.  Hum Gene Ther. 2003;  14 577-590
• 82 Weiner H L. Oral tolerance: immune mechanisms and treatment of autoimmune diseases.  Immunol Today. 1997;  18 335-343
• 83 Chen Y H, Weiner H L. Dose-dependent activation and deletion of antigen-specific T cells following oral tolerance.  Ann N Y Acad Sci. 1996;  778 111-121
• 84 Chen Y, Inobe J-I, Marks R, Gonnella P, Kuchroo V K, Weiner H L. Peripheral deletion of antigen-reactive T cells in oral tolerance.  Nature. 1995;  376 177-180
• 85 Alpan O, Kamala T, Velander W et al.. Milky way: An inexpensive and easy method of inducing tolerance to human FIX.  Blood. 2001;  98 3430 , (abst)
• 86 Sabatino D E, Arruda V R, Liu Y-L et al.. Induction of oral tolerance to human factor IX in neonatal hemophilia B mice.  Mol Ther. 2002;  5 S89 , (abst)
• 87 Roy K, Mao H Q, Huang S K, Leong K W. Oral gene delivery with chitosan-DNA nanoparticles generates immunologic protection in a murine model of peanut allergy.  Nat Med. 1999;  5 387-391
• 88 Karachunski P I, Ostlie N S, Okita D K, Conti-Fine B M. Prevention of experimental myasthenia gravis by nasal administration of synthetic acetylcholine receptor T epitope sequences.  J Clin Invest. 1997;  100 3027-3035
• 89 Reding M T, Wu H, Krampf M et al.. CD4+ T cells specific for factor VIII as a target for specific suppression of inhibitor production.  Adv Exp Med Biol. 2001;  489 119-134
• 90 Shi F D, Li H, Wang H et al.. Mechanisms of nasal tolerance induction in experimental autoimmune myasthenia gravis: identification of regulatory cells.  J Immunol. 1999;  162 5757-5763
• 91 Monfardini C, Milani M, Ostlie N et al.. Adoptive protection from experimental myasthenia gravis with T cells from mice treated nasally with acetylcholine receptor epitopes.  J Neuroimmunol. 2002;  123 123-134
• 92 Jacquemin M, Vantomme V, Buhot C et al.. CD4+ T-cell clones specific for wild-type factor VIII: a molecular mechanism responsible for a higher incidence of inhibitor formation in mild/moderate hemophilia A.  Blood. 2003;  101 1351-1358
• 93 Reding M T, Wu H, Krampf M et al.. Sensitization of CD4+ T cells to coagulation factor VIII: response in congenital and acquired hemophilia patients and in healthy subjects.  Thromb Haemost. 2000;  84 643-652
• 94 Reding M T, Okita D K, Diethelm-Okita B M, Anderson T A, Conti-Fine B M. Human CD4+ T-cell epitope repertoire on the C2 domain of coagulation factor VIII.  J Thromb Haemost. 2003;  1 1777-1784
• 95 Pugliese A. Peptide-based treatment for autoimmune diseases: learning how to handle a double-edged sword.  J Clin Invest. 2003;  111 1280-1282