Display options
Cite
Basner-Tschakarjan E, Mingozzi F. Cell-Mediated Immunity to AAV Vectors, Evolving Concepts and Potential Solutions. Front Immunol. 2014;5:350doi: 10.3389/fimmu.2014.00350.
Basner-Tschakarjan, E., & Mingozzi, F. (2014). Cell-Mediated Immunity to AAV Vectors, Evolving Concepts and Potential Solutions. Frontiers in immunology, 5350. https://doi.org/10.3389/fimmu.2014.00350
Basner-Tschakarjan, Etiena, and Mingozzi, Federico. "Cell-Mediated Immunity to AAV Vectors, Evolving Concepts and Potential Solutions." Frontiers in immunology vol. 5 (2014): 350. doi: https://doi.org/10.3389/fimmu.2014.00350
Basner-Tschakarjan E, Mingozzi F. Cell-Mediated Immunity to AAV Vectors, Evolving Concepts and Potential Solutions. Front Immunol. 2014 Jul 23;5:350. doi: 10.3389/fimmu.2014.00350. eCollection 2014. PMID: 25101090; PMCID: PMC4107954.
Copy Download .nbib Format: NLM
Share it on

Front Immunol. 2014 Jul 23;5:350. doi: 10.3389/fimmu.2014.00350. eCollection 2014.

Cell-Mediated Immunity to AAV Vectors, Evolving Concepts and Potential Solutions.

Frontiers in immunology

Etiena Basner-Tschakarjan, Federico Mingozzi

Affiliations

  1. Department of Hematology, The Children's Hospital of Philadelphia , Philadelphia, PA , USA.
  2. University Pierre and Marie Curie , Paris , France ; Genethon , Evry , France.

PMID: 25101090 PMCID: PMC4107954 DOI: 10.3389/fimmu.2014.00350

Abstract

Adeno-associated virus (AAV) vectors are one of the most efficient in vivo gene delivery platforms. Over the past decade, clinical trials of AAV vector-mediated gene transfer led to some of the most exciting results in the field of gene therapy and, recently, to the market approval of an AAV-based drug in Europe. With clinical development, however, it became obvious that the host immune system represents an important obstacle to successful gene transfer with AAV vectors. In this review article, we will discuss the issue of cytotoxic T cell responses directed against the AAV capsid encountered on human studies. While over the past several years the field has acquired a tremendous amount of information on the interactions of AAV vectors with the immune system, a lot of questions are still unanswered. Novel concepts are emerging, such as the relationship between the total capsid dose and the T cell-mediated clearance of transduced cells, the potential role of innate immunity in vector immunogenicity highlighted in preclinical studies, and the cross talk between regulatory and effector T cells in the determination of the outcome of gene transfer. There is still a lot to learn about immune responses in AAV gene transfer, for example, it is not well understood what are the determinants of the kinetics of activation of T cells in response to vector administration, why not all subjects develop detrimental T cell responses following gene transfer, and whether the intervention strategies currently in use to block T cell-mediated clearance of transduced cells will be safe and effective for all gene therapy indications. Results from novel preclinical models and clinical studies will help to address these points and to reach the important goal of developing safe and effective gene therapy protocols to treat human diseases.

Keywords: AAV vectors; T cell responses; gene therapy; immune modulation; immunogenicity

References

  1. Blood. 2014 May 15;123(20):3195-9 - PubMed
  2. Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11854-9 - PubMed
  3. J Immunol. 2012 Jul 1;189(1):146-53 - PubMed
  4. J Clin Invest. 2000 Jun;105(11):1573-87 - PubMed
  5. Nat Med. 2007 Apr;13(4):419-22 - PubMed
  6. Science. 1965 Aug 13;149(3685):754-6 - PubMed
  7. N Engl J Med. 2009 Jan 29;360(5):447-58 - PubMed
  8. Mol Ther. 2001 Sep;4(3):201-10 - PubMed
  9. Sci Transl Med. 2013 Jul 17;5(194):194ra92 - PubMed
  10. Hepatology. 2012 Jan;55(1):287-97 - PubMed
  11. Mol Immunol. 2013 Sep;55(2):113-6 - PubMed
  12. J Virol. 2002 May;76(9):4580-90 - PubMed
  13. J Clin Invest. 2013 Mar;123(3):1390-401 - PubMed
  14. Blood. 2013 May 23;121(21):4396-403 - PubMed
  15. Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16363-8 - PubMed
  16. Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7827-32 - PubMed
  17. Front Immunol. 2014 Mar 03;5:82 - PubMed
  18. Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):15112-7 - PubMed
  19. J Clin Invest. 2013 Dec;123(12):5310-8 - PubMed
  20. PLoS One. 2009 Aug 04;4(8):e6376 - PubMed
  21. Lancet. 2007 Jun 23;369(9579):2097-105 - PubMed
  22. Mol Ther. 2007 Apr;15(4):792-800 - PubMed
  23. Ann Neurol. 2009 Sep;66(3):290-7 - PubMed
  24. Blood. 2009 Sep 3;114(10):2077-86 - PubMed
  25. Blood. 2012 Mar 29;119(13):3038-41 - PubMed
  26. N Engl J Med. 2010 Oct 7;363(15):1429-37 - PubMed
  27. J Med Virol. 1999 Nov;59(3):406-11 - PubMed
  28. Mol Ther Methods Clin Dev. 2014;1(9):20139 - PubMed
  29. Gastroenterology. 2011 Jul;141(1):348-57, 357.e1-3 - PubMed
  30. Arterioscler Thromb Vasc Biol. 2008 Dec;28(12):2303-4 - PubMed
  31. J Virol. 2008 Mar;82(6):2727-40 - PubMed
  32. Curr Gene Ther. 2011 Aug;11(4):321-30 - PubMed
  33. Science. 2013 Aug 23;341(6148):1233151 - PubMed
  34. EMBO Mol Med. 2013 Nov;5(11):1684-97 - PubMed
  35. Mol Ther. 2011 May;19(5):876-85 - PubMed
  36. Gene Ther. 2005 Jun;12(11):873-80 - PubMed
  37. Am J Hum Genet. 2007 Nov;81(5):1042-9 - PubMed
  38. Mol Ther. 2012 Aug;20(8):1571-81 - PubMed
  39. Neurology. 2009 Nov 17;73(20):1662-9 - PubMed
  40. J Gene Med. 2006 May;8(5):577-88 - PubMed
  41. Proc Natl Acad Sci U S A. 2010 Jun 1;107(22):10220-5 - PubMed
  42. J Immunol. 2012 Jun 15;188(12):6418-24 - PubMed
  43. J Virol. 1998 Apr;72(4):3241-7 - PubMed
  44. Lancet Neurol. 2010 Dec;9(12):1164-1172 - PubMed
  45. Ann Neurol. 2010 Nov;68(5):629-38 - PubMed
  46. Science. 2002 Apr 12;296(5566):301-5 - PubMed
  47. Blood. 2011 Jan 20;117(3):798-807 - PubMed
  48. Mol Ther. 2013 Sep;21(9):1727-37 - PubMed
  49. J Clin Invest. 2009 Jun;119(6):1688-95 - PubMed
  50. Mol Ther. 2010 Jul;18(7):1318-29 - PubMed
  51. Lancet Neurol. 2008 May;7(5):400-8 - PubMed
  52. Mol Ther. 2014 Jan;22(1):42-51 - PubMed
  53. Blood. 2010 Dec 23;116(26):5842-8 - PubMed
  54. Science. 2009 Nov 6;326(5954):818-23 - PubMed
  55. J Virol. 2007 Jul;81(14):7540-7 - PubMed
  56. Science. 2013 Aug 23;341(6148):1233158 - PubMed
  57. Gene Ther. 2012 Mar;19(3):288-94 - PubMed
  58. Blood. 2013 Apr 25;121(17):3335-44 - PubMed
  59. J Diabetes Res. 2013;2013:621693 - PubMed
  60. Blood. 2010 Jun 10;115(23):4678-88 - PubMed
  61. Blood. 2012 Nov 29;120(23):4517-20 - PubMed
  62. Front Immunol. 2013 Sep 12;4:273 - PubMed
  63. J Card Fail. 2009 Apr;15(3):171-81 - PubMed
  64. Hum Gene Ther. 2005 Aug;16(8):921-8 - PubMed
  65. Blood. 2003 Apr 15;101(8):2963-72 - PubMed
  66. Sci Transl Med. 2012 Dec 19;4(165):165ra163 - PubMed
  67. Mol Ther. 2010 Jan;18(1):135-42 - PubMed
  68. J Virol. 2002 Mar;76(5):2043-53 - PubMed
  69. Hum Gene Ther. 2011 May;22(5):605-12 - PubMed
  70. Nature. 2010 Sep 16;467(7313):318-22 - PubMed
  71. World J Gastroenterol. 2012 Aug 28;18(32):4288-99 - PubMed
  72. N Engl J Med. 2008 May 22;358(21):2240-8 - PubMed
  73. Blood. 2012 Nov 29;120(23):4521-3 - PubMed
  74. Gene Ther. 2005 Oct;12(19):1453-64 - PubMed
  75. Proc Biol Sci. 2009 Jun 22;276(1665):2233-42 - PubMed
  76. J Clin Invest. 2013 Jul 1;123(8):3254-3271 - PubMed
  77. EMBO Mol Med. 2013 Jan;5(1):1-3 - PubMed
  78. Mol Ther. 2012 Aug;20(8):1501-7 - PubMed
  79. Mol Ther. 2006 May;13(5):967-75 - PubMed
  80. EMBO Mol Med. 2013 Nov;5(11):1698-709 - PubMed
  81. Hum Gene Ther. 2012 May;23(5):460-72 - PubMed
  82. Blood. 2004 Aug 15;104(4):969-77 - PubMed
  83. Virol J. 2013 Mar 06;10:74 - PubMed
  84. Blood. 2011 Jun 16;117(24):6459-68 - PubMed
  85. Nat Rev Genet. 2011 May;12(5):301-15 - PubMed
  86. Blood. 2004 May 15;103(10):3700-9 - PubMed
  87. Front Immunol. 2013 Oct 18;4:341 - PubMed
  88. Front Microbiol. 2011 Sep 19;2:194 - PubMed
  89. Blood. 2013 Mar 21;121(12):2224-33 - PubMed
  90. N Engl J Med. 2011 Dec 22;365(25):2357-65 - PubMed
  91. Hum Reprod. 2008 Jan;23(1):29-36 - PubMed
  92. Blood. 2009 Jan 22;113(4):797-806 - PubMed
  93. J Transl Med. 2014 Jan 25;12:25 - PubMed
  94. Blood. 2008 Oct 15;112(8):3303-11 - PubMed
  95. Gene Ther. 2013 Apr;20(4):361-9 - PubMed
  96. N Engl J Med. 2008 May 22;358(21):2231-9 - PubMed
  97. Neurotoxicology. 2014 Jul;43:28-35 - PubMed
  98. Hum Gene Ther. 2013 May;24(5):545-53 - PubMed
  99. Brain. 2012 Feb;135(Pt 2):483-92 - PubMed
  100. Nat Rev Genet. 2011 May;12(5):341-55 - PubMed
  101. J Clin Invest. 2013 Jul;123(7):2994-3001 - PubMed
  102. Blood. 2007 Oct 1;110(7):2334-41 - PubMed
  103. Gene Ther. 2009 Jan;16(1):60-9 - PubMed
  104. Hum Gene Ther. 2008 May;19(5):463-74 - PubMed
  105. Blood. 2007 Aug 15;110(4):1132-40 - PubMed
  106. Front Immunol. 2013 Aug 30;4:261 - PubMed
  107. Hum Gene Ther. 2007 Mar;18(3):185-94 - PubMed
  108. Hum Gene Ther. 2011 Oct;22(10):1239-47 - PubMed
  109. J Transl Med. 2012 Jun 15;10:122 - PubMed
  110. J Clin Invest. 2009 Aug;119(8):2388-98 - PubMed
  111. Cancer Immunol Immunother. 2011 Jan;60(1):15-22 - PubMed
  112. Blood. 2009 Jan 15;113(3):538-45 - PubMed
  113. Blood. 2006 Nov 15;108(10):3321-8 - PubMed
  114. J Clin Invest. 2003 May;111(9):1347-56 - PubMed
  115. Nat Med. 2006 Mar;12(3):342-7 - PubMed
  116. Mol Ther. 2010 Jan;18(1):151-60 - PubMed
  117. Hum Gene Ther. 2013 Apr;24(4):393-405 - PubMed
  118. Clin Vaccine Immunol. 2011 Sep;18(9):1586-8 - PubMed

Publication Types

Grant support