Suppression of Immune Response to Adenovirus Serotype 5 Vector by Immunization with Peptides Containing an MHC Class II Epitope and a Thio-Oxidoreductase Motif
Restricted accessResearch articleFirst published online March, 2016
Suppression of Immune Response to Adenovirus Serotype 5 Vector by Immunization with Peptides Containing an MHC Class II Epitope and a Thio-Oxidoreductase Motif
The main obstacle to viral vector-mediated gene therapy remains the elicitation of an immune response to the vector, resulting in clearance of transgene and resistance to further transgenesis. Specific antibody production contributes to such immune responses. A single class II-restricted epitope of adenovirus serotype 5 (Ad5) vector hexon-6 capsid protein containing a thiol-oxidoreductase motif was used in an attempt to prevent specific antibody production in response to Ad5 vectors. We demonstrate here that such immunization carried out before intravenous administration of Ad5 vectors prevents antibody production to the ensemble of Ad5 vector proteins in both BALB/c and C57BL/6 mice. The antibody response to Ad5 is dependent on innate immune activation, seemingly involving natural killer T (NKT) cells. We observed that immunization with a class II-restricted Ad5 peptide prevents such NKT cell activation. Increased transgenesis and prolonged transgene expression result from such immunization, providing a simple protocol for improving gene therapy.
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References
1.
HoffmannD, and WildnerO. Comparison of herpes simplex virus- and conditionally replicative adenovirus-based vectors for glioblastoma treatment. Cancer Gene Ther, 2007; 14:627–639.
2.
KozarskyK, GrossmanM, and WilsonJM. Adenovirus-mediated correction of the genetic defect in hepatocytes from patients with familial hypercholesterolemia. Somat Cell Mol Genet, 1993; 19:449–458.
NayakS, and HerzogRW. Progress and prospects: immune responses to viral vectors. Gene Ther, 2010; 17:295–304.
5.
KhareR, ChenCY, WeaverEA, et al.Advances and future challenges in adenoviral vector pharmacology and targeting. Curr Gene Ther, 2011; 11:241–258.
6.
MichouAI, SantoroL, ChristM, et al.Adenovirus-mediated gene transfer: influence of transgene, mouse strain and type of immune response on persistence of transgene expression. Gene Ther, 1997; 4:473–482.
7.
Basner-TschakarjanE, GaffalE, O'KeeffeM, et al.Adenovirus efficiently transduces plasmacytoid dendritic cells resulting in TLR9-dependent maturation and IFN-α production. J Gene Med, 2006; 8:1300–1306.
8.
SeilerMP, CerulloV, and LeeB. Immune response to helper dependent adenoviral mediated liver gene therapy: challenges and prospects. Curr Gene Ther, 2007; 7:297–305.
9.
ThackerEE, TimaresL, and MatthewsQL. Strategies to overcome host immunity to adenovirus vectors in vaccine development. Expert Rev Vaccines, 2009; 8:761–777.
10.
ZhuJ, HuangX, and YangY. Myeloid-derived suppressor cells regulate natural killer cell response to adenovirus-mediated gene transfer. J Virol, 2012; 86:13689–13696.
11.
UlasovIV, RiveraAA, HanY, et al.Targeting adenovirus to CD80 and CD86 receptors increases gene transfer efficiency to malignant glioma cells. J Neurosurg, 2007; 107:617–627.
12.
RoyS, GaoG, LuY, et al.Characterization of a family of chimpanzee adenoviruses and development of molecular clones for gene transfer vectors. Hum Gene Ther, 2004; 15:519–530.
13.
SumidaSM, TruittDM, LemckertAA, et al.Neutralizing antibodies to adenovirus serotype 5 vaccine vectors are directed primarily against the adenovirus hexon protein. J Immunol, 2005; 174:7179–7185.
14.
Markine-GoriaynoffD, van der LogtJT, TruyensC, et al.IFN-γ-independent IgG2a production in mice infected with viruses and parasites. Int Immunol, 2000; 12:223–230.
15.
CoutelierJP, van der LogtJT, HeessenFW, et al.IgG2a restriction of murine antibodies elicited by viral infections. J Exp Med, 1987; 165:64–69.
16.
WuH, DmitrievI, KashentsevaE, et al.Construction and characterization of adenovirus serotype 5 packaged by serotype 3 hexon. J Virol, 2002; 76:12775–12782.
17.
PengSL, SzaboSJ, and GlimcherLH. T-bet regulates IgG class switching and pathogenic autoantibody production. Proc Natl Acad Sci U S A, 2002; 99:5545–5550.
18.
ZhangY, ChirmuleN, GaoGP, et al.Acute cytokine response to systemic adenoviral vectors in mice is mediated by dendritic cells and macrophages. Mol Ther, 2001; 3:697–707.
19.
National Institutes of Health Recombinant DNA Advisory Committee. Assessment of adenoviral vector safety and toxicity: report of the National Institutes of Health Recombinant DNA Advisory Committee. Hum Gene Ther, 2002; 13:3–13.
20.
FujiiS-I, ShimizuK, OkamotoY, et al.NKT cells as an ideal anti-tumor immunotherapeutic. Front Immunol, 2013; 4:409.
21.
YoshidaO, AkbarSMF, ChenS, et al.Regulatory natural killer cells in murine liver and their immunosuppressive capacity. Liver Int, 2010; 30:906–912.
22.
Asselin-PaturelC, BrizardG, CheminK, et al.Type I interferon dependence of plasmacytoid dendritic cell activation and migration. J Exp Med, 2005; 201:1157–1167.
23.
KawakamiK, KinjoY, YaraS, et al.Activation of Vα14+ natural killer T cells by α-galactosylceramide results in development of Th1 response and local host resistance in mice infected with Cryptococcus neoformans. Infect Immun, 2001; 69:213–220.
24.
BenlaghaK, WeissA, BeavisA, et al.In vivo identification of glycolipid antigen-specific T cells using fluorescent CD1d tetramers. J Exp Med, 2000; 191:1895–1903.
25.
LeeW-Y, MoriartyTJ, WongCHY, et al.An intravascular immune response to Borrelia burgdorferi involves Kupffer cells and iNKT cells. Nat Immunol, 2010; 11:295–302.
26.
VelázquezP, CameronTO, KinjoY, et al.Cutting edge: activation by innate cytokines or microbial antigens can cause arrest of natural killer T cell patrolling of liver sinusoids. J Immunol, 2008; 180:2024–2028.
27.
GeissmannF, CameronTO, SidobreS, et al.Intravascular immune surveillance by CXCR6+ NKT cells patrolling liver sinusoids. PLoS Biol, 2005; 3:e113.
28.
BucklandKF, and Bobby GasparH. Gene and cell therapy for children—new medicines, new challenges?. Adv Drug Deliv Rev, 2014; 73:162–169.
29.
CarlierVA, VanderElstL, JanssensW, et al.Increased synapse formation obtained by T cell epitopes containing a CxxC motif in flanking residues convert CD4+ T cells into cytolytic effectors. PLoS One, 2012; 7:e45366.
30.
SungRS, QinL, and BrombergJS. TNFα and IFNγ induced by innate anti-adenoviral immune responses inhibit adenovirus-mediated transgene expression. Mol Ther, 2001; 3:757–767.
31.
SchnellMA, ZhangY, TazelaarJ, et al.Activation of innate immunity in nonhuman primates following intraportal administration of adenoviral vectors. Mol Ther, 2001; 3:708–722.
32.
ThaciB, UlasovIV, WainwrightDA, et al.The challenge for gene therapy: innate immune response to adenoviruses. Oncotarget, 2011; 2:113–121.
33.
ZhuJ, HuangX, and YangY. A critical role for type I IFN-dependent NK cell activation in innate immune elimination of adenoviral vectors in vivo. Mol Ther, 2008; 16:1300–1307.
34.
De GeestB, SnoeysJ, Van LinthoutS, et al.Elimination of innate immune responses and liver inflammation by PEGylation of adenoviral vectors and methylprednisolone. Hum Gene Ther, 2005; 16:1439–1451.
35.
SakuraiT, InamineA, IinumaT, et al.Activation of invariant natural killer T cells in regional lymph nodes as new antigen-specific immunotherapy via induction of interleukin-21 and interferon-γ. Clin Exp Immunol, 2014; 178:65–74.
36.
SmileyST, KaplanMH, and GrusbyMJ. Immunoglobulin E production in the absence of interleukin-4-secreting CD1-dependent cells. Science, 1997; 275:977–979.
37.
MingozziF, and HighKA. Immune responses to AAV in clinical trials. Curr Gene Ther, 2011; 11:321–330.
38.
SunC-P, WuT-H, ChenC-C, et al.Studies of efficacy and liver toxicity related to adeno-associated virus-mediated RNA interference. Hum Gene Ther, 2013; 24:739–750.
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