Soluble CD8 Attenuates Cytotoxic T Cell Responses Against Replication-Defective Adenovirus Affording Transprotection of Transgenes In Vivo

Peng, You; Falck-Pedersen, Erik; Elkon, Keith B.

doi:10.4049/jimmunol.165.3.1470

Cited by 9 publications

(17 citation statements)

References 49 publications

(38 reference statements)

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“…All viruses used in this study, including Ad null, lacked E1 and E3 (Ad type 5) and were replication defective (20). Ad type 5 expressing the ectodomain of murine CD8-␣ (Ly2.1) or chloramphenicol acetyltransferase (CAT) (AdsCD8 or AdCAT) was produced as described elsewhere (20).…”

Section: Methodsmentioning

confidence: 99%

“…Unlike these two strains of mice however, BALB/c mice rapidly eliminated the Ad vector expressing sCD8. Paradoxically, in vitro studies revealed that splenic T cells obtained from BALB/c mice were less activated and exhibited less antigen-specific cytotoxicity after restimulation compared to B6 mice (20). This finding suggested that the rapid extinction of transgene expression was most likely facilitated by non-CD8 effector cell(s).…”

mentioning

confidence: 96%

“…Based on the evidence that CD8 ϩ T cells play a dominant role in elimination of replication-defective Ad (36), we recently demonstrated that an Ad-encoded soluble CD8 (sCD8) protein could prolong transgene expression in C57BL/6 (B6) and C3H mice (20). Unlike these two strains of mice however, BALB/c mice rapidly eliminated the Ad vector expressing sCD8.…”

mentioning

confidence: 99%

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Variation in Adenovirus Transgene Expression between BALB/c and C57BL/6 Mice Is Associated with Differences in Interleukin-12 and Gamma Interferon Production and NK Cell Activation

Peng¹,

Falck-Pedersen

Elkon³

2001

J Virol

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The innate immune response against replication-defective adenoviruses (Ad) is poorly defined. We and others have previously observed striking differences in the rate at which the Ad vector itself or the virus encoding a variety of transgenes is eliminated in different mouse strains. Here, we report that Ad infection of BALB/ mice is associated with sixfold-higher levels of serum alanine aminotransferase and that Ad transgenes induce two- to threefold-higher levels of intrahepatic NK cells and NK activity compared to C57BL/6 mice. The increase in NK activation in BALB/c mice was associated with approximately 4-fold higher level of mRNA expression of a newly described NKG2 receptor activator, H-60, as well as increased expression of interleukin-12 and gamma interferon mRNAs in BALB/c mice compared to C57BL/6 mice. NK depletion in BALB/c mice or defective NK function in C3H beige mice extended transgene expression compared to their appropriate controls, and attenuation of NK together with CD8 T-cell function had a synergistic effect. These findings indicate that there are intrinsic differences in the innate immune responses of different mouse strains to Ad and Ad transgenes and that NK cells, in cooperation with CD8 T cells, play a pivotal role in the early extinction of transgene expression in BALB/c mice.

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Section: Methodsmentioning

confidence: 99%

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confidence: 96%

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Variation in Adenovirus Transgene Expression between BALB/c and C57BL/6 Mice Is Associated with Differences in Interleukin-12 and Gamma Interferon Production and NK Cell Activation

Peng¹,

Falck-Pedersen

Elkon³

2001

J Virol

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“…20 Additional strategies being evaluated to attenuate the host antiadeno response include serotype switching 21,22 and the coadministration of immunosuppressants. 3,[23][24][25] In addition to quantitating the T-cell response to adenovirus epitopes in vitro using the ELISPOT assay, we developed a semiquantitative method to assess the strength of the T-cell response to adenovirus in vivo. The use of Ad5SEAP in Jh mice is a highly effective assay for measuring the effects of adenovirus T-cell responses in vivo.…”

Section: Discussionmentioning

confidence: 99%

T-cell response to adenovirus hexon and DNA-binding protein in mice

et al. 2004

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The successful development of adenovirus vectors for vaccines and gene therapy will require a better understanding of the host immune response. Using the ELISPOT assay to measure IFN-g-secreting CD8þ cells, we identify immunodominant epitopes of the adenovirus hexon and DNA-binding protein in BALB/c and C57BL/6 mice. The T-cell response to the intramuscular administration of adenovirus serotype 5 peaks within a few weeks and gradually declines but is still detectable after 12 weeks. A second administration did not substantially increase the number of reactive T cells. The CD8 þ T-cell response was also similar between wild type and E1-deleted adenovirus. When B-cell-deficient mice were injected with adenovirus encoding the gene for secreted alkaline phosphatase, sera phosphatase activity was reduced more quickly in mice pre-exposed to adenovirus. These results add to the evidence that cell-mediated immunity is a substantial barrier to therapeutic adenoviral vectors and provide more quantitative tools to measure cellular immune responses to adenovirus.

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“…1A). This is likely due to the fact that BALB/c inbred mice eliminate cells containing the Ad transgene much more rapidly than do C57BL/6 mice (23,24). While 4 of 15 BALB/cJ mice had milligram per milliliter levels of VNA, the rest had levels of 1 to 100 g/ml.…”

Section: Resultsmentioning

confidence: 90%

Adenoviral Expression of a Bispecific VHH-Based Neutralizing Agent That Targets Protective Antigen Provides Prophylactic Protection from Anthrax in Mice

Moayeri

Tremblay

Debatis

et al. 2016

Clin Vaccine Immunol

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dBacillus anthracis, the causative agent of anthrax, secretes three polypeptides, which form the bipartite lethal and edema toxins (LT and ET, respectively). The common component in these toxins, protective antigen (PA), is responsible for binding to cellular receptors and translocating the lethal factor (LF) and edema factor (EF) enzymatic moieties to the cytosol. Antibodies against PA protect against anthrax. We previously isolated toxin-neutralizing variable domains of camelid heavy-chain-only antibodies (VHHs) and demonstrated their in vivo efficacy. In this work, gene therapy with an adenoviral (Ad) vector (Ad/VNA2-PA) (VNA, VHH-based neutralizing agents) promoting the expression of a bispecific VHH-based neutralizing agent (VNA2-PA), consisting of two linked VHHs targeting different PA-neutralizing epitopes, was tested in two inbred mouse strains, BALB/cJ and C57BL/6J, and found to protect mice against anthrax toxin challenge and anthrax spore infection. Two weeks after a single treatment with Ad/VNA2-PA, serum VNA2-PA levels remained above 1 g/ml, with some as high as 10 mg/ml. The levels were 10-to 100-fold higher and persisted longer in C57BL/6J than in BALB/cJ mice. Mice were challenged with a lethal dose of LT or spores at various times after Ad/VNA2-PA administration. The majority of BALB/cJ mice having serum VNA2-PA levels of >0.1 g/ml survived LT challenge, and 9 of 10 C57BL/6J mice with serum levels of >1 g/ml survived spore challenge. Our findings demonstrate the potential for genetic delivery of VNAs as an effective method for providing prophylactic protection from anthrax. We also extend prior findings of mouse strain-based differences in transgene expression and persistence by adenoviral vectors. Bacillus anthracis produces two toxins, which are responsible for allowing the bacterium to establish disease and induce lethality in the host. Lethal toxin (LT) and edema toxin (ET) are composed of three proteins: protective antigen (PA), lethal factor (LF), and edema factor (EF). PA is a receptor-binding component that transports LF (a protease) or EF (an adenylate cyclase) into cells where they can manifest their catalytic activities through the targeting of ubiquitous substrates. EF targets ATP and converts it to cyclic AMP (cAMP), resulting in cellular dysfunction and vascular events that can lead to lethality. LF cleaves the mitogen-activated protein kinase (MEK) family and rodent nucleotide-binding domain and leucine-rich repeat containing a pyrin domain 1 (NLRP1) inflammasome sensors. LF plays an important role in both early and late anthrax infection. Early in infection, inactivation of the MEK proteins by cleavage leads to the inhibition of a wide variety of innate immune cell responses, which allows the bacterium to evade the immune system, divide, and disseminate. The cleavage of NLRP1 early in infection in certain inbred rodents results in the activation of the inflammasome, macrophage pyroptosis, and induction of proinflammatory cytokines, which induce a protective immune response. Thus,...

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Soluble CD8 Attenuates Cytotoxic T Cell Responses Against Replication-Defective Adenovirus Affording Transprotection of Transgenes In Vivo

Cited by 9 publications

References 49 publications

Variation in Adenovirus Transgene Expression between BALB/c and C57BL/6 Mice Is Associated with Differences in Interleukin-12 and Gamma Interferon Production and NK Cell Activation

Variation in Adenovirus Transgene Expression between BALB/c and C57BL/6 Mice Is Associated with Differences in Interleukin-12 and Gamma Interferon Production and NK Cell Activation

T-cell response to adenovirus hexon and DNA-binding protein in mice

Adenoviral Expression of a Bispecific VHH-Based Neutralizing Agent That Targets Protective Antigen Provides Prophylactic Protection from Anthrax in Mice

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