Significant alterations of biodistribution and immune responses in Balb/c mice administered with adenovirus targeted to CD40(+) cells

Huang, Danning; Pereboev, Alexander; Korokhov, Nikolay; He, Runtao; Larocque, Louise; Gravel, Caroline; Jaentschke, Bozena; Tocchi, Monika; Casley, William L.; Lemieux, Maxime; Curiel, David T.; Chen, W; Li, X

doi:10.1038/sj.gt.3303085

Cited by 30 publications

(35 citation statements)

References 56 publications

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“…Initial experiments showed that the construct missing the S, designated as rAd-NP40L, is unable to induce any immune response or afford any protection against influenza challenge, underscoring the importance of the secretion of the fusion protein. It could be envisaged that because many cell types are susceptible to adenovirus infection including proliferating and nonproliferating cells (23,27), gene products with S produced by the adenovirus-infected cells would increase the Ag loads in vivo (Fig. 12).…”

Section: Discussionmentioning

confidence: 99%

“…Blood samples or cells from spleens and/or draining lymph nodes (LNs) were collected as described previously (23). BALB/c and C57BL/6J mice were intranasally challenged with 103 LD 50 Weight loss is expressed as percentage of animal weight at each time point from their initial body weight.…”

Section: Animal Studiesmentioning

confidence: 99%

“…Several groups have investigated the potential of CD40L as a molecular adjuvant by either codelivering CD40L with Ags (13)(14)(15)(16)(17)(18)(19)(20) or retargeting the Ag-delivery vector to CD40 on APCs (21)(22)(23)(24)(25)(26)(27)(28)(29)(30). Although enhanced immune responses against various pathogens and tumors were observed, little is known about in vivo B cell responses, functional roles of CD4 + and CD8 + T cells during induction phase, or the contributions of Abs and CD8 + T cells in protection.…”

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confidence: 99%

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CD40 Ligand Preferentially Modulates Immune Response and Enhances Protection against Influenza Virus

Hashem

Gravel

Chen³

et al. 2014

The Journal of Immunology

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CD40L, a key regulator of the immune system, was studied as both a targeting ligand and a molecular adjuvant in nucleoprotein (NP)-based host defense against influenza in mouse models with different genetic backgrounds. Adenoviral vectors secreting NP-CD40L fusion protein (denoted as rAd-SNP40L) afforded full protection of immunocompetent and immunocompromised mice (CD40L−/− and CD4−/−) against lethal influenza infection. Mechanistically, rAd-SNP40L preferentially induced early and persistent B cell germinal center formation, and accelerated Ig isotype-switching and Th1-skewed, NP-specific Ab response. Moreover, it drastically augmented primary and memory NP-specific CTL activity and polyfunctional CD8+ T cells. The markedly enhanced nonneutralizing Abs and CTLs significantly reduced viral burdens in the lungs of mice upon lethal virus challenge. Data generated from CD40L−/− and CD4−/− mice revealed that the protection was indeed CD40L mediated but CD4+ T cell independent, demonstrating the viability of the fusion Ags in protecting immunodeficient hosts. Notably, a single dose of rAd-SNP40L completely protected mice from lethal viral challenge 4 mo after immunization, representing the first report, to our knowledge, on NP in conjunction with a molecular adjuvant inducing a robust and long-lasting memory immune response against influenza. This platform is characterized by an increased in vivo load of CD40-targeted Ag upon the secretion of the fusion protein from adenovirus-infected cells and may represent a promising strategy to enhance the breadth, durability, and potency of Ag-specific immune responses.

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Section: Discussionmentioning

confidence: 99%

Section: Animal Studiesmentioning

confidence: 99%

mentioning

confidence: 99%

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CD40 Ligand Preferentially Modulates Immune Response and Enhances Protection against Influenza Virus

Hashem

Gravel

Chen³

et al. 2014

The Journal of Immunology

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“…As a result, CD40-targeted adenovirus may be able to sustain longer in vivo than untargeted adenovirus in the presence of Ad-specific neutralizing antibodies, and thus have a higher therapeutic index. Studies by Huang et al, which show that neutralizing antibodies had no inhibitory effects on CFm40L mediated Ad-luc transduction of human DCs in vitro, supports this possibility [35]. Regardless of all possibilities, there is no doubt that the CD40-targeted Ad5-CMV-SV40 T-Ag is an effective adenoviral vaccine, whose potency is as good as that of untargeted Ad5-CMV-SV40 T-Ag, if not better.…”

Section: Discussionmentioning

confidence: 49%

“…Furthermore, the delivery of genetic material allows for prolonged expression and therefore presentation of antigens. Both nonviral [21,26,[43][44][45] and viral [22,25,28,33,35,42,46-53] methods have been described for introduction of DNA sequences, which have shown to promote specific CTL responses and protective and therapeutic anti-tumor immunity of tumors expressing the antigen sequence delivered. However, because the endogenously expressed antigens may have only limited access to the class II presentation pathway, it is possible that there will be a deficiency in generating CD4+ T helper cells, required for an effective and durable CTL response.…”

Section: The Use Of Dendritic Cells In Tumor Vaccination Approachesmentioning

confidence: 99%

Dendritic Cell-Based Genetic Immunotherapy for Ovarian Cancer

Mathis¹

2007

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE (DD-MM-YYYY) PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBERLouisiana State University Shreveport, LA 71130-3932 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTAdenovirus (Ad)-mediated transduction of dendritic cells (DCs) is inefficient because of the lack of the primary Ad receptor, CAR. CD40 is a surface marker expressed by DCs that plays a crucial role in their maturation and subsequent stimulation of T cells. DC infection with Ad targeted to the CD40 results in increased gene transfer. Cells transduced with CD40-targeted Ad5-SV40-TAg vector showed increased expression of transgene and expression of co-stimulatory molecules at 48 hours post-infection compared to cells transduced with untargeted Ad5-SV40-TAg vector. We demonstrated that CD40-targeted gene transfer promotes DC maturation with induction of a complex signaling cascade accompanied by characteristic changes in cytokine production. These results demonstrate that DCs can be successfully transduced using a CD40 targeted adenoviral vector and that transduced DCs show activation.

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Enhanced T cell responses against hepatitis C virus by ex vivo targeting of adenoviral particles to dendritic cells

et al. 2011

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Injection of dendritic cells (DCs) presenting viral proteins constitutes a promising approach to stimulate T cell immunity against hepatitis C virus (HCV). Here we describe a strategy to enhance antigen loading and immunostimulatory functions of DCs useful in the preparation of therapeutic vaccines. Incubation of murine DCs with CFm40L, an adapter molecule containing the coxsackie-adenovirus receptor fused to the ecto-domain of murine CD40L-induced DC maturation, produced high amounts of interleukin-12 and up-regulation of molecules associated with T helper 1 responses. Accordingly, targeting of an adenovirus encoding HCV NS3 protein (AdNS3) to DCs with CFm40L strongly enhanced NS3 presentation in vitro, activating interferon-c-producing T cells. Moreover, immunization of mice with these DCs promoted strong CD4 and CD8 T cell responses against HCV NS3. CFh40L, a similar adapter molecule containing human CD40L, enhanced transduction and maturation of human monocyte-derived DCs. Comparison of DCs transduced with AdNS3 and CFh40L from patients with chronic HCV infection and healthy donors revealed similar maturation levels. More importantly, DCs from the patients induced NS3-specific responses when transduced with AdNS3 and CFh40L but not with AdNS3 alone. Conclusion: DCs transduced with AdNS3 and the adapter molecule CFm/h40L exhibit enhanced immunostimulatory functions, induce robust anti-HCV NS3 immunity in animals, and can induce antiviral immune responses in subjects with chronic HCV infection. This strategy may serve as therapeutic vaccination for patients with chronic hepatitis C. (HEPATOLOGY 2011;54:28-37) T he antiviral T cell immunity found in patients with chronic hepatitis C virus (HCV) infection is characterized by its low magnitude and the narrow repertoire of epitopes recognized by T cells. By contrast, individuals who clear the virus have strong and multispecific T cell responses against viral antigens. 1 These results suggest that T cell immunity may be responsible for viral clearance and support the notion that induction of these responses may be advantageous for the treatment of chronic hepatitis C.

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Significant alterations of biodistribution and immune responses in Balb/c mice administered with adenovirus targeted to CD40(+) cells

Cited by 30 publications

References 56 publications

CD40 Ligand Preferentially Modulates Immune Response and Enhances Protection against Influenza Virus

CD40 Ligand Preferentially Modulates Immune Response and Enhances Protection against Influenza Virus

Dendritic Cell-Based Genetic Immunotherapy for Ovarian Cancer

Enhanced T cell responses against hepatitis C virus by ex vivo targeting of adenoviral particles to dendritic cells

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