Nonmethylated CG Motifs Packaged into Virus-Like Particles Induce Protective Cytotoxic T Cell Responses in the Absence of Systemic Side Effects

Storni, Tazio; Ruedl, Christiane; Schwarz, Katrin; Schwendener, Reto A.; Renner, Wolfgang A.; Bachmann, Martin F.

doi:10.4049/jimmunol.172.3.1777

Cited by 265 publications

(234 citation statements)

References 44 publications

(34 reference statements)

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“…At high doses (nanomolar range), CpG induced elevated serum levels of the acute-phase protein SAA and caused increased cell numbers in the spleen, confirming previous studies showing that such doses of CpG induce systemic side effects and splenomegaly in mice [15,19,21,24]. These systemic adverse effects did not depend on the route of administration, but only on the dose of CpG ODN, likely due to the systemic biodistribution of such motifs when delivered in nanomolar doses.…”

Section: Discussionsupporting

confidence: 82%

“…CpG treatment promotes Th1 immune responses, which can be therapeutic in allergy and asthma and enhance resistance to various viral, bacterial and protozoan infections [5,[9][10][11][12]. The combination of antigens with CpG was shown to induce maturation of professional antigen-presenting cells (APC), such as DC and macrophages, resulting in effective display of resulting epitopes on MHC class I and class II molecules, with subsequent activation and expansion of antigen-specific CD4 and CD8 T lymphocytes [10,11,[13][14][15][16]. Importantly, CpG ODN were shown to stimulate APC to a level allowing cross-priming of CD8 + T cells [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

“…The combination of antigens with CpG was shown to induce maturation of professional antigen-presenting cells (APC), such as DC and macrophages, resulting in effective display of resulting epitopes on MHC class I and class II molecules, with subsequent activation and expansion of antigen-specific CD4 and CD8 T lymphocytes [10,11,[13][14][15][16]. Importantly, CpG ODN were shown to stimulate APC to a level allowing cross-priming of CD8 + T cells [13][14][15]. These results illustrate the potential of CpG as adjuvant in vaccines against infectious disease, allergy and cancer [3], reflected in the several ongoing clinical trials [17].…”

Section: Introductionmentioning

confidence: 99%

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Improving the therapeutic index of CpG oligodeoxynucleotides by intralymphatic administration

et al. 2005

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Signal transduction initiated by TLR such as TLR9, a natural receptor for unmethylated cytosine-guanine-rich motifs (CpG), results in activation of transcription factors, including NF-jB, with substantial impact on the innate and adaptive immunity. However, practical application of new adjuvants such as CpG oligodeoxynucleotides (ODN) remains a challenge, since prominent systemic activation of NF-jB may result in severe side effects reminiscent of septic shock, thus limiting their therapeutic index (TI). Low-dose administration of CpG ODN into lymph nodes has been evaluated as a means to reduce systemic side effects while retaining strong adjuvant properties. To this aim, a prototype immune-stimulating CpG ODN was used to enhance the antibody production against the antigen phospholipase A 2 and the CD8 + T cell responses to ovalbumin in mice. When administered subcutaneously, high CpG ODN doses (>10 nmol) were required to enhance antibody and CD8 + T cell responses. In contrast, when administered directly into a lymph node, much lower amounts of CpG (<0.1 nmol) were sufficient for a similar immune-enhancing effect. Systemic adverse reactions induced by CpG ODN were only detected at higher doses (1-10 nmol), independently of the route of administration. Finally, low-dose CpG ODN, administered in a targeted fashion to HLA-A2.1 + transgenic mice, greatly elevated anti-tumor CD8 + T cell immunity. Thus, intralymphatic administration of CpG ODN considerably improves the TI and may greatly enable a safe and effective use in the clinic.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Improving the therapeutic index of CpG oligodeoxynucleotides by intralymphatic administration

et al. 2005

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“…For example, molecular danger signals that mimic the effect of the endotoxin lipopolysaccharide (LPS), such as monophosphoryl lipid A, have been explored 7 , as well as the cytokines CD40 ligand and interferon (IFN)-g 1,2,16 . Delivery of danger signals with antigen by co-encapsulation in liposomes 3,16 , packaging into virus-like particles 14 or co-injection with dendritic cell-targeting antibody fusion proteins 1,4,22 have been successful at producing adaptive immune responses, but despite such promising results, many complexities remain including toxicity, physiological transport and economic feasibility. As an alternative adjuvant strategy, we explored the possibility of using the complement cascade as a danger signal of innate immunity, designing our nanoparticles with a surface chemistry that spontaneously induces complement activation in situ.…”

mentioning

confidence: 99%

Exploiting lymphatic transport and complement activation in nanoparticle vaccines

et al. 2007

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“…We therefore decided to extend our experiments to an additional TLR ligand, CpG. In order to test the influence of CpG on cross-presentation of p33, we generated p33-VLP loaded with CpG [32]. To this end, VLP were RNAse digested and incubated with CpG.…”

Section: Cpg Inhibit Rather Then Enhance Cross-presentationmentioning

confidence: 99%

Innate signaling regulates cross‐priming at the level of DC licensing and not antigen presentation

Keller¹,

Schwarz²,

Manolova³

et al. 2009

Eur J Immunol

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Innate stimuli, such as TLR ligands, are known to greatly facilitate cross-priming. Currently it is unclear whether innate stimuli enhance cross-priming at the level of crosspresentation or at the level of T-cell priming. In this study, we addressed this question by measuring cross-presentation as well as cross-priming by virus-like particles (VLP) displaying peptide p33 derived of lymphocytic choriomeningitis virus. Innate stimuli were varied by either packaging different TLR ligands into virus-like particles or using mice deficient in two key molecules of TLR-signaling, namely the adaptor molecule MyD88 as well as IFN-a/b receptor. While efficient cross-presentation occurred despite strongly reduced activation of DC in the absence of TLR ligand-mediated signals, T-cell priming was abolished. Thus, innate stimuli regulate cross-priming at the level of DC licensing for T-cell activation and not antigen presentation.Key words: Antigen presentation/processing . Cross-presentation/priming . DC Introduction CD8 1 T cells play an important role in defense against infectious agents. Activated CD8 1 T cells differentiate into CTL that kill infected cells. CTL recognize endogenously synthesized antigenic peptides complexed with MHC class I molecules on the surface of APC. Since not all pathogens directly infect APC, it is necessary that APC are able to internalize exogenous antigens and present them on MHC class I molecules for CD8 1 T-cell recognition, a process known as cross-presentation [1][2][3]. Such cross-presented antigens may make an important contribution to the induction of CTL responses, in particular for non-replicating antigens, such as virus-like particles (VLP) [4]. The main cell types involved in cross-presentation are professional APC, such as DC [5,6] as well as macrophages [7,8] but not B cells [9].The primary function of immature DC is to sample foreign antigens for T-cell and perhaps B-cell priming. To this end, DC either sit at strategic positions within lymphoid organs or act as sentinels in peripheral tissues. In any event, for optimal T-cell priming, DC need pathogen-derived signals in order to mature [10]. In a first step, DC are activated by various pathogen-derived molecules (known as PAMP), including ligands for TLR, lectins, intracellular nucleotide-binding oligomerization domain receptors or retinoic acid induced gene [11][12][13][14]. So far 11 TLR have been identified in mice [15]. TLR recognize invariant viral or bacterial structures. A number of receptors are specialized in recognizing nucleic acids, such as dsRNA (TLR3), ssRNA (TLR7 and TLR8), and DNA rich in non-methlylated CG motifs (CpG, TLR9). The interaction of microbial ligands with innate immune system receptors initiates the maturation of DC. Stimulation of DC with such innate stimuli results in licensed DC. Such DC express intermediate levels of cell surface costimulatory molecules. Endogenous mediators, such as TNF family members, chemokines, or other cytokines facilitate the full differentiation of DC, expressing high leve...

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Nonmethylated CG Motifs Packaged into Virus-Like Particles Induce Protective Cytotoxic T Cell Responses in the Absence of Systemic Side Effects

Cited by 265 publications

References 44 publications

Improving the therapeutic index of CpG oligodeoxynucleotides by intralymphatic administration

Improving the therapeutic index of CpG oligodeoxynucleotides by intralymphatic administration

Exploiting lymphatic transport and complement activation in nanoparticle vaccines

Innate signaling regulates cross‐priming at the level of DC licensing and not antigen presentation

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