Rapid generation of broad T-cell immunity in humans after a single injection of mature dendritic cells

Dhodapkar, Madhav V.; Steinman, Ralph M.; Sapp, Mark; Desai, Hina; Fossella, C; Krasovsky, Joseph; Donahoe, Sean M.; Dunbar, P. Rod; Cerundolo, Vincenzo; Nixon, Douglas F.; Bhardwaj, Nina

doi:10.1172/jci6909

Cited by 424 publications

(307 citation statements)

References 31 publications

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“…Currently, the use of PGE 2 for maturation of DCs used for cancer vaccines is ambivalently perceived. In principle, PGE 2 -matured DC loaded with tumor antigens has been shown to effectively increase the number of circulating tumor-specific T cells [44]. PGE 2 originally was added to DC maturation strategies in cancer vaccine trials to In conclusion, our herein presented findings are compatible with a concept suggesting that the effect of PGE 2 -matured DCs stimulating allogeneic T cells is diverse and may be highly contextdependent.…”

supporting

confidence: 84%

Ambivalent effects of dendritic cells displaying prostaglandin E2‐induced indoleamine 2,3‐dioxygenase

et al. 2012

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Prostaglandin E2 (PGE 2 ), an abundantly produced lipid messenger in mammalian organisms, has been attributed to possess potent albeit ambivalent immunological functions. Recently, PGE 2 has been reported to stimulate the commonly believed immunosuppressive indoleamine 2,3-dioxygenase (IDO) pathway in human dendritic cells (DCs), but without promoting DC immunosuppressive activity. Here, we report that PGE 2 used as a DC maturation agent apparently has more diverse functions. PGE 2 -matured DCs acquired powerful IDO activity, which was sustained even after removing PGE 2 . These IDO-competent DCs were able to stimulate allogeneic T-cell proliferation, but achieved inhibitory activity as their content in DC/T-cell co-cultures increased. The DC inhibitory activity was reversed upon blockade of IDO activity, confirming that the suppressive effect was in fact mediated by IDO and occurred in a dose-dependent fashion. IDO-mediated T-cell suppression was restored upon re-stimulation of T cells in the absence of IDO activity, confirming its reversibility. T cells stimulated by PGE 2 -matured IDO-competent DCs were sensitized to produce multiple cytokines, comprising Th1, Th2, and Th17 phenotypes. Collectively, these data suggest that T cells stimulated by PGE 2 -matured DCs are not terminally differentiated and their ultimate type of response may be formed by microenvironmental conditions. Keywords: Human dendritic cells r IL-23 r Immunosuppression r Indoleamine 2,3-dioxygenase (IDO) r Prostaglandin E2 Supporting Information available online IntroductionThe intracellular enzyme indoleamine 2,3-dioxygenase (IDO) has a key function in tryptophan metabolism along the kynurenine pathway [1]. IDO's metabolic activity has been perceived to play a significant role in immune regulation. On the cellular level, the complementary effects of IDO-mediated metabolism, tryptophan starvation, and accumulation of immunomodulatory kynurenines Correspondence: Dr. Andreas Heitger e-mail: andreas.heitger@ccri.at at the antigen-presenting cell (APC)/T-cell synapse were proposed to effect regulation of T-cell activation and proliferation [1,2]. In fact, in the last decade, multiple studies corroborated the role of IDO in immune regulation and induction of tolerance (reviewed in [3,4]). IDO competence, i.e. IDO expression and activity [5,6], has been suggested to play a critical role in numerous clinical conditions entailing immune regulation, including tolerance induction in pregnancy [7], transplantation [8,9], and tumor immune evasion [10]. * These authors contributed equally to the work. Eur. J. Immunol. 2012Immunol. . 42: 1117Immunol. -1128 Effective induction of IDO competence is, by and large, restricted to cells of the monocyte/macrophage lineage and, in humans is predominantly found in dendritic cells (DCs) [4,11]. Numerous agents, most prominently interferon (IFN)-γ, have been described to induce IDO activity in DCs [12]. IDO induction is generally believed to represent a feedback mechanism of APC activation [8]. This understanding...

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supporting

confidence: 84%

Ambivalent effects of dendritic cells displaying prostaglandin E2‐induced indoleamine 2,3‐dioxygenase

et al. 2012

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“…Tolerance may be maintained at the level of T cell expansion through defective signaling pathways [59]. While steady-state conditions lead to tolerance, Signals that promote DC maturation lead to immunity [60][61][62]. Several characteristics that mature DCs possess including increased presentation of peptide-MHC complexes and induced expression of co-stimulatory molecules like CD80 and CD86, cytokines and chemokines are critical for the initiation and enhancement of immune responses.…”

Section: Light Regulates Dcs At the Tumor Site To Promote Primingmentioning

confidence: 99%

Targeting tumors with LIGHT to generate metastasis-clearing immunity

Yü¹,

Fu²

2008

Cytokine & Growth Factor Reviews

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Metastastic diseases cause the majority of morbidity and mortality of cancer patients. Established tumors form both physical and immunological barriers to limit immune detection and destruction. Current immunotherapy of vaccination and adoptive transfer shows limited effect at least in part due to the existing barriers in the tumors and depending on the knowledge of tumor antigens. Tumor necrosis factor superfamily member 14 (TNFSF14) LIGHT interacts with stromal cells, dendritic cells, NK cells, naïve and activated T cells and tumor cells inside the tumor tissues via its two functional receptors, HVEM and lymphotoxin β receptor (LTβR). Targeting tumor tissues with LIGHT leads to augmentation of priming, recruitment, and retention of effector cells at tumor sites, directly or indirectly, to induce strong anti-tumor immunity to inhibit the growth of primary tumors as well as eradicate metastases. Intratumor treatment would break tumor barriers and allow strong immunity against various tumors without defining tumor antigens. This review summarizes recent findings to support that LIGHT is a promising candidate for an effective cancer immunotherapy.

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“…Also, in the absence of costimulatory signaling between antigen-presenting cells (APC) and T cells, peptides can induce tolerance [2]. Therefore, research efforts have focused on developing potent adjuvants and on the use of dendritic cells (DC) to enhance the immunogenicity of peptides [3][4][5][6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Direct intralymphatic injection of peptide vaccines enhances immunogenicity

Johansen¹,

Haffner²,

Koch³

et al. 2005

Eur J Immunol

111

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Research to enhance the efficiency of vaccines focuses mainly on improving either the adjuvant or the type and form of the antigen. This study evaluates the influence of the administration route on the efficiency of a peptide-based vaccine. Peptide vaccines are generally administered subcutaneously or intradermally, from where they must reach secondary lymphatic organs to induce an immune response. We analyzed the efficacy of peptide vaccines administered directly into a lymph node. Using a MHC class I-binding peptide from lymphocytic choriomeningitis virus, we found that intralymphatic injection enhanced immunogenicity by as much as 10 6 times when compared to subcutaneous and intradermal vaccination. Intralymphatic administration induced CD8 T cell responses with strong cytotoxic activity and IFN-c production that conferred longterm protection against viral infections and tumors. These results should have immediate implications for clinical immunotherapy of infectious disease and cancer.

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Rapid generation of broad T-cell immunity in humans after a single injection of mature dendritic cells

Cited by 424 publications

References 31 publications

Ambivalent effects of dendritic cells displaying prostaglandin E2‐induced indoleamine 2,3‐dioxygenase

Ambivalent effects of dendritic cells displaying prostaglandin E2‐induced indoleamine 2,3‐dioxygenase

Targeting tumors with LIGHT to generate metastasis-clearing immunity

Direct intralymphatic injection of peptide vaccines enhances immunogenicity

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