Immunotherapeutic Potential of Tumor Antigen-Pulsed and Unpulsed Dendritic Cells Generated from Murine Bone Marrow

Yang, Shan; Darrow, Timothy L.; Vervaert, Carol E.; Seigler, Hilliard F.

doi:10.1006/cimm.1997.1151

Cited by 44 publications

(26 citation statements)

References 35 publications

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“…The use of DCs as a cellular adjuvant is a promising approach in immunotherapy of infectious disease and cancer. Numerous animal models demonstrate conclusively that ex vivo generated DCs pulsed with protein antigen are useful for the immunotherapy of infectious diseases and cancer (11)(12)(13)(14)(15)(16). Initial clinical studies indicate that tumor antigen-pulsed DCs can be effective in the immunotherapy of cancer patients (17)(18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

CpG DNA: A potent signal for growth, activation, and maturation of human dendritic cells

Hartmann

Weiner

Krieg

1999

Proc. Natl. Acad. Sci. U.S.A.

555

329

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DNA molecules containing unmethylated CpG-dinucleotides in particular base contexts (''CpG motifs'') are excellent adjuvants in rodents, but their effects on human cells have been less clear. Dendritic cells (DCs) form the link between the innate and the acquired immune system and may inf luence the balance between T helper 1 (Th1) and Th2 immune responses. We evaluated the effects of CpG oligodeoxynucleotides alone or in combination with granulocytemacrophage colony-stimulating factor (GMCSF) on different classes of purified human DCs. For primary dendritic precursor cells isolated from human blood, CpG oligonucleotides alone were superior to GMCSF in promoting survival and maturation (CD83 expression) as well as expression of class II MHC and the costimulatory molecules CD40, CD54, and CD86 of DCs. Both CD4-positive and CD4-negative peripheral blood dendritic precursor cells responded to CpG DNA which synergized with GMCSF but these DCs showed little response to lipopolysaccharide (LPS). In contrast, monocyte-derived DCs did not respond to CpG, but they were highly sensitive to LPS, suggesting an inverse correlation between CpG and LPS sensitivity in different subsets of DCs. Compared with GMCSF, CpG-treated peripheral blood DCs showed enhanced functional activity in the mixed lymphocyte reaction and induced T cells to secrete increased levels of Th1 cytokines. These findings demonstrate the ability of specific CpG motifs to strongly activate certain subsets of human DCs to promote Th1-like immune responses, and support the use of CpG DNA-based trials for immunotherapy against cancer, allergy, and infectious diseases.The vertebrate immune system has the ability to recognize the presence of bacterial DNA on the basis of recognition of so-called CpG motifs, unmethylated cytidine-guanosine dinucleotides within a specific pattern of flanking bases (1). It is known from the literature that CpG oligonucleotides are excellent adjuvants in murine models. CpG DNA is as potent as the complete Freund's adjuvant regarding the induction of B cell and T cell responses, but it is less toxic and it induces a T helper 1 (Th1) response (2, 3). Alum, the adjuvant that is used routinely in human vaccination, induces the less favorable Th2 response. CpG is more effective than alum, and the combination of CpG and alum shows synergy in mice (4, 5). CpG oligonucleotides enhance the efficacy of immunization with tumor antigen in a murine B cell lymphoma model (2), induce antigen-specific cytotoxic T cell responses (5, 6), and have utility in the immunotherapy of allergy, infectious disease, and cancer disease models (7-9). Furthermore, the presence of immunostimulatory DNA sequences in plasmids has been shown to be required for effective intradermal gene immunization (10).Dendritic cells (DCs) form the link between the innate and the acquired immune system by presenting antigens and by their expression of pattern recognition receptors that detect microbial molecules in their local environment. The use of DCs as a cellular adju...

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Section: Introductionmentioning

confidence: 99%

CpG DNA: A potent signal for growth, activation, and maturation of human dendritic cells

Hartmann

Weiner

Krieg

1999

Proc. Natl. Acad. Sci. U.S.A.

555

329

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“…Vaccine strategies using DCs generated ex vivo can be classified under the following: (1) DCs pulsed with peptides or proteins 3,9-11 ; (2) DCs transduced with genes encoding tumor specific antigens (TSAs) using naked DNA 12,13 or viral vectors [14][15][16] ; and (3) DCs armed with the full antigenic spectrum of tumor cells (for tumors with uncharacterized tumor specific antigens). [17][18][19] All of these strategies employing DC-based vaccines have demonstrated varying degrees of enhancement in immune responses and anti-tumor effects.…”

Section: Introductionmentioning

confidence: 99%

Intramuscular administration of E7-transfected dendritic cells generates the most potent E7-specific anti-tumor immunity

Wang¹,

Ling²,

Im³

et al. 2000

Gene Ther

108

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Dendritic cells (DCs) are highly efficient antigen-presenting cells capable of priming both cytotoxic and helper T cells in vivo. Recent studies have demonstrated the potential use of DCs that are modified to carry tumor-specific antigens in cancer vaccines. However, the optimal administration route of DC-based vaccines to generate the greatest anti-tumor effect remains to be determined. This study is aimed at comparing the levels of immune responses and anti-tumor effect generated through different administration routes of DCbased vaccination. We chose the E7 gene product of human papillomavirus (HPV) as the model antigen and generated a stable DC line (designated as DC-E7) that constitutively

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“…The authors conclude that the DC-mediated NK cell activation was likely to be through an intermediate interaction of DCs with CD4 þ T cells rather than a direction effect on the NK cells. Furthermore, although small in number there have been other reports that unpulsed DCs can induce tumour protection (Yang et al, 1997;DeMatos et al, 1998). Interestingly, early studies by Knight (Knight et al, 1985) also suggested that normal syngeneic DCs could induce tumour regression or delayed tumour growth.…”

Section: Discussionmentioning

confidence: 99%

Immunisation with ‘naïve’ syngeneic dendritic cells protects mice from tumour challenge

et al. 2008

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Dendritic cells (DCs) 'pulsed' with an appropriate antigen may elicit an antitumour immune response in mouse models. However, while attempting to develop a DC immunotherapy protocol for the treatment of breast cancer based on the tumour-associated MUC1 glycoforms, we found that unpulsed DCs can affect tumour growth. Protection from RMA-MUC1 tumour challenge was achieved in C57Bl/6 MUC1 transgenic mice by immunising with syngeneic DCs pulsed with a MUC1 peptide. However, unpulsed DCs gave a similar level of protection, making it impossible to evaluate the effect of immunisation of mice with DCs pulsed with the specific peptide. Balb/C mice could also be protected from tumour challenge by immunisation with unpulsed DCs prior to challenge with murine mammary tumour cells (410.4) or these cells transfected with MUC1 (E3). Protection was achieved with as few as three injections of 50 000 naïve DCs per mouse per week, was not dependent on injection route, and was not specific to cell lines expressing human MUC1. However, the use of Rag2-knockout mice demonstrated that the adaptive immune response was required for tumour rejection. Injection of unpulsed DCs into mice bearing the E3 tumour slowed tumour growth. In vitro, production of IFN-g and IL-4 was increased in splenic cells isolated from mice immunised with DCs. Depleting CD4 T cells in vitro partially decreased cytokine production by splenocytes, but CD8 depletion had no effect. This paper shows that naïve syngeneic DCs may induce an antitumour immune response and has implications for DC immunotherapy preclinical and clinical trials.

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Immunotherapeutic Potential of Tumor Antigen-Pulsed and Unpulsed Dendritic Cells Generated from Murine Bone Marrow

Cited by 44 publications

References 35 publications

CpG DNA: A potent signal for growth, activation, and maturation of human dendritic cells

CpG DNA: A potent signal for growth, activation, and maturation of human dendritic cells

Intramuscular administration of E7-transfected dendritic cells generates the most potent E7-specific anti-tumor immunity

Immunisation with ‘naïve’ syngeneic dendritic cells protects mice from tumour challenge

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