Melanocytes and Pigmentation Are Affected in Dopachrome Tautomerase Knockout Mice

Guyonneau, Laurence; Murisier, Fabien; Rossier, A.; Moulin, Alexandre; Beermann, Friedrich

doi:10.1128/mcb.24.8.3396-3403.2004

Cited by 118 publications

(106 citation statements)

References 41 publications

(53 reference statements)

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“…TRP-2 (dopachrome tautomerase) is a critical enzyme for pigment synthesis in melanocytes (19). We previously reported that mice sensitized to a GM-CSF-expressing B16 vaccine and treated with anti-CTLA-4 developed an anti-TRP-2 180 -188 T cell response.…”

Section: Blockade Of Ctla-4 During Vaccination Enhances Ag-specific Imentioning

confidence: 99%

Provision of Granulocyte-Macrophage Colony-Stimulating Factor Converts an Autoimmune Response to a Self-Antigen into an Antitumor Response

Gondek

Hurwitz

2005

The Journal of Immunology

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Many tumor Ags recognized by T cells are self-Ags. Because high avidity, self-reactive T cells are deleted in the thymus, any residual self-reactive T cells existing in the periphery are likely to be low avidity and nonresponsive due to peripheral tolerance mechanisms. Activation of these residual T cells is critical for targeting tumors for immunotherapy. In this study, we studied immune responses against the murine B16 melanoma using a tyrosinase-related protein 2 (TRP-2) peptide as a model tumor/self-Ag. Our results showed that TRP-2 peptide vaccination alone elicited a weak T cell response and modestly decreased B16 lung tumor nodules. The combination of peptide vaccination and treatment with an Ab directed against the inhibitory receptor CTLA-4 enhanced the immune response against TRP-2 peptide, inducing autoimmune depigmentation and further decreasing lung tumor nodules. However, both vaccination methods failed to protect against orthotopic (s.c.) B16 tumor challenge. The addition of an irradiated GM-CSF-expressing, amelanotic tumor cell vaccine significantly delayed s.c. B16 tumor growth. Subsequent studies revealed that provision of GM-CSF increased dendritic cell numbers in lymph nodes and spleen. Furthermore, addition of CTLA-4 blockade increased the frequency of TRP-2-specific, IFN-secreting T cells in spleen and lymph nodes. Overall, our results indicate that combining enhancement of Ag presentation with removal of CTLA-4-mediated inhibition can convert a “weaker” autoimmune response into a more potent antitumor immune response.

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Section: Blockade Of Ctla-4 During Vaccination Enhances Ag-specific Imentioning

confidence: 99%

Provision of Granulocyte-Macrophage Colony-Stimulating Factor Converts an Autoimmune Response to a Self-Antigen into an Antitumor Response

Gondek

Hurwitz

2005

The Journal of Immunology

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“…CAG-CAT-EGFP mice (a gift from J. Miyazaki, Osaka University, Osaka, Japan) (Kawamoto et al, 2000) were bred with Dct tm1(Cre)Bee mice (a gift from F. Beermann, Swiss Institute for Experimental Cancer Research, Epalinges, Switzerland) to generate compound heterozygotes (Yonetani et al, 2008;Osawa et al, 2005). Genotyping was performed as described previously (Guyonneau et al, 2004).…”

Section: Animalsmentioning

confidence: 99%

Two distinct types of mouse melanocyte: differential signaling requirement for the maintenance of non-cutaneous and dermal versus epidermal melanocytes

et al. 2009

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Unlike the thoroughly investigated melanocyte population in the hair follicle of the epidermis, the growth and differentiation requirements of the melanocytes in the eye, harderian gland and inner ear -the so-called non-cutaneous melanocytes -remain unclear. In this study, we investigated the in vitro and in vivo effects of the factors that regulate melanocyte development on the stem cells or the precursors of these non-cutaneous melanocytes. In general, a reduction in KIT receptor tyrosine kinase signaling leads to disordered melanocyte development. However, melanocytes in the eye, ear and harderian gland were revealed to be less sensitive to KIT signaling than cutaneous melanocytes. Instead, melanocytes in the eye and harderian gland were stimulated more effectively by endothelin 3 (ET3) or hepatocyte growth factor (HGF) signals than by KIT signaling, and the precursors of these melanocytes expressed the lowest amount of KIT. The growth and differentiation of these non-cutaneous melanocytes were specifically inhibited by antagonists for ET3 and HGF. In transgenic mice induced to express ET3 or HGF in their skin and epithelial tissues from human cytokeratin 14 promoters, the survival and differentiation of non-cutaneous and dermal melanocytes, but not epidermal melanocytes, were enhanced, apparently irrespective of KIT signaling. These results provide a molecular basis for the clear discrimination between non-cutaneous or dermal melanocytes and epidermal melanocytes, a difference that might be important in the pathogenesis of melanocyte-related diseases and melanomas.

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“…DCT-deficient mice 43 were bred at McMaster University. All of our investigations have been approved by the McMaster Animal Research Ethics Board.…”

Section: Micementioning

confidence: 99%

High-dose chemotherapy augments the efficacy of recombinant adenovirus vaccines and improves the therapeutic outcome

et al. 2008

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We have investigated the therapeutic potential of a prototypic melanoma vaccine based on recombinant adenovirus expressing human dopachrome tautomerase in the B16F10 murine melanoma model. We found that in the presence of a tumor, the magnitude of T-cell immunity evoked by the vaccine was significantly reduced. This impairment was compounded by defects in cytokine production and degranulation within the tumor-infiltrating lymphocytes (TILs). We showed that the combination of vaccination with high-dose cyclophosphamide was able to skew the response toward the target antigen and enhanced both the quantity and quality of antigen-specific CD8 þ and CD4 þ T-cell responses in tumor-bearing mice, which resulted in the inhibition of tumor growth. Furthermore, when tumor-specific antigens were targeted by the vaccine, the combination therapy could actually produce tumor regression, which appeared to result from the high frequency of antigen-specific T cells. These data show that recombinant adenovirus vaccines are compatible with conventional high-dose chemotherapy and that the combined treatment results in improved therapeutic outcomes relative to either agent individually.

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Melanocytes and Pigmentation Are Affected in Dopachrome Tautomerase Knockout Mice

Cited by 118 publications

References 41 publications

Provision of Granulocyte-Macrophage Colony-Stimulating Factor Converts an Autoimmune Response to a Self-Antigen into an Antitumor Response

Provision of Granulocyte-Macrophage Colony-Stimulating Factor Converts an Autoimmune Response to a Self-Antigen into an Antitumor Response

Two distinct types of mouse melanocyte: differential signaling requirement for the maintenance of non-cutaneous and dermal versus epidermal melanocytes

High-dose chemotherapy augments the efficacy of recombinant adenovirus vaccines and improves the therapeutic outcome

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