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Elimination of CD4(+) T cells enhances anti-tumor effect of locally secreted interleukin-12 on B16 mouse melanoma and induces vitiligo-like coat color alteration.
J Invest Dermatol. 2000 Dec; 115(6):1059-64.JI

Abstract

CD4(+) T cells have been reported to suppress immunity against cancer in certain animal models. In this study, we investigated the role of CD4(+) T cells in the anti-tumor immune response when interleukin-12-producing melanoma cells are inoculated in mice. We found that interleukin-12-transfected B16 melanoma showed retarded tumor growth in syngeneic mice; however, all the mice developed tumors eventually. In vivo depletion of CD4(+) T cells led to complete regression of B16/interleukin-12 tumors in 12 of 20 mice (60%). Immunohistochemical analyses revealed that a number of CD8(+) T cells accumulated in close proximity to the B16/interleukin-12 tumors in the CD4(+) T cell-depleted mice, whereas CD8(+) T cells were only scarcely observed at the periphery of the tumors in control immunocompetent mice. Furthermore, 10 of 20 mice treated with both B16/interleukin-12 inoculation and CD4(+) T cell depletion exhibited vitiligo-like coat color alteration. B16/interleukin-12 tumors completely regressed in all the mice with vitiligo. Histologic examination showed that CD8(+) lymphocytes accumulated around the hair bulbs of mice with vitiligo, but not in those without vitiligo. These results suggest that CD4(+) T cells have an inhibitory effect on tumor rejection by suppressing cytotoxic CD8(+) T cells in this melanoma loading model with local interleukin-12 secretion. To investigate the mechanism of enhanced anti-tumor effects by CD4(+) T cell depletion, we examined the T helper type 1/2 cytokine profile in the tumor draining lymph nodes of B16/interleukin-12-bearing mice with or without CD4(+) T cell depletion using the reverse transcription-polymerase chain reaction method. We found that CD4(+) T cell depletion eliminated T helper type 2 cells and resulted in a T helper type 1-dominant cytokine profile in tumor draining lymph nodes. We emphasize that this T helper type 1-dominant cytokine profile may generate further activated CD8(+) T cells against B16 melanoma cells, lead B16/interleukin-12 to regress, and result in the destruction of the melanocytes in hair bulbs due to cross-antigenicity between both cell types. This mouse model not only demonstrates the depletion of CD4(+) T cells as a useful strategy for cancer gene therapy with interleukin-12 but also provides a model for human melanoma-associated vitiligo.J Invest Dermatol 115:1059-1064 2000

Authors+Show Affiliations

Department of Dermatology, Kobe University School of Medicine, Kobe, Japan. hnagai@med.kobe-u.ac.jpNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11121142

Citation

Nagai, H, et al. "Elimination of CD4(+) T Cells Enhances Anti-tumor Effect of Locally Secreted Interleukin-12 On B16 Mouse Melanoma and Induces Vitiligo-like Coat Color Alteration." The Journal of Investigative Dermatology, vol. 115, no. 6, 2000, pp. 1059-64.
Nagai H, Hara I, Horikawa T, et al. Elimination of CD4(+) T cells enhances anti-tumor effect of locally secreted interleukin-12 on B16 mouse melanoma and induces vitiligo-like coat color alteration. J Invest Dermatol. 2000;115(6):1059-64.
Nagai, H., Hara, I., Horikawa, T., Oka, M., Kamidono, S., & Ichihashi, M. (2000). Elimination of CD4(+) T cells enhances anti-tumor effect of locally secreted interleukin-12 on B16 mouse melanoma and induces vitiligo-like coat color alteration. The Journal of Investigative Dermatology, 115(6), 1059-64.
Nagai H, et al. Elimination of CD4(+) T Cells Enhances Anti-tumor Effect of Locally Secreted Interleukin-12 On B16 Mouse Melanoma and Induces Vitiligo-like Coat Color Alteration. J Invest Dermatol. 2000;115(6):1059-64. PubMed PMID: 11121142.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Elimination of CD4(+) T cells enhances anti-tumor effect of locally secreted interleukin-12 on B16 mouse melanoma and induces vitiligo-like coat color alteration. AU - Nagai,H, AU - Hara,I, AU - Horikawa,T, AU - Oka,M, AU - Kamidono,S, AU - Ichihashi,M, PY - 2000/12/20/pubmed PY - 2001/3/3/medline PY - 2000/12/20/entrez SP - 1059 EP - 64 JF - The Journal of investigative dermatology JO - J Invest Dermatol VL - 115 IS - 6 N2 - CD4(+) T cells have been reported to suppress immunity against cancer in certain animal models. In this study, we investigated the role of CD4(+) T cells in the anti-tumor immune response when interleukin-12-producing melanoma cells are inoculated in mice. We found that interleukin-12-transfected B16 melanoma showed retarded tumor growth in syngeneic mice; however, all the mice developed tumors eventually. In vivo depletion of CD4(+) T cells led to complete regression of B16/interleukin-12 tumors in 12 of 20 mice (60%). Immunohistochemical analyses revealed that a number of CD8(+) T cells accumulated in close proximity to the B16/interleukin-12 tumors in the CD4(+) T cell-depleted mice, whereas CD8(+) T cells were only scarcely observed at the periphery of the tumors in control immunocompetent mice. Furthermore, 10 of 20 mice treated with both B16/interleukin-12 inoculation and CD4(+) T cell depletion exhibited vitiligo-like coat color alteration. B16/interleukin-12 tumors completely regressed in all the mice with vitiligo. Histologic examination showed that CD8(+) lymphocytes accumulated around the hair bulbs of mice with vitiligo, but not in those without vitiligo. These results suggest that CD4(+) T cells have an inhibitory effect on tumor rejection by suppressing cytotoxic CD8(+) T cells in this melanoma loading model with local interleukin-12 secretion. To investigate the mechanism of enhanced anti-tumor effects by CD4(+) T cell depletion, we examined the T helper type 1/2 cytokine profile in the tumor draining lymph nodes of B16/interleukin-12-bearing mice with or without CD4(+) T cell depletion using the reverse transcription-polymerase chain reaction method. We found that CD4(+) T cell depletion eliminated T helper type 2 cells and resulted in a T helper type 1-dominant cytokine profile in tumor draining lymph nodes. We emphasize that this T helper type 1-dominant cytokine profile may generate further activated CD8(+) T cells against B16 melanoma cells, lead B16/interleukin-12 to regress, and result in the destruction of the melanocytes in hair bulbs due to cross-antigenicity between both cell types. This mouse model not only demonstrates the depletion of CD4(+) T cells as a useful strategy for cancer gene therapy with interleukin-12 but also provides a model for human melanoma-associated vitiligo.J Invest Dermatol 115:1059-1064 2000 SN - 0022-202X UR - https://www.unboundmedicine.com/medline/citation/11121142/Elimination_of_CD4_+__T_cells_enhances_anti_tumor_effect_of_locally_secreted_interleukin_12_on_B16_mouse_melanoma_and_induces_vitiligo_like_coat_color_alteration_ DB - PRIME DP - Unbound Medicine ER -