期刊
JOURNAL OF IMMUNOTHERAPY
卷 32, 期 7, 页码 677-688出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CJI.0b013e3181ab1824
关键词
CD4 T cells; tolerance/suppression/anergy; tumor immunity; knockout mice; melanoma
资金
- American Surgical Association
- NIH [T32 AI 060519]
Despite progress made over the past 25 years. existing immunotherapies have limited clinical effectiveness in patients, with cancer. Immune tolerance consistently blunts the generated immune response. and the largely solitary focus on CD8(+) T cell immunity has proven ineffective in the absence of CD4(+) T cell help. To address these twin-tier deficiencies, we developed a translational model of melanoma immunotherapy focused oil the exploitation high-avidity CD4(+) T cells that become generated in germline antigen-deficient mice. We had previously identified a tyrosinase-related protein-1 specific HLA-DRB1*0401-restricted epitope. Using this epitope in conjunction with a newly described tyrosinase-related protein-1 germline-knockout, we demonstrate that endogenous tyrosinase-related protein-1 expression alters the functionality of the autoreactive T cell repertoire. More importantly, we show, by using major histocompatibility complex-mismatched combinations, that CD4(+) T cells derived from the self-antigen deficient host indirectly triggers the eradication OF established B16 lung metastases. We demonstrate that the treatment effect is mediated entirely by endogenous CD8(+) T cells and is not affected by the depletion of host regulatory T cells, These findings suggest that high-avidity CD4(+) T cells call overcome endogenous conditions and mediate their antitumor effects exclusively through the elicitation of CD8(+) T cell immunity.
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