Wolchok J D, Srinivasan R, Perales M A, Houghton A N, Bowne W B, Blachere N E
The Swim Across America Laboratory, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Cancer Immun. 2001 Aug 16;1:9.
Tyrosinase-related proteins-1 and -2 (gp75/TRP-1 and TRP-2) are melanosomal membrane glycoproteins recognized by antibodies and T-cells from patients with melanoma. Xenogeneic DNA immunization against gp75/TRP-1 generates antibody-dependent tumor immunity and autoimmune depigmentation. In contrast xenogeneic TRP-2 DNA immunization induces immunity mediated by CD8+ T-cells. The role of IFN-gamma in the generation of tumor immunity and autoimmune depigmentation in these two models was investigated. No tumor protection and minimal depigmentation was observed after immunization with human TRP-2 DNA in mice deficient in IFN-gamma ligand. Repletion with recombinant murine IFN-gamma restored tumor immunity. Experiments using IL4 deficient mice demonstrated that tumor immunity was unaffected but that autoimmune depigmentation was potentially accelerated, consistent with down-modulation of autoimmunity against TRP-2 by IL4. In contrast, IFN-gamma was not required for the generation of immunity to gp75/TRP-1. In fact, exogenous IFN-gamma ablated autoantibody responses against gp75/TRP-1 after xenogeneic DNA immunization, consistent with a down-regulatory effect of IFN-gamma. These results show that immunity to TRP-2 following DNA immunization uses an IFN-gamma-dependent Th1 pathway, but immunity to gp75/TRP-1 is down-regulated by IFN-gamma.
酪氨酸酶相关蛋白-1和-2（gp75/TRP-1和TRP-2）是黑素小体膜糖蛋白，可被黑色素瘤患者的抗体和T细胞识别。针对gp75/TRP-1的异种DNA免疫可产生抗体依赖性肿瘤免疫和自身免疫性色素脱失。相比之下，异种TRP-2 DNA免疫可诱导由CD8 + T细胞介导的免疫。研究了IFN-γ在这两种模型中肿瘤免疫和自身免疫性色素脱失产生中的作用。在用缺乏IFN-γ配体的小鼠进行人TRP-2 DNA免疫后，未观察到肿瘤保护作用，色素脱失也极少。用重组鼠IFN-γ补充可恢复肿瘤免疫。使用IL4缺陷小鼠的实验表明，肿瘤免疫未受影响，但自身免疫性色素脱失可能加速，这与IL4对TRP-2自身免疫的下调作用一致。相比之下，对gp75/TRP-1产生免疫不需要IFN-γ。事实上，外源性IFN-γ在异种DNA免疫后消除了针对gp75/TRP-1的自身抗体反应，这与IFN-γ的下调作用一致。这些结果表明，DNA免疫后对TRP-2的免疫使用IFN-γ依赖性Th1途径，但对gp75/TRP-1的免疫被IFN-γ下调。
