Terasaki Foundation Laboratory, Los Angeles, CA 90064, USA.
J Immunotoxicol. 2012 Jul-Sep;9(3):282-91. doi: 10.3109/1547691X.2011.645582. Epub 2012 Jan 30.
HLA-E expressed on the surface of melanoma cells and shed into circulation are known to inhibit killing of tumor cells by binding to CD94/NKGA2 receptors on cytotoxic T- and NKT cells. Interferon (IFN)-γ is known to promote HLA-E over-expression on the cell surface and shedding. The shed HLA-E heavy chain may expose cryptic epitopes to elicit antibodies (Abs). The anti-HLA-E Abs may bind to shed HLA-E or to the tumor cell surface to block its interaction with CTL/NKT cells. This is the basis for a melanoma cell vaccine that will generate anti-HLA-E Abs. The objective of this study was to characterize the antibody response and characterize the cross-reactivity of the antibodies produced in melanoma patients immunized with autologous melanoma cells treated with IFNγ. Anti-HLA-E murine mAbs and serum anti-HLA-E Abs in healthy individuals were known to react with HLA-Ia alleles, which is attributed to the presence of peptide sequences shared between HLA-E and HLA-Ia. Therefore, pre- and post-immune (weeks 4 and 24) serum Abs reacting to both HLA-E and HLA-Ia alleles were measured by multiplex Luminex®-based immunoassay. To ascertain whether the reactivity of the serum Abs to HLA-Ia was due to anti-HLA-E Abs, the shared-peptides were used to inhibit anti-HLA-E and HLA-Ia reactivities. The level of anti-HLA-E IgG in sera has increased post-immunization from its pre-immune level. Concomitantly, the HLA-Ia reactivity of the sera was also augmented. The reactivity of both anti-HLA-E Abs and HLA-Ia were inhibited by the shared-peptides. The HLA-Ia reactivity of the anti-HLA-E Abs in patients' sera is similar to the HLA-Ia reactivity of the anti-HLA-E mAbs and anti-HLA-E Abs in normal sera. The results establish the immunogenicity of HLA-E and also ascertain that the HLA-Ia reactivity of the anti-HLA-E Abs is due to shared-peptide epitopes.
已知黑色素瘤细胞表面表达的 HLA-E 及其脱落进入循环的部分能够与细胞毒性 T 细胞和自然杀伤 T 细胞上的 CD94/NKG2 受体结合，从而抑制肿瘤细胞的杀伤。已知干扰素（IFN）-γ可促进细胞表面 HLA-E 的过度表达和脱落。脱落的 HLA-E 重链可能会暴露隐匿表位，从而引发抗体（Abs）。抗 HLA-E Abs 可能与脱落的 HLA-E 或肿瘤细胞表面结合，从而阻断其与 CTL/NKT 细胞的相互作用。这就是基于黑色素瘤细胞疫苗的基础，该疫苗将产生抗 HLA-E Abs。本研究的目的是描述黑色素瘤患者免疫自体黑色素瘤细胞后产生的抗体反应，并描述其交叉反应性。已知抗 HLA-E 鼠单克隆抗体和健康个体血清中的抗 HLA-E Abs 可与 HLA-Ia 等位基因反应，这归因于 HLA-E 和 HLA-Ia 之间存在共享肽序列。因此，通过多重 Luminex®基于免疫测定法测量了免疫前（第 4 周）和免疫后（第 24 周）血清 Abs 对 HLA-E 和 HLA-Ia 等位基因的反应。为了确定血清 Abs 对 HLA-Ia 的反应性是否归因于抗 HLA-E Abs，使用共享肽来抑制抗 HLA-E 和 HLA-Ia 反应性。与免疫前相比，免疫后血清中抗 HLA-E IgG 的水平增加。同时，血清的 HLA-Ia 反应性也增强。共享肽抑制了抗 HLA-E Abs 和 HLA-Ia 的反应性。患者血清中抗 HLA-E Abs 的 HLA-Ia 反应性与正常血清中抗 HLA-E mAbs 和抗 HLA-E Abs 的 HLA-Ia 反应性相似。结果确立了 HLA-E 的免疫原性，并确定抗 HLA-E Abs 的 HLA-Ia 反应性归因于共享肽表位。
