Auci D, Nicoletti F, Mangano K, Pieters R, Nierkens S, Morgan L, Offner H, Frincke J, Reading C
Hollis-Eden Pharmaceuticals, 4435 Eastgate Mall, Suite 400, San Diego, CA 92121, USA.
Ann N Y Acad Sci. 2005 Jun;1051:730-42. doi: 10.1196/annals.1361.117.
5-Androsten-3beta, 17beta-diol (HE2100), and a synthetic analogue HE3204 are regarded as immune-regulating hormones, because both induce changes in the reporter antigen-popliteal lymph node assay (RA-PLNA). Mice were injected in the footpad with either HE2100 or HE3204 (0.01-3 mg), and a nonsensitizing dose of trinitrophenyl ovalbumin (TNP-OVA) was used as bystander reporter antigen. Seven days later, nodes were removed and numbers of cells (CD3, CD4, CD8, CD19; flow cytometry), TNP-specific IgM, IgG1, and IgG2a antibody-forming cells (AFCs; ELISPOT assay), and cytokines (interleukin-4 [IL-4], interferon-gamma [IFN-gamma]; ELISA) were measured. HE2100 and HE3204 increased cell numbers in a dose-dependent fashion. T (helper and suppressor) cells and B cells were increased (>5-fold). HE3204 was apparently twice as potent as HE2100. Both increased the B/T ratio (fivefold), increased TNP-specific IgM and IgG1 ( approximately 50-fold), and induced IgG2a AFCs. Both increased IL-4 and IFN-gamma secretion (up to threefold). Both displayed anti-inflammatory activity in the murine model of carrageenan-induced pleurisy, as evidenced by reduced neutrophil numbers and exudate volumes. Our observations suggest that both HE2100 and HE3204 are immune-regulating steroid hormones that exhibit anti-inflammatory properties. HE2100 (1 mg/mouse per day) provided significant benefit when given at disease onset in the SJL/J female mouse model of experimental autoimmune encephalomyelitis. These compounds and their analogues are candidates for further testing in autoimmune diseases.
5-雄甾烯-3β,17β-二醇（HE2100）和一种合成类似物HE3204被视为免疫调节激素，因为二者均可在报告抗原-腘窝淋巴结试验（RA-PLNA）中引起变化。给小鼠足垫注射HE2100或HE3204（0.01 - 3毫克），并使用非致敏剂量的三硝基苯基卵清蛋白（TNP-OVA）作为旁观者报告抗原。7天后，取出淋巴结，检测细胞数量（CD3、CD4、CD8、CD19；流式细胞术）、TNP特异性IgM、IgG1和IgG2a抗体形成细胞（AFCs；酶联免疫斑点分析）以及细胞因子（白细胞介素-4 [IL-4]、干扰素-γ [IFN-γ]；酶联免疫吸附测定）。HE2100和HE3204以剂量依赖方式增加细胞数量。T（辅助性和抑制性）细胞和B细胞增加（>5倍）。HE3204的效力明显是HE2100的两倍。二者均增加B/T比值（5倍），增加TNP特异性IgM和IgG1（约50倍），并诱导IgG2a AFCs。二者均增加IL-4和IFN-γ分泌（高达3倍）。在角叉菜胶诱导的胸膜炎小鼠模型中，二者均表现出抗炎活性，表现为中性粒细胞数量和渗出液体积减少。我们的观察结果表明，HE2100和HE3204均为具有抗炎特性的免疫调节类固醇激素。在实验性自身免疫性脑脊髓炎的SJL/J雌性小鼠模型中，疾病发作时给予HE2100（每天1毫克/小鼠）可带来显著益处。这些化合物及其类似物是自身免疫性疾病进一步试验的候选药物。
