Vasilakos J P, Smith R M, Gibson S J, Lindh J M, Pederson L K, Reiter M J, Smith M H, Tomai M A
Department of Pharmacology, 3M Pharmaceuticals, St. Paul, Minnesota 55144, USA.
Cell Immunol. 2000 Aug 25;204(1):64-74. doi: 10.1006/cimm.2000.1689.
R-848 and imiquimod belong to a class of immune response modifiers that are potent inducers of cytokines, including IFN-alpha, TNF-alpha, IL-12, and IFN-gamma. Many of these cytokines can affect the acquired immune response. This study examines the effects of R-848 on aspects of acquired immunity, including immunoglobulin secretion, in vivo cytokine production, and Ag-specific T cell cytokine production. Results are compared with those of Th1 CpG ODN. R-848 and CpG ODN are effective at skewing immunity in the presence of Alum toward a Th1 Ab response (IgG2a) and away from a Th2 Ab response (IgE). R-848 and CpG ODN are also capable of initiating an immune response in the absence of additional adjuvant by specifically enhancing IgG2a levels. Both R-848 and imiquimod showed activity when given subcutaneously or orally, indicating that the compound mechanism was not through generation of a depot effect. Although CpG ODN behaves similarly to R-848, CpG ODN has a distinct cytokine profile, is more effective than R-848 when given with Alum in the priming dose, and is active only when given by the same route as the Ag. The mechanism of R-848's adjuvant activity is linked to cytokine production, where increases in IgG2a levels are associated with IFN-alpha, TNF-alpha, IL-12, and IFN-gamma induction, and decreases in IgE levels are associated with IFN-alpha and TNF-alpha. Imiquimod also enhances IgG2a production when given with Ag. The above results suggest that the imidazoquinolines R-848 and imiquimod may be attractive compounds for use as vaccine adjuvants and in inhibiting pathological responses mediated by Th2 cytokines.
R - 848和咪喹莫特属于一类免疫反应调节剂，它们是细胞因子的强效诱导剂，包括干扰素 - α、肿瘤坏死因子 - α、白细胞介素 - 12和干扰素 - γ。这些细胞因子中的许多都能影响获得性免疫反应。本研究考察了R - 848对获得性免疫各方面的影响，包括免疫球蛋白分泌、体内细胞因子产生以及抗原特异性T细胞细胞因子产生。将结果与Th1型CpG寡脱氧核苷酸的结果进行比较。在存在明矾的情况下，R - 848和CpG寡脱氧核苷酸能有效地使免疫反应偏向Th1抗体反应（IgG2a），并远离Th2抗体反应（IgE）。R - 848和CpG寡脱氧核苷酸还能够在没有额外佐剂的情况下通过特异性提高IgG2a水平引发免疫反应。R - 848和咪喹莫特经皮下或口服给药时均表现出活性，表明其复合机制不是通过产生储库效应。虽然CpG寡脱氧核苷酸的行为与R - 848相似，但CpG寡脱氧核苷酸具有独特的细胞因子谱，在初免剂量与明矾一起给药时比R - 848更有效，并且仅在与抗原相同的给药途径下才具有活性。R - 848的佐剂活性机制与细胞因子产生有关，其中IgG2a水平的升高与干扰素 - α、肿瘤坏死因子 - α、白细胞介素 - 12和干扰素 - γ的诱导有关，而IgE水平的降低与干扰素 - α和肿瘤坏死因子 - α有关。咪喹莫特与抗原一起给药时也能增强IgG2a的产生。上述结果表明，咪唑喹啉类化合物R - 848和咪喹莫特可能是用作疫苗佐剂以及抑制由Th2细胞因子介导的病理反应的有吸引力的化合物。
