Hughes H P, Rossow S, Campos M, Rossi-Campos A, Janssen S, Godson D L, Daflon B, Voirol M J, Gerber C, Babiuk L A
Veterinary Infectious Disease Organization, Saskatoon, Canada.
Antiviral Res. 1994 Jan;23(1):33-44. doi: 10.1016/0166-3542(94)90031-0.
Recombinant bovine interferon-alpha I1 (rBoIFN-alpha) has known antiviral and immunomodulatory effects which have been exploited to reduce clinical disease in a number of clinical situations including bovine respiratory diseases. A slow release rBoIFN-alpha formulation may be of value to reduce bovine respiratory disease under field conditions by extending the period of protection, and hence improving the prophylactic benefits of rBoIFN-alpha. In this report, we describe a formulation of rBoIFN-alpha in sesame oil containing calcium stearate which can successfully sustain the release of rBoIFN-alpha over an 8-day period. Recombinant bovine IFN-alpha could be measured in serum for 8 days following treatment with an initial burst of release 6 h after injection. After a single subcutaneous depot injection of 50 mg and 100 mg of rBoIFN-alpha, initial serum levels reached 12-15 ng/ml and 25 ng/ml respectively. Correlating with this burst of release, there was a decrease in the number of circulating CD4-CD8- gamma delta+ T lymphocytes, and a slight neutropenia. No alterations in other cell phenotypes tested (CD4, CD8, CD2, CD6, B cells, monocytes or MHC class II) were observed, nor were there changes in lymphokine activated killer (LAK), natural killer (NK) cell activity, or oxygen radical formation (assessed by reduction of nitroblue tetrazolium). However, despite the rapid and short-lived burst of rBoIFN-alpha, levels of 2-5 oligoadenylate (2-5 A) synthetase remained elevated for 8 days. The sustained increase of 2-5 A synthetase was not due to the high initial dose released during the burst 6-12 h after injection, since injection of a bioavailable equivalent dose of interferon induced a significant rise in 2-5 A synthetase activity for 4 days only. As 2-5 A synthetase is known to be a correlate of antiviral activity, we propose that this formulation of rBoIFN-alpha may be one approach to increase the window of protection, leading to more effective prevention of bovine respiratory disease.
重组牛α-干扰素I1（rBoIFN-α）具有抗病毒和免疫调节作用，已被用于在包括牛呼吸道疾病在内的多种临床情况下减轻临床疾病。一种缓释rBoIFN-α制剂可能通过延长保护期而在野外条件下减轻牛呼吸道疾病具有价值，从而提高rBoIFN-α的预防效益。在本报告中，我们描述了一种含有硬脂酸钙的芝麻油中的rBoIFN-α制剂，其可在8天内成功维持rBoIFN-α的释放。注射后6小时有一个初始释放高峰，之后在8天内均可在血清中检测到重组牛干扰素-α。单次皮下注射50毫克和100毫克rBoIFN-α后，初始血清水平分别达到12 - 15纳克/毫升和25纳克/毫升。与这种释放高峰相关的是，循环中的CD4 - CD8 - γδ + T淋巴细胞数量减少，以及轻度中性粒细胞减少。未观察到所测试的其他细胞表型（CD4、CD8、CD2、CD6、B细胞、单核细胞或MHC II类）有改变，也未观察到淋巴因子激活的杀伤细胞（LAK）、自然杀伤（NK）细胞活性或氧自由基形成（通过硝基蓝四唑还原评估）有变化。然而，尽管rBoIFN-α有快速且短暂的释放高峰，但2 - 5寡腺苷酸（2 - 5A）合成酶水平在8天内仍保持升高。2 - 5A合成酶的持续增加并非由于注射后6 - 12小时高峰期间释放的高初始剂量，因为注射同等生物利用度剂量的干扰素仅在4天内导致2 - 5A合成酶活性显著升高。由于已知2 - 5A合成酶是抗病毒活性的一个相关指标，我们提出这种rBoIFN-α制剂可能是增加保护窗口的一种方法，从而更有效地预防牛呼吸道疾病。
