Barrow Paul C, Horand Françoise, Ravel Guillaume
MDS Pharma Services, Les Oncins, Saint-Germain sur l'Arbresle, France.
Birth Defects Res B Dev Reprod Toxicol. 2006 Oct;77(5):430-7. doi: 10.1002/bdrb.20093.
The development and function of the immune system was assessed in juvenile SD rats following pre- or post-natal exposure to cyclosporin. The main objective was to assess the feasibility of the methods available for the detection of adverse effects on the development of the immune system for use in the safety assessment of medicines.
In a pre-natal experiment, 15 pregnant rats were given 10 mg/kg/day of cyclosporin by gavage from day 6 of gestation until 4 days after parturition. A control group received olive oil. In a post-natal experiment, the pups from 35 litters were given 10 mg/kg/day of cyclosporin by gavage from 4 to 28 days of age. Half of the pups in each litter were given water and acted as controls. Immune endpoints were determined in the pups in both experiments from two to 10 weeks of age, including: lymphocyte subsets, serum immunoglobulin titres, serum autoantibodies, primary antibody response to sheep red blood cells (SRBC), delayed-type hypersensitivity response, humoral response to keyhole limpet haemocyanin, spleen cellularity, immune organ weights, and histopathology.
Pre-natal exposure caused no effects on immune function. Post-natal exposure caused immune depression during the treatment period and a persistent impairment of the immune system characterised by lymphoid hyperplasia in the spleen and a reduced primary antibody response to SRBC at 10 weeks of age.
These results demonstrate the importance of a post-treatment follow-up period in developmental immunotoxicity studies, in order to distinguish between the transient effects of immune modulation and the persistent consequences of developmental toxicity.
在幼年SD大鼠出生前或出生后暴露于环孢素后，评估其免疫系统的发育和功能。主要目的是评估现有方法在药物安全性评估中检测对免疫系统发育的不良影响的可行性。
在一项产前实验中，15只怀孕大鼠从妊娠第6天至产后4天经口灌胃给予10mg/kg/天的环孢素。对照组给予橄榄油。在一项产后实验中，35窝幼崽从4至28日龄经口灌胃给予10mg/kg/天的环孢素。每窝幼崽中有一半给予水并作为对照。在两项实验中，对2至10周龄的幼崽测定免疫终点，包括：淋巴细胞亚群、血清免疫球蛋白滴度、血清自身抗体、对绵羊红细胞（SRBC）的初次抗体反应、迟发型超敏反应、对钥孔戚血蓝蛋白的体液反应、脾细胞数量、免疫器官重量和组织病理学。
产前暴露对免疫功能无影响。产后暴露在治疗期间引起免疫抑制，并导致免疫系统持续受损，其特征为脾脏淋巴样增生以及10周龄时对SRBC的初次抗体反应降低。
这些结果证明了在发育免疫毒性研究中治疗后随访期的重要性，以便区分免疫调节的短暂影响和发育毒性的持续后果。
