Immunotoxicological assessment of cyclosporin A by conventional pathological techniques and immune function testing in the rat

Abstract

<jats:p> 1 Groups of male rats were given different doses of cyclosporin A, ranging from the maximum tolerated dose (20 mg/kg/day) downwards, 7 days a week for 28 days using a protocol derived from OECD test guide line 407. </jats:p><jats:p> 2 At the end of the test, one set of animals underwent a detailed necropsy and histopathological examination of lymphoid tissues. Immune function was assessed using the lymphoproliferative response and natural killer cell activity of their spleen cells. Another set of animals was immunised with sheep erythrocytes on day 25 and used to evaluate the ability to produce specific anti-sheep red blood cell antibody. </jats:p><jats:p> 3 Cyclosporin A produced detectable effects on the immune system at all doses and at doses lower than other toxic effects. Both histopathological techniques and one of the immune function tests were able to identify changes at the lowest dose, 1.25 mg/kg/day. </jats:p><jats:p> 4 The results of this investigation suggest that conven tional histopathological techniques, if applied to a range of lymphoid organs, are sufficient to identify potential immunotoxicants without recourse to im mune function tests. </jats:p>

Changes in the Immune System of Female Wistar Rats After Exposure to Immunosuppressive Treatment During Pregnancy

“…We have not observed statistically significant differences in basic haematological parameters between control and treatment groups of dams. In study of Crevel et al ., similar results were obtained – white blood cell counts were largely unaffected by treatment with CsA . In another study carried on male adult rats, a reduction in white blood cell counts and lymphocyte counts, a decrease in red blood counts and haemoglobin concentration and an increase in platelet counts were observed in rats treated with CsA and/or MMF .…”

“…After exposure of rat splenocytes in vitro to CsA lymphocyte, transformation and IL-2 mRNA expression in splenocytes were suppressed by this drug [24]. Data from previous studies also show increased natural killer activity with CsA treatment in rats [18]. In our study, this dependence was notable in dams treated simultaneously with CsA and everolimus, but not with CsA and MMF.…”

“…Most of studies focused on immunotoxicity were carried out generally on male rats [15,18]. In our experimental study, we assessed the impact of immunosuppressive drugs on changes in the immune system in female Wistar rats during pregnancy.…”

Primary antibody response to keyhole limpet hemocyanin in rat as a model for immunotoxicity evaluation

“…Pharmaceutical grade olive oil was used as the vehicle for cyclosporin and USP grade saline for both azathioprine and prednisolone. Cyclosporin, azathioprine and prednisolone were administered at maximum tolerated doses indicated in previously published reports (Dean and Remandet, 1997;Crevel et al, 1997;The ICICIS Group Investigators, 1998;Matsuura et al, 2000).…”

“…Footpad immunization was included in the route comparison study to characterize potential histopathological changes in the draining lymph nodes, while i.v. route was included as an alternative, not only in the interest of animal welfare but also based on recently published reports on immunization in the context of immunotoxicologic evaluations (Crevel et al, 1997;Ladics et al, 1998;The ICICIS Group Investigators, 1998). The s.c. route was also assessed as this is a conventional route of immunization widely used in both pre-clinical and clinical study designs.…”