The peripheral lymphocyte count predicts graft survival in DA to Lewis heterotopic heart transplantation treated with FTY720 and SDZ RAD

Objective: The new immunomodulator 2-amino-2-(2-{4-octylphenyl}ethyl)-1,3-p ropanediol hydrochloride (FTY720) lowers the peripheral lymphocyte count (P LC) by inducing migration of circulating lymphocytes to secondary lymphoid organs. This effect is dose-dependent at low (up to 0.1 mg/kg per day) dose s in rats. We investigated the correlation between PLC and the later reject ion, when FTY720 was combined with RAD. Methods : Heterotopic cardiac graft ing was performed using the DA-Lewis strain combination. FTY720 and RAD wer e administered as single daily doses by gavage alone and in combination sta rting 3 days before to 28 days after transplantation. Graft survival was mo nitored daily by palpation. PLC was determined at 1 and 3 weeks, body weigh t (BW) weekly. Histologic evaluation of grafted hearts was performed after rejection. Main findings: FTY720 at doses of 0.03, 0.1 and 0.3 mg/kg per da y prolonged graft survival dose-dependently from 6 (placebo) to 7, 9.5 and 15 days median survival time (MST). RAD at doses of 0.3, 1 and 3 mg/kg per day delayed rejection to 8.5, 18 and 37.5 days MST. Very small FTY720 doses added to the lower RAD doses were effective in maintaining grafts througho ut the treatment period and with normal weight gain, as opposed to regimens with 1 mg/kg or more per day RAD, which resulted in delayed weight gain. F TY720 lowered the PLC significantly and dose-dependently. The PLC correlate d well with graft survival [Spearman rank correlation (n = 30, rs = - 0.75) ]. Conclusions: Fully effective FTY720 + RAD combination regimens caused no side effects with respect to the rats' general well-being or weight gain a nd were better tolerated than equiactive RAD monotherapy, suggesting a broa der therapeutic window for the combinations. Under the experimental conditi ons, the PLC decrease showed an interesting correlation with the anti-rejec tion effects in these two-drug regimens. Thus, in rats the PLC is helpful f or monitoring the biological activity of FTY720 at low doses (< 0.1 mg/kg p er day), i.e. in the range of the steep part of its dose-response relations hip. (C) 2000 Elsevier Science B.V. All rights reserved.