Transplantation. 2005
Jan 15;79(1):116-8. Effect of leflunomide and cidofovir
on replication of BK virus in an in vitro culture system.
Farasati NA, Shapiro R, Vats A, Randhawa P.
Department of Pathology, University of Pittsburgh Medical Center,
Pittsburgh, PA 15213, USA.
BACKGROUND: Cidofovir and Leflunomide are used empirically in the
treatment of BK virus nephropathy. The aim of this study is to quantify
the antiviral activity of these drugs. METHODS: BK virus was grown
in a cell-culture system. The rate of viral replication in the presence
or absence of the drug being tested was assessed using a quantitative
polymerase chain reaction assay. RESULTS: The inhibitory concentration,
effective concentration, and selectivity index for Leflunomide are
39.7+/-6.9, 11.3+/-2.8, and 3.8+/-0.8 microg/mL, respectively. For
Cidofovir, these indices were, respectively, 63.9+/-17.2, 36.3+/-11.7,
and 2.3+/-0.8 microg/mL. CONCLUSIONS: The in vitro activity of Cidofovir
and Leflunomide is modest, and the selectivity index is low. There
is a need to develop more effective and less toxic anti-BK virus
drugs for clinical use.
Transplantation. 2005 Jan 27;79(2):135-41;
discussion 133-4. Effects of a short course of leflunomide
on T-independent B-lymphocyte xenoreactivity and on susceptibility
of xenografts to acute or chronic rejection.
Yan Y, Verbeken E, Yu L, Rutgeerts O, Goebels J, Segers C, Lin
Y, Waer M.
Laboratory for Experimental Transplantation, University of Leuven,
Herestraat 49, Leuven, B-3000, Belgium.
BACKGROUND: Leflunomide is a novel immunosuppressive agent with
promising activity for xenotransplantation. It is not clear yet
which mechanisms of action of leflunomide are responsible for
that. METHODS: In a hamster-to-C57BL/6 nude mouse heart transplantation
model, a 2-week course of leflunomide was used after transplantation
or for pretreating donors. Nontolerant B lymphocytes were transferred
to recipients after transplantation of first or second xenogeneic
heart grafts that were transplanted with or without leflunomide
treatment. RESULTS: Hamster xenogeneic hearts transplanted into
athymic C57BL/6 nude mice receiving leflunomide did not induce
immunoglobulin (Ig) M xenoantibodies (XAb) and survived without
signs of chronic rejection. Second xenogeneic hearts transplanted
4 weeks after withdrawal of leflunomide survived without induction
of XAb but developed chronic vascular lesions. After injection
of naive B lymphocytes at 6 weeks after grafting a first or second
hamster heart, only in the latter case were XAb induced. These
were deposited in, and provoked acute rejection of, only the second
grafts. Pretreatment of donors with leflunomide decreased the
ex vivo xenoantibody deposition on the xenogeneic heart endothelia.
CONCLUSIONS: A short posttransplant course of leflunomide induces
T-independent B-lymphocyte xenotolerance. Leflunomide treatment
also influences xenoantigen expression, as nontolerant B lymphocytes
provoke IgM XAb formation and rejection of only second xenografts
(transplanted without leflunomide) and not of first xenografts
(transplanted with leflunomide treatment). The ex vivo experiments
that show that XAb deposition is decreased in leflunomide-pretreated
xenografts further confirm this. The latter may also explain the
resistance of first and not second xenografts against chronic
rejection.
