Prevention of acute allograft rejection in nonhuman primate lung transplant recipients - Induction with chimeric anti-interleukin-2 receptor monoclonal antibody improves the tolerability and potentiates the immunosuppressiveactivity of a regimen using low doses of both microemulsion cyclosporine and 40-O-(2-hydroxyethyl)-rapamycin
B. Hausen et al., Prevention of acute allograft rejection in nonhuman primate lung transplant recipients - Induction with chimeric anti-interleukin-2 receptor monoclonal antibody improves the tolerability and potentiates the immunosuppressiveactivity of a regimen using low doses of both microemulsion cyclosporine and 40-O-(2-hydroxyethyl)-rapamycin, TRANSPLANT, 69(4), 2000, pp. 488-496
Background In previous studies of cynomolgus monkey lung allograft recipien
ts, we demonstrated significant immunosuppressive efficacy but, reduced tol
erability after combined treatment with high doses of microemulsion cyclosp
orine (CsA) and SDZ RAD (40-O-(2-hydroxyethyl)-rapamycin). The current stud
y was designed to compare efficacy and tolerability of a combination of low
-dose CsA and high-dose SDZ RAD (CTL group) to triple therapy using the chi
meric anti-interleukin-2 (IL-2) receptor (CD25) monoclonal antibody (mAb) b
asiliximab (anti-IL-2 receptor mAb) for induction therapy (basiliximab: 5 m
g intravenously on days 0 and 4) plus low-dose CsA and low-dose SDZ RAD for
maintenance immunosuppression (CD25 group). CsA and anti-IL-P receptor mAb
are drugs that reduce cytokine synthesis and block IL-2-mediated lymphocyt
e stimulation; respectively, SDZ RAD blocks lymphocyte stimulation by other
cytokines (e.g., IL-15) that are not inhibited by anti-IL-2 receptor mAb,
Methods, Tpvelve unilateral lung transplants were performed. Recipients wer
e observed for 49 days by daily weight assessment, hemograms, blood chemist
ries, radiographs, and lung biopsies. Monkeys were euthanized. before day 4
9 in the event of excessive weight loss (>25%) or organ failure. Target CsA
trough levels were 100-200 ng/ml. Target SDZ RAD trough levels in the CTL
group (no mAb) were 20-40 ng/nl, and 10-20 ng/ml in the CD25 group.
Results. None of the monkeys in the CD25 group needed to be euthanized earl
y due to signs of drug toxicity. In contrast, four monkeys in the CTL group
were sacrificed on days 28-35 as a result of excessive weight loss (n=3) a
nd renal functional impairment (n=1), Three recipients in the CD25 group we
re euthanized on days 36, 38, and 46 as a result of persistent high fever a
ssociated with severe rejection. The median animal survival in the CTL grou
p was 32 vs. 46 days in the CD25 group (P<0.04), The only two longterm surv
ivors in the CTL group showed moderate rejection at day 49, The median reje
ction scores at day 14 (A0) and day 28 (A2) were identical in the two group
s, despite the fact that the mean SDZ RAD trough level was significantly lo
wer in the CD25 group (CTL: 38+/-3 ng/ml, CD25: 18+/-2 ng/ml, P<0.0001), Af
ter basiliximab levels fell below the minimum therapeutic level (1 mg/ml) o
n day 28, the median rejection score at day 49 increased to A4 in the CD25
group,
Conclusion. This is the first study to combine an anti-IL-2 receptor mAb wi
th a drug from the rapamycin class plus CsA. Our study shows that induction
therapy with basiliximab enabled SDZ RAD blood levels to be significantly
reduced, which led to improved tolerability without the penalty of increase
d rejection.