ANALYSIS OF FUNCTIONAL RENAL-ALLOGRAFT TOLERANCE WITH SINGLE-DOSE RAPAMYCIN BASED INDUCTION IMMUNOSUPPRESSION

The induction of transplantation tolerance is one of the primary goals following solid organ transplantation. The combination of a single do se of rapamycin (RAPA) with a short course of cyclosporine (CsA) has b een shown to induce transplantation tolerance in the nonfunctional rat heterotopic cardiac transplant model. The purpose of this study was t o assess this effective induction protocol in a functional renal trans plant model. Male ACI (RTI(a)) and Lewis (RTI(1)) rats were used as do nor and recipients respectively. Allografts received a single RAPA dos e of (1.5 mg/kg) combined with CsA (10 mg/kg) 12-14 hr prior 60 transp lantation. CsA (5 mg/kg) mas given daily on days +1-+7. Untreated Lewi s to Lewis isografts served as histological controls. Chimerism, asses sed in recipient shin, and intragraft interleukin (IL) 10 expression w as determined utilizing PCR and RT-PCR techniques respectively. Treate d animals and isografts were sacrificed 120-130 days post transplant f or functional and histological evaluation, Allografts (n=9) were funct ionally tolerant with serum creatinine (0.77+/-0.1 vs. 0.88+/-0.1; P=0 .275), blood urea nitrogen (37.6+/-4.6 vs. 23.3+/-1.9; P=0.123), and 2 4 hr protein excretion (27.0+/-4.4 vs. 17.9+/-5.2; P=0.131) similar to single kidney ACI controls. Histologically, 45% (4/9) allografts were indistinguishable from isografts with no evidence of rejection, and w ere considered immunologically tolerant. Donor/recipient chimerism was not detected. All immunologically tolerant allografts had evidence of intragraft IL-10 expression. Rejecting allografts and isografts did n ot express intragraft IL-10. This study confirms the efficacy of pre-e ngraftment single-dose RAPA combined with CsA in inducing true immunol ogic tolerance in this stringent functional renal transplant model. Th e expression of intragraft IL-10 in tolerant recipients suggests a Th- 2 shift as the mechanism of tolerance in this model.