title: Analysis of functional renal allograft tolerance with single-dose rapamycin based induction immunosuppression.
abstract: The induction of transplantation tolerance is one of the primary goals following solid organ transplantation. The combination of a single dose of rapamycin (RAPA) with a short course of cyclosporine (CsA) has been shown to induce transplantation tolerance in the nonfunctional rat heterotopic cardiac transplant model. The purpose of this study was to assess this effective induction protocol in a functional renal transplant model. Male ACI (RTl(a)) and Lewis (RT1(1)) rats were used as donor and recipients respectively. Allografts received a single RAPA dose of (1.5 mg/kg) combined with CsA (10 mg/kg) 12-14 hr prior to transplantation. CsA (5 mg/kg) was given daily on days +1 - +7. Untreated Lewis to Lewis isografts served as histological controls. Chimerism, assessed in recipient skin, and intragraft interleukin (IL) 10 expression was determined utilizing PCR and RT-PCR techniques respectively. Treated animals and isografts were sacrificed 120-130 days posttransplant for functional and histological evaluation. Allografts (n=9) were functionally 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 24 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 were 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 not express intragraft IL-10. This study confirms the efficacy of pre-engraftment single-dose RAPA combined with CsA in inducing true immunologic tolerance in this stringent functional renal transplant model. The expression of intragraft IL-10 in tolerant recipients suggests a Th-2 shift as the mechanism of tolerance in this model.
authors.affiliation: Department of Surgery, Medical College of Virginia/Virginia Commonwealth University, Richmond 23298, USA.
authors.forename: W C
authors.initials: WC
authors.lastname: Goggins
authors.forename: R A
authors.initials: RA
authors.lastname: Fisher
authors.forename: J B
authors.initials: JB
authors.lastname: Dattilo
authors.forename: D S
authors.initials: DS
authors.lastname: Cohen
authors.forename: J W
authors.initials: JW
authors.lastname: Tawes
authors.forename: M P
authors.initials: MP
authors.lastname: Dattilo
authors.forename: G F
authors.initials: GF
authors.lastname: Babcock
authors.forename: S E
authors.initials: SE
authors.lastname: Frede
authors.forename: P E
authors.initials: PE
authors.lastname: Wakely
authors.forename: M P
authors.initials: MP
authors.lastname: Posner
mesh_terms: D000199:Actins / Q000096:biosynthesis; D000818:Animals; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000627:therapeutic use; D017931:DNA Primers; D004359:Drug Therapy, Combination; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology; D007108:Immune Tolerance; D007165:Immunosuppression Therapy / Q000379:methods; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016753:Interleukin-10 / Q000096:biosynthesis; D016030:Kidney Transplantation / Q000276:immunology* / Q000473:pathology / Q000502:physiology; D008297:Male; D011090:Polyenes / Q000627:therapeutic use*; D016133:Polymerase Chain Reaction; D011507:Proteinuria; D051381:Rats; D011912:Rats, Inbred ACI; D011917:Rats, Inbred Lew; D020123:Sirolimus; D018183:Transplantation Chimera; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
chemical_list: D000199:Actins; D017931:DNA Primers; D007166:Immunosuppressive Agents; D011090:Polyenes; D016753:Interleukin-10; D016572:Cyclosporine; D003404:Creatinine; D020123:Sirolimus