Login to Access Video or Poster Abstract: MP30-04
Sources of Funding: NIH/NIAID U19AI102405-01

Introduction

We have previously reported successful induction of renal allograft tolerance following a period of conventional immunosuppression (Delayed tolerance) using a nonmyeloablative conditioning with anti-CD154 and anti-CD8 mAbs or LFA3-Ig in MHC-mismatched kidney transplantation (KTx). However, since these reagents are not currently clinically available, the protocol needs to be revised to apply this approach to clinical deceased donor transplantation. In this study, we tested clinically available reagents, CTLA4Ig(belatacept) and rabbit-ATG(Thymoglobulin), for induction of delayed tolerance.

Methods

KTx was performed with a triple drug immunosuppression (I.S.) (tacrolimus, mycophenolate mofetil and predonisone) in MHC mismatched cynomolgus monkeys. Four months after KTx, recipients received donor bone marrow transplant (BMT) with a nonmyeloablative conditioning regimen that consisted of low dose TBI, thymic irradiation, belatacept, Thymoglobulin and a one month course of CyA.

Results

The first monkey received the regimen with Thymoglobulin (20mg/kg×3) and belatacept (20mg/kg ×4). Although the recipient developed mixed chimerism (MC), he died due to lethal CMV on day 19 after BMT. Another recipient received a reduced dose of Thymoglobulin (10mg/kg×2) but increased dose of belatacept (20mg/kg ×6). The recipient developed MC but died due to lymphoma on day 49. All four recipients that received Thymoglobulin (10mg/kg×2) and belatacept (20mg/kg ×4) developed MC without infectious complications or lymphoma and 3/4 achieved long-term renal allograft survival without I.S. (>300 days). The last recipient in this group did not develop rejection but died on day 108 due to ischemic kidney injury caused by hypotension during the renal allograft biopsy.

Conclusions

Induction of delayed renal allograft tolerance is achieved in nonhuman primates by a nonmyeloablative conditioning with belatacept and Thymoglobulin. This protocol for delayed tolerance is directly applicable to clinical deceased donor kidney transplantation.

Funding

NIH/NIAID U19AI102405-01