BACKGROUND: We have previously reported successful induction of renal allograft tolerance in nonhuman primates (NHP) after an initial posttransplant period of conventional immunosuppression (delayed tolerance) using a nonmyeloablative conditioning regimen consisting of anti-CD154 and anti-CD8 mAbs plus equine antithymocyte globulin (Atgam) and donor bone marrow transplantation (DBMT). Because these reagents are not currently clinically available, the protocol was revised to be applicable to human recipients of deceased donor allografts. METHOD: Four cynomolgus monkeys received major histocompatibility complex-mismatched kidney allografts with conventional immunosuppression for 4 months. The recipients were then treated with a nonmyeloablative conditioning regimen consisting of thymoglobulin, belatacept, and DBMT. The results were compared with recipients treated with conditioning regimen consisting of Atgam and anti-CD154 mAb, with and without anti-CD8 mAb. RESULTS: In 4 consecutive NHP recipients treated with the modified conditioning regimen, homeostatic recovery of CD8 TEM was delayed until after day 20 and multilineage chimerism was successfully induced. Three of the 4 recipients achieved long-term allograft survival (>728, >540, >449 days) without ongoing maintenance immunosuppression. Posttransplant MLR showed loss of antidonor CD8 T cell and CD4 IFNγ responses with expansion of CD4FOXP3 regulatory T cells. However, the late development of donor-specific antibody in NHP recipients confirms the need for additional anti-B-cell depletion with agents, such as rituximab, as has been shown in our clinical trials. CONCLUSIONS: This study provides proof of principle that induction of mixed chimerism and long-term renal allograft survival without immunosuppression after delayed DBMT is possible with clinically available reagents.
BACKGROUND: We have previously reported successful induction of renal allograft tolerance in nonhuman primates (NHP) after an initial posttransplant period of conventional immunosuppression (delayed tolerance) using a nonmyeloablative conditioning regimen consisting of anti-CD154 and anti-CD8 mAbs plus equine antithymocyte globulin (Atgam) and donor bone marrow transplantation (DBMT). Because these reagents are not currently clinically available, the protocol was revised to be applicable to human recipients of deceased donor allografts. METHOD: Four cynomolgus monkeys received major histocompatibility complex-mismatched kidney allografts with conventional immunosuppression for 4 months. The recipients were then treated with a nonmyeloablative conditioning regimen consisting of thymoglobulin, belatacept, and DBMT. The results were compared with recipients treated with conditioning regimen consisting of Atgam and anti-CD154 mAb, with and without anti-CD8 mAb. RESULTS: In 4 consecutive NHP recipients treated with the modified conditioning regimen, homeostatic recovery of CD8TEM was delayed until after day 20 and multilineage chimerism was successfully induced. Three of the 4 recipients achieved long-term allograft survival (>728, >540, >449 days) without ongoing maintenance immunosuppression. Posttransplant MLR showed loss of antidonor CD8 T cell and CD4 IFNγ responses with expansion of CD4FOXP3 regulatory T cells. However, the late development of donor-specific antibody in NHP recipients confirms the need for additional anti-B-cell depletion with agents, such as rituximab, as has been shown in our clinical trials. CONCLUSIONS: This study provides proof of principle that induction of mixed chimerism and long-term renal allograft survival without immunosuppression after delayed DBMT is possible with clinically available reagents.
Authors: D C Brennan; K Flavin; J A Lowell; T K Howard; S Shenoy; S Burgess; S Dolan; J M Kano; M Mahon; M A Schnitzler; R Woodward; W Irish; G G Singer Journal: Transplantation Date: 1999-04-15 Impact factor: 4.939
Authors: Shelby L O'Connor; Alex J Blasky; Chad J Pendley; Ericka A Becker; Roger W Wiseman; Julie A Karl; Austin L Hughes; David H O'Connor Journal: Immunogenetics Date: 2007-03-24 Impact factor: 2.846
Authors: Y Yamada; S Boskovic; A Aoyama; T Murakami; P Putheti; R N Smith; T Ochiai; O Nadazdin; I Koyama; O Boenisch; N Najafian; M K Bhasin; R B Colvin; J C Madsen; T B Strom; D H Sachs; G Benichou; A B Cosimi; T Kawai Journal: Am J Transplant Date: 2011-11-04 Impact factor: 8.086
Authors: Tatsuo Kawai; A Benedict Cosimi; Thomas R Spitzer; Nina Tolkoff-Rubin; Manikkam Suthanthiran; Susan L Saidman; Juanita Shaffer; Frederic I Preffer; Ruchuang Ding; Vijay Sharma; Jay A Fishman; Bimalangshu Dey; Dicken S C Ko; Martin Hertl; Nelson B Goes; Waichi Wong; Winfred W Williams; Robert B Colvin; Megan Sykes; David H Sachs Journal: N Engl J Med Date: 2008-01-24 Impact factor: 91.245
Authors: S Lee; Y Yamada; M Tonsho; S Boskovic; O Nadazdin; D Schoenfeld; K Cappetta; M Atif; R-N Smith; A B Cosimi; G Benichou; T Kawai Journal: Am J Transplant Date: 2013-10-24 Impact factor: 8.086
Authors: Lisa M Willoughby; Mark A Schnitzler; Daniel C Brennan; Brett W Pinsky; Nino Dzebisashvili; Paula M Buchanan; Luca Neri; Lisa A Rocca-Rey; Kevin C Abbott; Krista L Lentine Journal: Transplantation Date: 2009-05-27 Impact factor: 4.939
Authors: Tim A Weaver; Ali H Charafeddine; Avinash Agarwal; Alexandra P Turner; Maria Russell; Frank V Leopardi; Robert L Kampen; Linda Stempora; Mingqing Song; Christian P Larsen; Allan D Kirk Journal: Nat Med Date: 2009-07-05 Impact factor: 53.440
Authors: Wiebke Sommer; Jane M O; Kurt B Pruner; Abbas Dehnadi; Kyu Ha Huh; Kortney A Robinson; Isabel Hanekamp; Ivy Rosales; Alison S Bean; Josh Paster; Tetsu Oura; Rex Neal Smith; Robert Colvin; Gilles Benichou; Tatsuo Kawai; Joren C Madsen; James S Allan Journal: Transplant Direct Date: 2021-05-25
Authors: Rainer Oberbauer; Matthias Edinger; Gabriela Berlakovich; Peter Kalhs; Nina Worel; Georg Heinze; Michael Wolzt; Thomas Lion; Thomas Wekerle Journal: Front Med (Lausanne) Date: 2021-01-27
Authors: Erik J Woods; Aubrey M Sherry; John R Woods; James W Hardin; Michael LaFontaine; Gerald Brandacher; Brian H Johnstone Journal: J Transl Med Date: 2020-08-05 Impact factor: 5.531