BACKGROUND: We recently reported that durable chimerism can be safely established in mismatched kidney recipients through nonmyeloablative conditioning followed by infusion of a facilitating cell (FC)-based hematopoietic stem cell transplantation termed FCRx. Here we provide intermediate-term follow-up on this phase II trial. METHODS: Fifteen human leukocyte antigen-mismatched living donor renal transplant recipients underwent low-intensity conditioning (fludarabine, cyclophosphamide, 200 cGy TBI), received a living donor kidney transplant on day 0, then infusion of cryopreserved FCRx on day +1. Maintenance immunosuppression, consisting of tacrolimus and mycophenolate, was weaned over 1 year. RESULTS: All but one patient demonstrated peripheral blood macrochimerism after transplantation. Engraftment failure occurred in a highly sensitized (panel reactive antibody [PRA] of 52%) recipient. Chimerism was lost in three patients at 2, 3, and 6 months after transplantation. Two of these subjects had received either a reduced cell dose or incomplete conditioning; the other two had PRA greater than 20%. All demonstrated donor-specific hyporesponsiveness and were weaned from full-dose immunosuppression. Complete immunosuppression withdrawal at 1 year after transplantation was successful in all patients with durable chimerism. There has been no graft-versus-host disease or engraftment syndrome. Renal transplantation loss occurred in one patient who developed sepsis following an atypical viral infection. Two subjects with only transient chimerism demonstrated subclinical rejection on protocol biopsy despite donor-specific hyporesponsiveness. CONCLUSIONS: Low-intensity conditioning plus FCRx safely achieved durable chimerism in mismatched allograft recipients. Sensitization represents an obstacle to successful induction of chimerism. Sustained T-cell chimerism is a more robust biomarker of tolerance than donor-specific hyporeactivity.
BACKGROUND: We recently reported that durable chimerism can be safely established in mismatched kidney recipients through nonmyeloablative conditioning followed by infusion of a facilitating cell (FC)-based hematopoietic stem cell transplantation termed FCRx. Here we provide intermediate-term follow-up on this phase II trial. METHODS: Fifteen human leukocyte antigen-mismatched living donor renal transplant recipients underwent low-intensity conditioning (fludarabine, cyclophosphamide, 200 cGy TBI), received a living donor kidney transplant on day 0, then infusion of cryopreserved FCRx on day +1. Maintenance immunosuppression, consisting of tacrolimus and mycophenolate, was weaned over 1 year. RESULTS: All but one patient demonstrated peripheral blood macrochimerism after transplantation. Engraftment failure occurred in a highly sensitized (panel reactive antibody [PRA] of 52%) recipient. Chimerism was lost in three patients at 2, 3, and 6 months after transplantation. Two of these subjects had received either a reduced cell dose or incomplete conditioning; the other two had PRA greater than 20%. All demonstrated donor-specific hyporesponsiveness and were weaned from full-dose immunosuppression. Complete immunosuppression withdrawal at 1 year after transplantation was successful in all patients with durable chimerism. There has been no graft-versus-host disease or engraftment syndrome. Renal transplantation loss occurred in one patient who developed sepsis following an atypical viral infection. Two subjects with only transient chimerism demonstrated subclinical rejection on protocol biopsy despite donor-specific hyporesponsiveness. CONCLUSIONS: Low-intensity conditioning plus FCRx safely achieved durable chimerism in mismatched allograft recipients. Sensitization represents an obstacle to successful induction of chimerism. Sustained T-cell chimerism is a more robust biomarker of tolerance than donor-specific hyporeactivity.
Authors: Joseph Leventhal; Michael Abecassis; Joshua Miller; Lorenzo Gallon; Kadiyala Ravindra; David J Tollerud; Bradley King; Mary Jane Elliott; Geoffrey Herzig; Roger Herzig; Suzanne T Ildstad Journal: Sci Transl Med Date: 2012-03-07 Impact factor: 17.956
Authors: A B Farris; D Taheri; T Kawai; L Fazlollahi; W Wong; N Tolkoff-Rubin; T R Spitzer; A J Iafrate; F I Preffer; S A Locascio; B Sprangers; S Saidman; R N Smith; A B Cosimi; M Sykes; D H Sachs; R B Colvin Journal: Am J Transplant Date: 2011-06-10 Impact factor: 8.086
Authors: A Page; S Srinivasan; K Singh; M Russell; K Hamby; T Deane; S Sen; L Stempora; F Leopardi; A A Price; E Strobert; K A Reimann; A D Kirk; C P Larsen; L S Kean Journal: Am J Transplant Date: 2011-09-19 Impact factor: 8.086
Authors: M Takatsuki; S Uemoto; Y Inomata; H Egawa; T Kiuchi; S Fujita; M Hayashi; T Kanematsu; K Tanaka Journal: Transplantation Date: 2001-08-15 Impact factor: 4.939
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: Nina Pilat; Benedikt Mahr; Lukas Unger; Karin Hock; Christoph Schwarz; Andreas M Farkas; Ulrike Baranyi; Fritz Wrba; Thomas Wekerle Journal: JCI Insight Date: 2016-05-19