title: Successful transplantation of kidney allografts in sensitized rats after syngeneic hematopoietic stem cell transplantation and fludarabine.
abstract: Current methods to remove donor-specific HLA antibody (DSA) from sensitized patients remain imperfect. We tested novel approaches to desensitization using an animal model of allogeneic sensitization with skin grafts from dark agouti (DA) to Lewis rats. At the peak IgG alloantibody response we transplanted DA kidneys into nephrectomized Lewis recipients (n = 6) and all died within 10 days from antibody-mediated rejection (AMR). Allogeneic hematopoietic stem cell transplants (HSCT) from DA donors failed to engraft after lethal or sub-lethal irradiation. Sensitized rats given lethal irradiation plus syngeneic green fluorescent protein (GFP) + HSCT had repopulation of blood, spleen, thymus and lymph nodes by GFP+ cells. At 2 months after HSCT, serum DSA levels were reduced 60-70% and DSA (IgG) production in cultured splenocytes was also significantly decreased. However, there was only a modest improvement in graft survival from an average of 6.5 to 13.9 (n = 9) days. Adding seven daily doses of fludarabine to the preconditioning regimen resulted in long-term survival (>90 days) in 7 out of 10 rat kidney allografts. We conclude that syngeneic HSCT performed after preconditioning with irradiation and fludarabine can reduce DSA, prevent DSA rebound and AMR, enabling successful transplantation in animals with strong antibody reactivity to the donor MHC.
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Transplant Surgery, Tianjin First Central Hospital Clinic Institute, Tianjin Medical University, Tianjin, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Fu
authors.forename: Z
authors.initials: Z
authors.lastname: Sun
authors.forename: E J
authors.initials: EJ
authors.lastname: Fuchs
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: Z-Y
authors.initials: ZY
authors.lastname: Shen
authors.forename: H
authors.initials: H
authors.lastname: Maeda
authors.forename: Q
authors.initials: Q
authors.lastname: Lin
authors.forename: D S
authors.initials: DS
authors.lastname: Warren
authors.forename: G M
authors.initials: GM
authors.lastname: Williams
authors.forename: R A
authors.initials: RA
authors.lastname: Montgomery
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D016030:Kidney Transplantation; D016133:Polymerase Chain Reaction; D051381:Rats; D011917:Rats, Inbred Lew; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D017931:DNA Primers; D014740:Vidarabine; C024352:fludarabine
keywords: Alloantibody; animal models; basic (laboratory) research; bone marrow; desensitization; dysfunction; hematopoietic stem cell transplantation; immunobiology; kidney (allograft) function; kidney transplantation; nephrology; science; stem cells; translational research