title: Antibody-Mediated Rejection in Sensitized Nonhuman Primates: Modeling Human Biology.
abstract: We have established a model of sensitization in nonhuman primates and tested two immunosuppressive regimens. Animals underwent fully mismatched skin transplantation, and donor-specific antibody (DSA) response was monitored by flow cross-match. Sensitized animals subsequently underwent kidney transplantation from their skin donor. Immunosuppression included tacrolimus, mycophenolate, and methylprednisolone. Three animals received basiliximab induction; compared with nonsensitized animals, they showed a shorter mean survival time (4.7 ± 3.1 vs. 187 ± 88 days). Six animals were treated with T cell depletion (anti-CD4/CD8 mAbs), which prolonged survival (mean survival time 21.6 ± 19.0 days). All presensitized animals showed antibody-mediated rejection (AMR). In two of three basiliximab-injected animals, cellular rejection (ACR) was prominent. After T cell depletion, three of six monkeys experienced early acute rejection within 8 days with histological evidence of thrombotic microangiopathy and AMR. The remaining three monkeys survived 27-44 days, with mixed AMR and ACR. Most T cell-depleted animals experienced a rebound of DSA that correlated with deteriorating kidney function. We also found an increase in proliferating memory B cells (CD20(+) CD27(+) IgD(-) Ki67(+) ), lymph node follicular helper T cells (ICOS(+) PD-1(hi) CXCR5(+) CD4(+) ), and germinal center (GC) response. Depletion controlled cell-mediated rejection in sensitized nonhuman primates better than basiliximab, yet grafts were rejected with concomitant DSA rise. This model provides an opportunity to test novel desensitization strategies.
authors.affiliation: Emory Transplant Center, Department of Surgery, Emory School of Medicine, Atlanta, GA.|Division of Transplantation, Department of Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: C K
authors.initials: CK
authors.lastname: Burghuber
authors.affiliation: Emory Transplant Center, Department of Surgery, Emory School of Medicine, Atlanta, GA.|Duke Transplant Center, Department of Surgery, Duke University, Durham, NC.
authors.forename: J
authors.initials: J
authors.lastname: Kwun
authors.affiliation: Emory Transplant Center, Department of Surgery, Emory School of Medicine, Atlanta, GA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Page
authors.affiliation: Duke Transplant Center, Department of Surgery, Duke University, Durham, NC.
authors.forename: M
authors.initials: M
authors.lastname: Manook
authors.affiliation: Emory Transplant Center, Department of Surgery, Emory School of Medicine, Atlanta, GA.
authors.forename: A C
authors.initials: AC
authors.lastname: Gibby
authors.affiliation: Emory Transplant Center, Department of Surgery, Emory School of Medicine, Atlanta, GA.|Duke Transplant Center, Department of Surgery, Duke University, Durham, NC.
authors.forename: F V
authors.initials: FV
authors.lastname: Leopardi
authors.affiliation: Emory Transplant Center, Department of Surgery, Emory School of Medicine, Atlanta, GA.|Duke Transplant Center, Department of Surgery, Duke University, Durham, NC.
authors.forename: M
authors.initials: M
authors.lastname: Song
authors.affiliation: Department of Pathology, Emory School of Medicine, Atlanta, GA.
authors.forename: A B
authors.initials: AB
authors.lastname: Farris
authors.affiliation: Department of Pathology, Emory School of Medicine, Atlanta, GA.|Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA.|National Primate Research Center (NPRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Korea.
authors.forename: J J
authors.initials: JJ
authors.lastname: Hong
authors.affiliation: Department of Pathology, Emory School of Medicine, Atlanta, GA.|Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA.
authors.forename: F
authors.initials: F
authors.lastname: Villinger
authors.affiliation: Emory Transplant Center, Department of Surgery, Emory School of Medicine, Atlanta, GA.
authors.forename: A B
authors.initials: AB
authors.lastname: Adams
authors.affiliation: Emory Transplant Center, Department of Surgery, Emory School of Medicine, Atlanta, GA.
authors.forename: N N
authors.initials: NN
authors.lastname: Iwakoshi
authors.affiliation: Emory Transplant Center, Department of Surgery, Emory School of Medicine, Atlanta, GA.|Duke Transplant Center, Department of Surgery, Duke University, Durham, NC.
authors.forename: S J
authors.initials: SJ
authors.lastname: Knechtle
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000188:drug therapy* / Q000209:etiology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007518:Isoantibodies / Q000276:immunology*; D016030:Kidney Transplantation / Q000009:adverse effects*; D008212:Lymphocyte Depletion; D008253:Macaca mulatta; D008297:Male; D016038:Skin Transplantation; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology
chemical_list: D007166:Immunosuppressive Agents; D007518:Isoantibodies