title: Preclinical Testing of Antihuman CD28 Fab' Antibody in a Novel Nonhuman Primate Small Animal Rodent Model of Xenogenic Graft-Versus-Host Disease.
abstract: BACKGROUND
  Graft-versus-host disease (GVHD) is a severe complication of hematopoietic stem cell transplantation. Current therapies to prevent alloreactive T cell activation largely cause generalized immunosuppression and may result in adverse drug, antileukemia and antipathogen responses. Recently, several immunomodulatory therapeutics have been developed that show efficacy in maintaining antileukemia responses while inhibiting GVHD in murine models. To analyze efficacy and better understand immunological tolerance, escape mechanisms, and side effects of clinical reagents, testing of species cross-reactive human agents in large animal GVHD models is critical.
  
  
  METHODS
  We have previously developed and refined a nonhuman primate (NHP) large animal GVHD model. However, this model is not readily amenable to semi-high throughput screening of candidate clinical reagents.
  
  
  RESULTS
  Here, we report a novel, optimized NHP xenogeneic GVHD (xeno-GVHD) small animal model that recapitulates many aspects of NHP and human GVHD. This model was validated using a clinically available blocking, monovalent anti-CD28 antibody (FR104) whose effects in a human xeno-GVHD rodent model are known.
  
  
  CONCLUSIONS
  Because human-reactive reagents may not be fully cross-reactive or effective in vivo on NHP immune cells, this NHP xeno-GVHD model provides immunological insights and direct testing on NHP-induced GVHD before committing to the intensive NHP studies that are being increasingly used for detailed evaluation of new immune therapeutic strategies before human trials.
authors.affiliation: Department of Pediatrics, Division of Hematology/Oncology and Blood and Marrow Transplantation, University of Minnesota; Minneapolis, MN USA 55455.
authors.forename: Keli L
authors.initials: KL
authors.lastname: Hippen
authors.affiliation: Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta GA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Watkins
authors.affiliation: Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle WA, the University of Washington, Seattle WA, and the Fred Hutchinson Cancer Research Center, Seattle WA.
authors.forename: Victor
authors.initials: V
authors.lastname: Tkachev
authors.affiliation: Department of Pediatrics, Division of Hematology/Oncology and Blood and Marrow Transplantation, University of Minnesota; Minneapolis, MN USA 55455.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Lemire
authors.affiliation: Department of Pediatrics, Division of Hematology/Oncology and Blood and Marrow Transplantation, University of Minnesota; Minneapolis, MN USA 55455.
authors.forename: Charles
authors.initials: C
authors.lastname: Lehnen
authors.affiliation: Department of Pediatrics, Division of Hematology/Oncology and Blood and Marrow Transplantation, University of Minnesota; Minneapolis, MN USA 55455.
authors.forename: Megan J
authors.initials: MJ
authors.lastname: Riddle
authors.affiliation: Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta GA.
authors.forename: Karnail
authors.initials: K
authors.lastname: Singh
authors.affiliation: Department of Pediatrics, Division of Hematology/Oncology and Blood and Marrow Transplantation, University of Minnesota; Minneapolis, MN USA 55455.
authors.forename: Angela
authors.initials: A
authors.lastname: Panoskaltsis-Mortari
authors.affiliation: INSERM, UMR 1064-Center for Research in Transplantation and Immunology, Nantes, F44093 France; ITUN, CHU Nantes, Nantes, F44093 France; University of Nantes, Nantes, F44093 France.|Effimune SA, Nantes, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Vanhove
authors.affiliation: Department of Pediatrics, Division of Hematology/Oncology and Blood and Marrow Transplantation, University of Minnesota; Minneapolis, MN USA 55455.
authors.forename: Jakub
authors.initials: J
authors.lastname: Tolar
authors.affiliation: Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle WA, the University of Washington, Seattle WA, and the Fred Hutchinson Cancer Research Center, Seattle WA.
authors.forename: Leslie S
authors.initials: LS
authors.lastname: Kean
authors.affiliation: Department of Pediatrics, Division of Hematology/Oncology and Blood and Marrow Transplantation, University of Minnesota; Minneapolis, MN USA 55455.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology*; D015415:Biomarkers; D018106:CD28 Antigens / Q000276:immunology*; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D007108:Immune Tolerance; D007165:Immunosuppression Therapy / Q000379:methods; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008213:Lymphocyte Activation; D008253:Macaca mulatta; D051379:Mice; D016688:Mice, Inbred NOD; D010641:Phenotype; D057170:Translational Research, Biomedical; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous
chemical_list: D000906:Antibodies; D015415:Biomarkers; D018106:CD28 Antigens