title: Effects of a short course of leflunomide on T-independent B-lymphocyte xenoreactivity and on susceptibility of xenografts to acute or chronic rejection.
abstract: BACKGROUND
  Leflunomide is a novel immunosuppressive agent with promising activity for xenotransplantation. It is not clear yet which mechanisms of action of leflunomide are responsible for that.
  
  
  METHODS
  In a hamster-to-C57BL/6 nude mouse heart transplantation model, a 2-week course of leflunomide was used after transplantation or for pretreating donors. Nontolerant B lymphocytes were transferred to recipients after transplantation of first or second xenogeneic heart grafts that were transplanted with or without leflunomide treatment.
  
  
  RESULTS
  Hamster xenogeneic hearts transplanted into athymic C57BL/6 nude mice receiving leflunomide did not induce immunoglobulin (Ig) M xenoantibodies (XAb) and survived without signs of chronic rejection. Second xenogeneic hearts transplanted 4 weeks after withdrawal of leflunomide survived without induction of XAb but developed chronic vascular lesions. After injection of naive B lymphocytes at 6 weeks after grafting a first or second hamster heart, only in the latter case were XAb induced. These were deposited in, and provoked acute rejection of, only the second grafts. Pretreatment of donors with leflunomide decreased the ex vivo xenoantibody deposition on the xenogeneic heart endothelia.
  
  
  CONCLUSIONS
  A short posttransplant course of leflunomide induces T-independent B-lymphocyte xenotolerance. Leflunomide treatment also influences xenoantigen expression, as nontolerant B lymphocytes provoke IgM XAb formation and rejection of only second xenografts (transplanted without leflunomide) and not of first xenografts (transplanted with leflunomide treatment). The ex vivo experiments that show that XAb deposition is decreased in leflunomide-pretreated xenografts further confirm this. The latter may also explain the resistance of first and not second xenografts against chronic rejection.
authors.affiliation: Laboratory for Experimental Transplantation, University of Leuven, Herestraat 49, Leuven, B-3000, Belgium.
authors.forename: Yehong
authors.initials: Y
authors.lastname: Yan
authors.forename: Eric
authors.initials: E
authors.lastname: Verbeken
authors.forename: Lisong
authors.initials: L
authors.lastname: Yu
authors.forename: Omer
authors.initials: O
authors.lastname: Rutgeerts
authors.forename: Jozef
authors.initials: J
authors.lastname: Goebels
authors.forename: Constant
authors.initials: C
authors.lastname: Segers
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lin
authors.forename: Mark
authors.initials: M
authors.lastname: Waer
mesh_terms: D000818:Animals; D003165:Complement System Proteins / Q000187:drug effects / Q000276:immunology; D006224:Cricetinae; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007555:Isoxazoles / Q000627:therapeutic use*; D000077339:Leflunomide; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D014183:Transplantation, Heterologous / Q000276:immunology* / Q000473:pathology
chemical_list: D007166:Immunosuppressive Agents; D007555:Isoxazoles; D003165:Complement System Proteins; D000077339:Leflunomide