title: Association of rapamycin and co-stimulation blockade using anti-B7 antibodies in renal allotransplantation in baboons.
abstract: BACKGROUND
  Co-stimulation blockade has already been shown to induce transplantation tolerance in rodents, but until now has failed in large animal models. We therefore sought to investigate whether the addition of rapamycin to a co-stimulation blockade regimen could induce tolerance in baboon recipients of a renal allograft and to characterize the immunological characteristics of rejection.
  
  
  METHODS
  Two baboons were used for a pharmacological and toxicological analysis and received anti-B7.1 and anti-B7 antibodies every other day for 60 days. Three groups of baboons underwent classical heterotopic renal allotransplantation; the first group received no treatment (control group; n = 2), the second received a combination of anti-CD80 and anti-CD86 monoclonal antibodies (mAbs) (B7 group; n = 4), and the third received the anti-B7 antibody treatment as above with an additional treatment of rapamycin (B7-Rapa; n = 4). Graft survival as well as immunological analyses were performed.
  
  
  RESULTS
  Anti-B7 mAb monotherapy prolonged allograft survival in three out of four of the animals, one of whom survived rejection free for 87 days but died from a pulmonary embolism; the fourth animal died without rejection. The addition of rapamycin to the regimen did not prolong survival further; three of the four animals underwent early rejection whereas the fourth survived long term but eventually rejected at day 114. Whereas alloimmunization only occurred in this latter animal, rejection was always characterized by a substantial lymphocyte and monocyte infiltration, associated with a strong pro-inflammatory/cytotoxic mRNA accumulation in the anti-B7-treated animals, but to a lesser extent in the B7-Rapa group. T cells extracted and cloned from a biopsy taken at a stable post-transplant time showed a lower frequency of anti-donor alloreactivity in vitro than those extracted from a rejected tissue. Nevertheless, these non-responding clones failed to show regulatory activity in vitro.
  
  
  CONCLUSIONS
  We thus confirm that blocking the CD28/B7 pathway by anti-B7 mAbs could prolong graft survival in baboons, but the addition of rapamycin was insufficient to induce tolerance.
authors.affiliation: INSERM U437, Immunointervention en Allo et Xénotransplantation, Nantes cedex, France.
authors.forename: Gwénola
authors.initials: G
authors.lastname: Boulday
authors.forename: Joanna
authors.initials: J
authors.lastname: Ashton-Chess
authors.forename: Pierre
authors.initials: P
authors.lastname: Bernard
authors.forename: Georges
authors.initials: G
authors.lastname: Karam
authors.forename: Henri
authors.initials: H
authors.lastname: Vié
authors.forename: Anne
authors.initials: A
authors.lastname: Moreau
authors.forename: David
authors.initials: D
authors.lastname: Minault
authors.forename: Katrien
authors.initials: K
authors.lastname: Lorré
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Soulillou
authors.forename: Gilles
authors.initials: G
authors.lastname: Blancho
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D016207:Cytokines / Q000502:physiology; D006084:Graft Rejection / Q000209:etiology / Q000517:prevention & control*; D006085:Graft Survival; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000276:immunology*; D048530:Papio anubis; D020123:Sirolimus / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; D007166:Immunosuppressive Agents; C437823:galiximab; D020123:Sirolimus