title: Gene transfer of human CD40Ig does not prevent rejection in a non-human primate kidney allotransplantation model.
abstract: BACKGROUND
  Blockade of costimulation signaling required for immune response, such as CD40/CD40L and CD28/B7, is a reasonable strategy to prevent rejection and in defined combinations may allow donor specific tolerance. Indeed, in rodents, costimulation blockade with CD28/B7 antagonists or with CD40Ig was able to induce regulatory T cells and transplant tolerance whereas in primates, anti-CD40 antibodies, anti-CD40L antibodies or CTLA4Ig, used as monotherapy, significantly delayed graft rejection.
  
  
  METHODS
  Using an adeno-associated virus (AAV) vector mediated gene transfer of a human CD40Ig fusion protein (hCD40Ig) in primates, we evaluated the capacity of this costimulation blockade molecule interfering with CD40/CD40L signaling in prolonging kidney transplants in cynomolgus monkeys.
  
  
  RESULTS
  This gene transfer strategy allowed for maintaining a plateau of hCD40Ig production within two months and avoided a high-scale production phase of this molecule. Although the hCD40Ig was able to bind efficiently to human and macaque CD40L and high (>200 μg/ml) transgene expression was obtained, no effect on graft survival was observed. In addition, there was no inhibition of humoral response to vaccination. In vitro, hCD40Ig strongly increased mixed lymphocyte reaction, and when compared to the anti-CD40L antibody h5C8, was not as potent to induce complement-dependent cytotoxicity.
  
  
  CONCLUSIONS
  These data suggest that CD40/CD40L blockade using a non-depleting CD40Ig fusion protein, a therapeutic strategy that showed efficacy in rodents, is not able to modulate the immune response in primates. These data highlight important biological differences between rodent and primate models to evaluate therapeutic strategies at the preclinical level.
authors.affiliation: INSERM UMR 1064-Center for Research in Transplantation and Immunology, CHU de Nantes, IUN, Nantes, Université de Nantes, Nantes, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Angin
authors.forename: Nicolas
authors.initials: N
authors.lastname: Poirier
authors.forename: Nahzli
authors.initials: N
authors.lastname: Dilek
authors.forename: Caroline
authors.initials: C
authors.lastname: Le Guiner
authors.forename: Alice
authors.initials: A
authors.lastname: Toromanoff
authors.forename: Antoine
authors.initials: A
authors.lastname: Blancher
authors.forename: Yan
authors.initials: Y
authors.lastname: Cherel
authors.forename: Jack-Yves
authors.initials: JY
authors.lastname: Deschamps
authors.forename: Xavier
authors.initials: X
authors.lastname: Tillou
authors.forename: Karine
authors.initials: K
authors.lastname: Renaudin
authors.forename: David
authors.initials: D
authors.lastname: Minault
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hervouet
authors.forename: Gilles
authors.initials: G
authors.lastname: Blancho
authors.forename: Bernard
authors.initials: B
authors.lastname: Vanhove
authors.forename: Ignacio
authors.initials: I
authors.lastname: Anegon
authors.forename: Brigitte
authors.initials: B
authors.lastname: Le Mauff
mesh_terms: D000818:Animals; D019013:CD40 Antigens / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D023201:CD40 Ligand / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control*; D006085:Graft Survival / Q000276:immunology; D006801:Humans; D056724:Immunity, Humoral; D007136:Immunoglobulins / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D016030:Kidney Transplantation / Q000276:immunology*; D008252:Macaca fascicularis; D008297:Male; D023421:Models, Animal; D011993:Recombinant Fusion Proteins / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D014181:Transplantation Immunology; D014184:Transplantation, Homologous
chemical_list: D019013:CD40 Antigens; C499839:CD40Ig protein, recombinant; D007136:Immunoglobulins; D011993:Recombinant Fusion Proteins; D023201:CD40 Ligand