Research Group

  • Dr. Bernard Vanhove, Principal Investigator
  • Dr. Gilles Blancho, Research Associate
  • Mr. David Minault, Research Associate
  • Mrs. Anne-Sophie Dugast, Research Associate
  • Mrs. Thomas Haudebourg, Research Associate
  • Mr. Bernard Martinet, Research Associate

Location

  • ITERT, CHU Hotel Dieu, Nantes, France

Title

  • Immunosuppression and Tolerance Induction by Selective Inhibition of CD28
Targeting CD28 with antagonist monovalent or modulating antibodies blocks T cell activation without preventing the engagement of B7 and CTLA4-dependant negative costimulation signals that are required in vivo for the development of regulatory mechanisms

Targeting CD28 with antagonist monovalent or modulating antibodies blocks T cell activation without preventing the engagement of B7 and CTLA4-dependant negative costimulation signals that are required in vivo for the development of regulatory mechanisms. Therefore antagonizing CD28 should promote tolerance induction. We have verified this hypothesis in rat models of kidney and heart grafts where transplant tolerance depended on the long term on the action of indoleamine 2,3-dioxygenase (IDO)-dependant monocytes and of iNOS-dependant myeloid-derived suppressor cells. The hypothesis was also verified in two pre-clinical models: in cynomolgus monkey heterotopic heart transplantation, CD28 antagonists synergized with calcineurin inhibitors (CNIs) and abrogated the cardiac allograft vasculopathy otherwise observed with CNIs alone. In a baboon kidney allograft model, an induction treatment with CD28 antagonists resulted in the induction of intragraft HO-1, CTL4-4 and IDO and in a quick increase of peripheral CD4+CD25+FoxP3+CD127low Treg cells that reached at one month a nearly 4-fold increase compared with CNI (tacrolimus) monotherapy recipients (4.70.8% of CD4+ T cells vs. 1.20.3%; see Fig. 1 for cell counts). These Tregs appeared even in the presence of CNI and were found to be suppressive at a ratio of 1 Treg for 128 T effectors. At 3 months, recipients presented a specific inhibition of anti-donor alloreactivity and, in contrast to animals that received CNI alone, did not acutely reject their graft after CNI withdrawal. In conclusion, the selective inhibition of CD28 is a form of costimulation blockade that favors the development of regulatory mechanisms in different models of organ transplantation.

Figure 1.

Figure 1

Figure 1. Antagonizing CD28 promotes Treg cell expansion after kidney transplantation. Baboons (P. anubis) were transplanted with MHC-incompatible kidney allografts and were untreated (Control) or received tacrolimus (target 15 ng/ml), a CD28 antagonist called sc28AT (4 mg/kg/day) or both. Treg cells were monitored in blood by FACS analyses.

Publications

  • Dugast AS, Haudebourg T, Coulon F, et al. Myeloid-derived suppressor cells accumulate in kidney allograft tolerance and specifically suppress effector T cell expansion. J Immunol 2008; 180:7898.
  • Guillonneau C, Seveno C, Dugast AS, et al. Anti-CD28 antibodies modify regulatory mechanisms and reinforce tolerance in CD40Ig-treated heart allograft recipients. J Immunol 2007; 179:8164.
  • Poirier N, Mary C, Allain-Launay E, et al. Immunomodulation induced by a CD28 antagonist in kidney allograft baboon recipient. Oral presentation, World Transplant Congress 2008; (Abstract).
  • Poirier N, Mary C, Allain-Launay E, et al. Regulatory cells accumulation in baboon kidney graft recipients treated with antagonist anti-CD28 antibodies. Oral presentation, Nantes Actualités Transplantation 2006; (Abstract).
  • Dugast A-S, Heslan M, Usal C, et al. Specific inhibition of effector T cells by myeloid derived suppressor cells (MDSC) in tolerant recipients of rat kidney allografts. Oral presentation, American Transplant Congress 2008; (Abstract).
  • Dugast A-S, Heslan M, Usal C, et al. Myeloid derived suppressor cells (MDSC) accumulate in tolerant recipients of rat kidney allografts after administration of anti-CD28 antibodies. Oral presentation, FOCIS 2008; (Abstract).
  • Vanhove B, Poirier N. Targeting CD28 with antagonist antibodies for immunomodulation. Oral presentation, New Key Opinion Leader Meeting of the Transplantation Society 2007.Dugast A-S., Heslan M., Usal C, et al. Myeloid suppressor cells in tolerant allograft recipients inhibits effector but not treg cells in a heme oxigenase-1 and iNOS-controlled manner. Oral presentation, European Society of Organ Transplantation 2007; (Abstract).
  • Dugast A-S, Heslan M, Coulon F, et al. Myeloid suppressor cells (MSC) in tolerant allograft recipients inhibits effector but not T reg cells in a heme oxygenase I and iNOS-controlled manner. Oral presentation, American Transplant Congress 2007; (Abstract).
  • Vanhive B, et al. Nouvelles perspectives pour le blocage de la costimulation: les anticorps anti-CD28. Oral presentation, 9th Meeting of the Société de Néphrologie and Société Francophone de Dialyse 2007; (Abstract).
  • Poirier N, Allain-Launay E, Mary C, et al. Blocage sélectif de CD28 en allotransplantation rénale chez le primate non-humain. Oral presentation, 9th Meeting of the Société de Néphrologie and Société francophone de Dialyse 2007; (Abstract).
  • Zhang T, Nguyen BH, Wu G, et al. Efficacy of a novel non-activating anti-CD28 scFv Ab in cynomolgus monkey cardiac allotransplantation. Oral presentation, World Transplant Congress 2006; (Abstract).
  • Dugast AS, Heslan M, Smit H, et al. Accumulation of Myeloid suppressor cells producing nitric oxide in blood of tolerant kidney allograft recipient. Oral presentation, World Transplant Congress 2006; (Abstract).
  • Vanhove B. Targeting CD28 to block, stimulate or kill. Oral presentation, Nantes Actualités Transplantation Nantes 2006; (Abstract).
  • Dugast AS, Heslan M, Smit H, et al. Accumulation of myeloid suppressor cells producing nitric oxide in blood of tolerant kidney allograft recipients. Oral presentation, 17th European Congress of Immunology 2006; (Abstract).