- 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
- ITERT, CHU Hotel Dieu, Nantes, France
- Immunosuppression and Tolerance Induction by Selective Inhibition of CD28
Manipulation of immune responses in rodents can lead to the induction of regulatory mechanisms sustaining tolerance in transplantation, i.e., acceptance of allogenic grafts without pharmacological immunosuppression. Induction of tolerance in primates and in humans, however, is still the focus of intense investigations. T cell costimulation blockade is an immunosuppressive strategy that has been considered for more than a decade and now has several applications in the clinic. One of the most explored costimulation systems is that involving the CD28/B7/CTLA-4 receptors, where CD28 and CTLA-4 on T cells interact with B7 molecules on antigen-presenting cells.
While it has been known for a very long time that CD28/B7 interactions promote T cell activation, it is more recently that we understood that CTLA-4/B7 interactions are implicated in the extinction of immune responses and in the maintenance of immune tolerance. Thereafter, it became obvious that an agent that would selectively block CD28 and not CTLA-4 may be very adaptive to maneuvers aimed at inducing tolerance.
Inhibition of the CD28 receptor, however, is hard to achieve experimentally. Due to the dimeric nature of this receptor, most dimeric antibodies used to block CD28/B7 interactions actually stimulate rather than inhibit T cell activation. The use of monovalent antibody fragments or of a modulating antibody, however, demonstrated that CD28 inhibition could indeed induce transplant tolerance and reverse ongoing autoimmune diseases in rodents. In our laboratory, we have identified and are currently characterizing mechanisms sustaining anti-CD28 induced tolerance in kidney grafts in the rat, that are different from those previously described in mice. In parallel, we have developed a monovalent recombinant inhibitor of primate/human CD28 to investigate its action in the pre-clinical model of baboon kidney allotransplantation.