Prolonged allograft survival but no tolerance induction by modulating CD28antibody JJ319 after high-responder rat heart transplantation

Background. Allograft rejection depends on T cell immune responses requirin g antigen recognition and costimulatory signals through accessory T cell re ceptors, including CD28. Inhibition of CD28 signaling with a CTLA-4-immunog lobulin (Ig) fusion protein has resulted in immunosuppression and occasiona l T cell anergy in mouse transplant models, but not in rats. Because this a pproach also inhibits a potentially tolerizing signal through CTLA-4, selec tive blockade of CD28 ligation might induce more profound immunosuppression and transplant tolerance. Methods. The effects of escalating doses of the rat CD28 monoclonal antibod y JJ319 on allograft survival were studied after vascularized heterotopic h eart transplantation in a high responder strain combination (DA to Lewis). CD28 antigen modulation and circulating antibody levels were monitored by f low cytometry, Results. CD28 antibody JJ319 markedly prolonged cardiac graft survival comp ared with untreated controls (7 days, range: 6-8). A strictly dose-dependen t increase in median graft survival time was demonstrated with a maximum of 36 days (range: 30-40; p < 0.001) after the administration of 8 x 1 mg JJ3 19 i.p, (days -1 to +6 before/after transplantation). However, indefinite g raft survival and tolerance could not be induced by JJ319 treatment. At the maximal dose, flow cytometry showed complete down modulation of the CD28 r eceptor for 10-14 days without T cell depletion in close temporal relation to antibody presence in serum. In vitro, CD28-modulated T cells showed sign ificantly reduced responses to activation. Conclusions. CD28 antibody JJ319 induces profound immunosuppression after r at heart transplantation, however without development of transplant toleran ce. The underlying mechanism seems to be receptor modulation during primary alloantigen recognition. While still potentially applicable clinically, th ere are no qualitative or quantitative differences to the treatment with CT LA-4/lg or the blockade of CD2 or LFA-1, as reported elsewhere, Thus, a CD2 8-modulating approach seems not to allow therapeutic exploitation of a tole rizing signal delivered by CTLA-4 but may still be clinically applicable, e specially in combined immune interventions.