Blockade of CD40-CD154 costimulatory pathway promotes survival of allogeneic corneal transplants

PURPOSE. To determine the effect of systemic anti-CD154 monoclonal antibody on the survival of orthotopic murine corneal transplants. METHODS. BALB/c mice were used as recipients of syngeneic, multiple minor h istocompatability (H)- disparate, or major trans-tocompatibility complex MH C-mismatched corneal transplants. Recipient beds were either avascular (nor mal risk) or neovascularized (high risk).,Mice were randomized to receive e ither anti-CD154 antibody or control immunoglobulin by intraperitoneal inje ction at surgery and once weekly after surgery. After orthotopic corneal tr ansplantation, all grafts were evaluated for signs of rejection by slit lam p biomicroscopy over 8 weeks. The high-risk transplants were continuously o bserved until week 18 after the therapy was discontinued at week 8. Allospe cific delayed-type hypersensitivity (DTH) was evaluated after transplantati on in high-risk graft recipients. Frequency of interferon (IFN)-gamma -secr eting T cells in the hosts was measured by enzyme-linked immunospot (ELISPO T) assay. RESULTS. In normal-risk transplantation, the 8-week survival rate improved from 25% in control mice to 88% in anti-CD154-treated hosts of minor ii-dis parate grafts (P = 0.0087) and from 78% in control mice to 100% in anti-CD1 54-treated recipients of MHC-mismatched transplants (P = 0.177). Of particu lar significance, in high-risk transplantation, anti-CD154 therapy dramatic ally enhanced the survival of both minor Hand MHC-disparate corneal transpl ants to 100% (P = 0.0001) and 92% (P = 0.0002), respectively. In addition, the anti-CD154-treated mice did not exhibit allospecific immunity. However, termination of anti-CD154 led to some loss in graft survival, especially a mong high-risk minor H-disparate grafts. The frequency of IFN-gamma -produc ing T cells was significantly reduced in anti-CD154-treated hosts. CONCLUSIONS. Continuous suppression of the CD-40-CD154 costimulator); pathw ay promotes the acceptance of corneal transplants, regardless of the degree of allodisparity or preoperative risk. The beneficial effect of anti-CD154 treatment may be due in part to inhibition of Th1-mediated responses.