Introduction: Tissue specific tolerance has been the goal of transplantation for many years. Anti-CD40L monoclonal antibody (anti-CD40LmAb) has been shown in previous studies to induce a hyporesponsive state to peripheral nerve allografts. However, it has not been determined if this hyporesponsiveness is persistent and tissue specific.

Methods: Sciatic nerve allografts were performed from Balb/c donor mice into C57BL/6 recipients. 1mg of anti-CD40LmAb was given to the recipient mice as an intra-peritoneal injection immediately post-op and on post-op days 1 and 2. After a 60 day recovery period, the mice were re-challenged with either nerve allograft, cardiac allograft, or nerve isograft . Sciatic nerve allografts were also performed from Balb/c mice into C57BL/6 recipients without anti-CD40L mAb as positive controls followed by a 60 day recovery period without tissue rechallenge.. After recovery, all mice were sacrificed and their spleens were harvested. Rejection was assessed by stimulating the recipient splenocytes with donor alloantigens and measuring the production of interferon gamma (INF- gamma), and interleukins (IL) -2, -4, and -5.

Results: Nerve allograft re-challenge at 60 days produced low cytokine levels in mice treated with anti-CD40LmAb compared to untreated controls (see table). These levels were comparable to nerve isograft cytokine production. Cardiac allograft challenge at 60 days however, produced significantly higher cytokine levels that were similar to untreated controls.

Conclusions: Consistent with previous studies, anti-CD40LmAb induces a hyporesponsive state to peripheral nerve allografts as seen by the lack of significant cytokine production with nerve allograft re-challenge at 60 days. In fact the response by nerve allografting was similar to that of nerve isografting.  However, our study shows that this hyporesponsiveness is tissue specific since cardiac allograft challenge at 60 days produced significantly higher cytokine levels that were similar to control mice not receiving anti-CD40LmAb. Thus, anti-CD40LmAb treatment appears to induce tissue specific tolerance in peripheral nerve allograft recipients.

Anti-CD40L Monoclonal Antibody Induces Tissue Specific Tolerance