Introduction:

The CD40-CD40L costimulatory pathway plays a crucial role in allograft rejection. Blockade of this pathway by anti-CD40L monoclonal antibody has been shown to prevent rejection of cardiac allografts. The purpose of this study was to determine the effectiveness of anti-CD40L mAb treatment as a method to induce tolerance to peripheral nerve allografts.

Methods:

Sciatic nerve grafts were transplanted from BALB/c mice into a subcutaneous pocket on the back of C57BL/6 mice. One gram of anti-CD40L mAb was then administered intraperitoneally on the day of transplantation, and on postoperative days 1 and 2. The control group received no anti-CD40L mAb. The mice were then allowed to convalesce for either 14 or 28 days. Following recovery, recipient mice were sacrificed and their spleens and brachial lymph nodes were harvested. Splenocytes and brachial node cells were stimulated with donor alloantigens, and subsequent production of interferon (INF)-γ, and interleukins (IL)-5, -4, and –2 were quantified using the ELISPOT technique.

Results:

At fourteen and twenty-eight days post-transplant, splenocytes from anti-CD40L mAb treated allograft recipients produce significantly less INF-γ, IL-4, and IL-2 as compared to untreated control animals (Table 1). Anti-CD40L mAb treatment did not affect IL-5 production at either time-point. In the brachial nodes 14 days post-transplant, cells producing INF- γ were considerably less in the treatment group compared with the untreated group. Similarly, 28 days post-transplant, cells producing INF-γ, IL-5, IL-4, and IL-2 were significantly less in the treatment group.

Discussion:

The tolerance induced by treatment administration on days 0, 1, and 2 persists for at least 24 days after the cessation of the anti-CD40L mAb treatment. These data imply that short-term anti-CD40L treatment at the time of peripheral nerve allografting may increase long-term graft survival through the induction of tolerance.

Table 1