Costimulation blockade inhibits the indirect pathway of allorecognition in nerve allograft rejection.

Nerve allografts provide a temporary scaffold for host nerve regeneration. The need for systemic immunosuppression limits clinical application. Characterization of the immunological mechanisms that induce immune hyporesponsiveness may provide a basis for optimizing immunomodulating regimens. We utilized wild-type and MHC class II-deficient mice, as both recipients and donors. Host treatment consisted of triple costimulatory blockade. Quantitative assessment was made at 3 weeks using nerve histomorphometry, and muscle testing was performed on a subset of animals at 7 weeks. Nerve allograft rejection occurred as long as either the direct or indirect pathways were functional. Indirect antigen presentation appeared to be more important. Nerve allograft rejection occurs in the absence of a normal direct or indirect immune response but may be more dependent on indirect allorecognition. The indirect pathway is required to induce costimulatory blockade immune hyporesponsiveness.