Fig. 1

Diagram showing immunological responses to donor PNAs. After about 7 days post-engraftment, donor demyelinated Schwann cells presenting donor antigens via MHCI are recognized by host CD8 T cells within the peripheral nerve allograft segment. Over a period of several weeks, activated CD8 T cells clonally expand and differentiate to produce populations of cytotoxic T lymphocytes (CTLs) when stimulated by IFN-γ, IL-12, and IL-2. CTLs find antigen-bound MHCI molecules on donor cells and then induce donor cell death (shown as red X’s) in donor cells via perforins, granzymes, and FasL. CD4 T cells activated by donor antigens on MHCII on either host or donor antigen-presenting cells differentiate into T helper 1 (Th1) cells and regulatory T cells (Tregs), among other T cell subtypes, depending on whether the CD4 T cells are stimulated by IFN-γ or TGF-β, respectively. Th1 cells secrete cytokines such as IFN-γ, IL-2, and/or TNF-α that stimulate survival and pro-inflammatory activation of CTLs and macrophages. Classically activated M1 macrophages contribute to donor Schwann cell death via release of reactive oxidative species (ROS), phagocytosis, TNF-α, and Antibody-Dependent Cellular Cytotoxicity (ADCC). M1 macrophages augment the activation of Th1 cells and CTLs via IL-12 secretion. Tregs and alternatively activated M2 macrophages secrete the anti-inflammatory cytokine IL-10 which regulates and suppresses pro-inflammatory functions in Th1 cells and CTLs. Fibroblasts produce large amounts of collagen throughout the wound healing process