Dendritic cells get VIP treatment

Comment on Fujita et al, page 3656, Gonzalez-Rey et al, page 3632, and Chorny et al, page 3787

Three manuscripts in this issue of Blood describe induction of immune tolerance by dendritic cells (DCs) generated in vitro in the presence of vasoactive intestinal polypeptide (VIP) or IL-10 and highlight the role of tolerogenic DCs in limiting the inflammation that follows activation of the immune system after allogeneic transplantation or sepsis.

Previously, the group led by Delgado had established that vasoactive intestinal polypeptide (VIP) exposure generates a population of tolerogenic murine dendritic cells (DCs) that express lower levels of costimulatory molecules and secrete high levels of IL-10 in contrast to DCs generated in the absence of VIP.¹  A new paper by Chorny and colleagues describes the ability of tolerogenic DCs generated in vitro by a short exposure to VIP (followed by activation with LPS) to suppress lethal graft-versus-host disease (GVHD) in a major MHC-mismatched model of murine bone marrow transplantation (BMT). To protect against GVHD, VIP-induced DCs had to be given at the same time as or shortly after bone marrow transplantation (BMT), and recipients of VIP-induced DCs had higher levels of T_reg cells. The VIP-induced DCs also efficiently generated CD4⁺ and CD8⁺ donor T_reg cells ex vivo that, when transplanted into MHC-mismatched transplant recipients, suppressed lethal GVHD (see figure). Strikingly, CD8⁺ T-cell–mediated graft-versus-leukemia activity was retained in recipients of VIP-induced tolerogenic DCs or T_reg cells, indicating that this approach did not globally suppress donor immunity. The study by Gonzalez-Rey and colleagues extends these observations to human DCs and demonstrates that VIP-stimulated DCs derived from CD14⁺ monocytes could generate CD4⁺ and CD8⁺ T_reg-cell populations that suppressed the proliferation of autologous T cells in an antigen-specific manner via local secretion of IL-10 and TGF-β and expression of CTLA4. The report by Fujita and colleagues describes the generation of regulatory DCs from murine BM cells cultured with IL-10 and human transforming growth factor beta and then activated with LPS. These regulatory DCs produced fewer proinflammatory cytokines, synthesized large amounts of IL-10, and, when transferred into mice with bacterial peritonitis or LPS-induced endotoxemia, protected the mice from early death.FIG1 

These provocative studies reaffirm the important counterregulatory role of DCs in limiting immune activation and suggest new lines of research to facilitate translation of these findings into new therapies. For both the VIP-induced and IL-10–induced DCs, the signaling mechanism for the generation of tolerogenic DCs was adenylate cyclase activity, suggesting potential pharmacologic approaches that might be used to alter the generation of these cells in vivo. Translating these findings into routine clinical practice will involve determining whether VIP or IL-10 can be targeted to dendritic cell precursors at the tissue sites in which GVHD, organ allograft rejection, or autoimmune diseases are initiated. The possibility that oral VIP (or a protease-resistant mimetic) could influence the regulatory properties of DCs in the Peyer patch, intestinal lamina propria, or mesenteric lymph nodes suggests that such an approach could have applications in the treatment of inflammatory bowel disease. We look forward to the day when the millions of patients who suffer from autoimmune disease, complications from allogeneic hematopoietic cell transplantation or organ allografts, or sepsis are able to receive “VIP treatment.” ▪