Dendritic Cell Activation in Allogeneic Haematopoietic Cell Transplantation: A Promising Target for Diagnosis and Therapy

Acute and chronic graft versus host disease (GVHD) are major limiting factors for the success of allogeneic hematopoietic cell transplantation (alloHCT) as curative therapy for haematological malignancies. Though the occurrence of GVHD is controlled in part by non-specific T cell directed immunosuppression, this contributes to disease relapse and increased risk of infections. Dendritic cells (DC) direct immune responses and reinforce regulatory mechanisms. Targeting DC activation as a novel immunosuppressive strategy may limit the generation of deleterious T cell responses and preserve regulatory T cell responses, whilst preserving T cell responses to leukemia and pathogens. We have shown that presence of activated CMRF-44⁺CD11c⁺ DC predicts for acute GVHD after clinical alloHCT (Transplantation 2007;83:839).  This may reflect systemic activation of blood DC or their migration after activation. Our recent data associating CCR5 expression on CD16⁺ DC with clinical acute GVHD (submitted) supports the latter concept. Such observations may enable earlier intervention with current agents or potentially new mAb targeting activated DC. Mice with human PBMC xenograft undergoing early graft versus host disease events have CMRF-44⁺CD11c⁺ DC. We have shown efficacy of an anti-human CD83 antibody in preventing xenogenic GVHD but preserving protective anti viral and leukemic responses (J Exp Med 2009;206:387). Similar efficacy of anti CD83 antibody in mouse alloHCT was reported recently (BMT 2011;46 Suppl:P837).  Our ongoing studies focus on human DC subpopulations in clinical alloHCT.  We have now identified activated CMRF-44⁺ DC in chronic GVHD and shown that they decline with effective extracorporeal photochemotherapy. This justifies the extended evaluation of new human anti CD83 mAb and new CMRF-44 like mAb being developed in our laboratory as potential new immunosuppressive agents. Current studies confirm their ability to inhibit human immune responses in vitro and in vivo and we plan to test these new anti-DC therapeutics in Phase 1 studies in alloHCT.