ORIGINAL ARTICLE Immunosuppressive human anti-CD83 monoclonal antibody depletion of activated dendritic cells in transplantation TA Seldon 1,2 , R Pryor 1 , A Palkova 1 , ML Jones 3 , ND Verma 4,5 , M Findova 1 , K Braet 1 , Y Sheng 1,2 , Y Fan 6 , EY Zhou 6 , JD Marks 6 , T Munro 3 , SM Mahler 3 , RT Barnard 7 , PD Fromm 4,5 , PA Silveira 4,5 , Z Elgundi 4,5 , X Ju 4,5 , GJ Clark 1,2,4,5 , KF Bradstock 4,5 , DJ Munster 1,2,8 and DNJ Hart 1,2,3,4,5,8 Current immunosuppressive/anti-inflammatory agents target the responding effector arm of the immune response and their nonspecific action increases the risk of infection and malignancy. These effects impact on their use in allogeneic haematopoietic cell transplantation and other forms of transplantation. Interventions that target activated dendritic cells (DCs) have the potential to suppress the induction of undesired immune responses (for example, graft versus host disease (GVHD) or transplant rejection) and to leave protective T-cell immune responses intact (for example, cytomegalovirus (CMV) immunity). We developed a human IgG 1 monoclonal antibody (mAb), 3C12, specific for CD83, which is expressed on activated but not resting DC. The 3C12 mAb and an affinity improved version, 3C12C, depleted CD83 + cells by CD16 + NK cell-mediated antibody-dependent cellular cytotoxicity, and inhibited allogeneic T-cell proliferation in vitro. A single dose of 3C12C prevented human peripheral blood mononuclear cell- induced acute GVHD in SCID mouse recipients. The mAb 3C12C depleted CMRF-44 + CD83 bright activated DC but spared CD83 dim/- DC in vivo. It reduced human T-cell activation in vivo and maintained the proportion of CD4 + FoxP3 + CD25 + Treg cells and also viral- specific CD8 + T cells. The anti-CD83 mAb, 3C12C, merits further evaluation as a new immunosuppressive agent in transplantation. Leukemia advance online publication, 2 October 2015; doi:10.1038/leu.2015.231 INTRODUCTION Current immunosuppressive/anti-inflammatory agents target the immune response at the cellular level (T and B cells) or attempt to block cytokines and other mediators. Advances in solid organ transplantation and allogeneic haematopoietic cell transplantation (alloHCT), as well as some autoimmune and chronic inflammatory diseases, have depended on azathioprine, cyclophosphamide, methotrexate, cyclosporine, sirolimus, tacrolimus, mycophenolate mofetil and corticosteroids. However, their use is limited not only by specific side effects, but also the fact that their nonspecific immunosuppressive action increases the risk of infections and cancer. More recently, monoclonal antibodies (mAbs) and other biological agents targeting co-stimulatory molecules (for example, the CD80/86-CD28/CD152 (CTLA-4) and CD40-CD40L pathways) and cytokines (for example, anti-IL-2 agents in transplantation and anti-tumour necrosis factor agents in rheumatoid arthritis) have been used as nonspecific immunosuppressive agents. Various mAb targeting effector T-cell populations, notably the anti-CD52 agent, alemtuzumab, control immune responses very effectively, but their nonspecific immunosuppressive action is a major risk for infection and cancer. 1,2 Dendritic cells (DCs) and other antigen-presenting cells (APC) initiate, direct and maintain the immune response. Early work in solid organ transplantation demonstrated the donor DC direct and the recipient DC indirect presentation of donor allo-antigens 3,4 and recipient DCs present membrane exchange-derived donor major histocompatibility complex antigens by trogocytosis or cross-dressing. 5 Clinically, acute and chronic rejection remains a major limitation to organ/tissue transplantation. The morbidity and mortality of infections induced by nonspecific immunosup- pression is well documented 6 and as the transplanted patient population rises, the major burden of secondary cancers has been highlighted. 7 Recipient and donor DCs have been implicated in causing graft versus host disease (GVHD) after alloHCT, although other APC may be involved. 8–10 It is noteworthy that activation induces changes in DC populations and the resulting biomarker expression profiles can predict acute GVHD in alloHCT patients. 11 Acute GVHD limits the wider application of alloHCT because the immunosuppression to control it not only increases infections but also, crucially, contributes to disease relapse by compromising the graft versus tumour response. The now common occurrence of Epstein–Barr virus-induced post-transplant lymphoproliferative disease/lymphoma after solid organ transplantation and alloHCT emphasizes the clinical need for more specific immunosuppression. 7 Interventions that target DC may prevent the induction of an undesired immune response, but importantly, leave pre-existing protective T-cell immune responses intact. Furthermore, prophy- lactic targeting of DC may suppress the immune system before the amplification of pathogenic effectors. DC are divided into functional subsets 12 and resting DCs have a regulatory role to prevent autologous T-cell-mediated autoimmune damage. 13 1 DC Program, Mater Medical Research Institute, Brisbane, Queensland, Australia; 2 Co-operative Research Centre for Biomarker Translation, Melbourne, Victoria, Australia; 3 Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Queensland, Australia; 4 Dendritic Cell Research, ANZAC Research Institute, Concord, New South Wales, Australia; 5 University of Sydney, Sydney, New South Wales, Australia; 6 Anesthesia, Helen Diller Family Comprehensive Cancer Centre, University of California, San Francisco, CA, USA and 7 School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, Australia. Correspondence: Professor DNJ Hart, Dendritic Cell Research, ANZAC Research Institute, Gate 3, Hospital Road, Concord, NSW 2139, Australia. E-mail: derek.hart@sydney.edu.au 8 These authors contributed equally to this work. Received 21 July 2015; accepted 27 July 2015; accepted article preview online 19 August 2015 Leukemia (2015), 1 – 9 © 2015 Macmillan Publishers Limited All rights reserved 0887-6924/15 www.nature.com/leu