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Stem cell transplantation

Immunosuppressive human anti-CD83 monoclonal antibody depletion of activated dendritic cells in transplantation

Leukemia volume 30, pages 692–700 (2016)Cite this article

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Abstract

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 IgG1 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+CD83bright activated DC but spared CD83dim/- 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.

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Acknowledgements

This work was supported by National Health and Medical Research Council (NHMRC) Project Grant 434513, NHMRC Program Grant 543727, NHMRC Fellowship 1025666, the Leukaemia Foundation of Australia, the Co-operative Research Centre for Biomarker Translation and a National Collaborative Research Infrastructure Strategy 2013 grant.

Author contributions

TAS performed 3C12C affinity maturation with help and advice from YS, YF, EYZ and JDM and contributed to experiment planning, data analysis and writing the manuscript. RP and AP undertook the xeno-transplant GVHD experiments and antibody purification and characterization. MLJ performed phage display to isolate 3C12 with help from YS and TAS, and along with TM and SMM designed and prepared constructs and expressed recombinant CD83 and the IgG1 and IgG4 3C12C mAbs. MF and KB designed, prepared constructs and established the CD83 transfected BB88 cell lines. Xeno-transplant experiments for subsequent cellular analysis and some in vitro experiments were performed by NDV, PDF, PAS, ZE and XJ with GJC planning and reviewing data with KFB who also reviewed the manuscript. DNJH and DJM conceived and managed the project, planned experiments, analyzed data and co-wrote the manuscript. DNJH and DJM obtained funding and supervised students with RTB who also reviewed the manuscript.

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Author notes

  1. D J Munster and D N J Hart: These authors contributed equally to this work.

Authors and Affiliations

  1. DC Program, Mater Medical Research Institute, Brisbane, Queensland, , Australia

    T A Seldon, R Pryor, A Palkova, M Findova, K Braet, Y Sheng, G J Clark, D J Munster & D N J Hart

  2. Co-operative Research Centre for Biomarker Translation, Melbourne, Victoria, , Australia

    T A Seldon, Y Sheng, G J Clark, D J Munster & D N J Hart

  3. Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Queensland, , Australia

    M L Jones, T Munro, S M Mahler & D N J Hart

  4. Dendritic Cell Research, ANZAC Research Institute, Concord, New South Wales, , Australia

    N D Verma, P D Fromm, P A Silveira, Z Elgundi, X Ju, G J Clark, K F Bradstock & D N J Hart

  5. University of Sydney, Sydney, New South Wales, Australia

    N D Verma, P D Fromm, P A Silveira, Z Elgundi, X Ju, G J Clark, K F Bradstock & D N J Hart

  6. Anesthesia, Helen Diller Family Comprehensive Cancer Centre, University of California, San Francisco, CA, , USA

    Y Fan, E Y Zhou & J D Marks

  7. School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, , Australia

    R T Barnard

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  1. T A Seldon
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Correspondence to D N J Hart.

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Competing interests

The Co-operative Research Centre for Biomarker Translation provided research support and has the rights to commercialize 3C12C. All the authors were involved in institutional or associated company (Transbio Ltd, AbCell Therapeutics Pty Ltd, Acyte Biotech, Merrimack Pharmaceuticals, Patheon Biologics) incentive schemes.

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Seldon, T., Pryor, R., Palkova, A. et al. Immunosuppressive human anti-CD83 monoclonal antibody depletion of activated dendritic cells in transplantation. Leukemia 30, 692–700 (2016). https://doi.org/10.1038/leu.2015.231

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