Aims: CD83 is an important surface marker of activated dendritic cells (DC). As such, it is an attractive target for novel immunosuppressive strategies using antibodies to deplete activated DC after transplantation, whilst preserving potentially tolerogenic CD83lo or CD83- DC (Wilson et al J Exp Med 2009;206:387). The human monoclonal antibody (mAb) 3C12C to CD83 (J Immunol Methods 2010;354:85, Seldon et al, in prep) is being evaluated further as a potential therapeutic for preventing graft versus host disease (GVHD), after an allogeneic haematopoietic cell transplant (alloHCT). We report on the ability of 3C12C to target activated human DC in vitro and in vivo using the human xenogeneic SCID mouse model of GVHD.
Methods: 3C12C or control human IgG1 (trastuzumab) mAb were added to human PBMC cultures for in vitro experiments. 3C12C or control mAb were administered on the day of human PBMC transplant into SCID mice conditioned with low dose irradiation and anti-asialoGM antibody on d-1 prior to transplant. Human DC and T cell numbers and activation was examined by flow cytometry and immunohistochemistry. T cell responses were analysed and clinical GVHD occurrence scored.
Results: 3C12C mAb depleted DC in autologous and allogeneic mixed lymphocyte cultures, reduced T cell proliferation and, importantly, preserved virus specific T cells. Mice receiving control mAb developed GVHD on d+8-13 and human cells had infiltrated the host mouse tissues (liver, lung, spleen and gut). Human DC were activated by d+2, expressing the CMRF-44 activation marker, plus CD83, CD80 and CD86. Treatment with 3C12CmAb eliminated CD83+ CMRF44+ DC early post-transplant and reduced the T cell activation profile but preserved Treg cells. GVHD was delayed.
Conclusion: Previous data indicates that activated CMRF-44+ DC predict for acute GVHD after clinical alloHCT. The novel human anti-CD83 mAb, 3C12C, targets activated human DC, preventing preclinical GVHD, whilst preserving potentially protective, post-transplant T cell responses.