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

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(+)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.

Pharmacological blockade of the CD39/CD73 pathway but not adenosine receptors augments disease in a humanized mouse model of graft‐versus‐host disease

“…Previous studies have shown that NSG mice engraft human monocytes and DCs when injected with human cord blood, 38 and engraft human monocytes when injected with hPBMCs. 39,40 Similarly, SCID mice injected with hPBMCs engraft human DCs, 41 but the current study is the first to demonstrate DC engraftment in NSG mice injected with hPBMCs. Human T cells recognize murine major histocompatibility complex I and II molecules in NSG mice to cause GVHD, 27 but the identity of the APCs involved remains to be determined.…”

A Kinetic Study of CD83 Reveals an Upregulation and Higher Production of sCD83 in Lymphocytes from Pregnant Mice

“…By targeting activated DCs, anti-CD83 depleting antibodies can prevent human peripheral blood mononuclear cell-induced acute graft vs. host disease in SCID mouse recipients (30, 31). Although the mechanisms through which membrane-bound CD83 regulates immune responses are still to be elucidated, one of the proposed pathways is though negative regulation of MARCH1 and MARCH8.…”

Alloantigen presentation and graft-versus-host disease: fuel for the fire

“…Antibodies with activity against molecules that are expressed on activated cells, including DCs, 98 may be effective if they can be administered in the right window after SCT when donor DCs are active and recipient DCs have been eliminated. Of note, because donor APCs are likely crucial for the generation of pathogen-specific immunity, targeting donor DC or APC subsets will need to be studied with caution in the clinic.…”