Antibody to the dendritic cell surface activation antigen CD83 prevents acute graft-versus-host disease

Abstract

Allogeneic (allo) hematopoietic stem cell transplantation is an effective therapy for hematological malignancies but it is limited by acute graft-versus-host disease (GVHD). Dendritic cells (DC) play a major role in the allo T cell stimulation causing GVHD. Current immunosuppressive measures to control GVHD target T cells but compromise posttransplant immunity in the patient, particularly to cytomegalovirus (CMV) and residual malignant cells. We showed that treatment of allo mixed lymphocyte cultures with activated human DC-depleting CD83 antibody suppressed alloproliferation but preserved T cell numbers, including those specific for CMV. We also tested CD83 antibody in the human T cell–dependent peripheral blood mononuclear cell transplanted SCID (hu-SCID) mouse model of GVHD. We showed that this model requires human DC and that CD83 antibody treatment prevented GVHD but, unlike conventional immunosuppressants, did not prevent engraftment of human T cells, including cytotoxic T lymphocytes (CTL) responsive to viruses and malignant cells. Immunization of CD83 antibody-treated hu-SCID mice with irradiated human leukemic cell lines induced allo antileukemic CTL effectors in vivo that lysed 51Cr-labeled leukemic target cells in vitro without further stimulation. Antibodies that target activated DC are a promising new therapeutic approach to the control of GVHD.

Selective, efficient modulation of activated CD4+ αβT cells by the novel humanized antibody GZ-αβTCR targeting human αβTCR

“…This capacity of GZ-αβTCR to discriminate activated versus nonactivated T cells allows us to assume a preferential elimination of naive αβ T cells during the induction phase of GvHD, where naive T cells get primed and activated on host DCs for recognition of recipient immunogens. 42,43 The observed preferential depletion of those T cells that are detrimental in transplant settings directly relates to emerging clinical trials performing CD45RA depletion from the haematopoietic graft to prevent a GvHD. 22,23 This will allow us to significantly reduce the risk of allograft rejection but spare memory T cells, desirable pathogen-reactive immunity, in the patient.…”

New perspectives on the biology of acute GVHD

“…Another potential therapeutic approach to modulate DC tolerance is the development of an antibody to the DC surface maturation antigen CD83; this antibody has been shown to prevent acute GVHD in a humanized mouse model with severe congenital immunodeficiency disorder. 50 Recent experimental observations have also shown that several innate and adaptive immune cellular subsets negatively affect the functions of APCs (Figure 2). For example, (1) gd T cells, which are innate immune cells commonly found in the gastrointestinal (GI) tract and skin.…”

CMRF-56+blood dendritic cells loaded with mRNA induce effective antigen-specific cytotoxic T-lymphocyte responses

“…42 Flow cytometric analysis of inguinal LNs, 6 h after intra-dermal injection of CMRF-56 BDC into the tail base, revealed that migrating human CD45 C cells were exclusively hCMRF-56 BDC and not CD14 C , CD19 C or CD20 C cells (Fig. 4C).…”

“…42,58 One million GM-CSF activated CMRF-56 C cells or cytokine matured Mo-DC were injected intra-dermally into the tail base. Inguinal LN were collected after 6 h, treated with collagenase type III (Worthington Biochemical Corporation, LS004180) as described 35 and migrated BDC quantitated by flow cytometry using CountBright Absolute Counting Beads.…”