Pro‐tolerogenic effects of photodynamic therapy with TH9402 on dendritic cells

Abstract

A major goal in transplantation immunology is to develop strategies that can specifically promote tolerance to foreign cells and tissues without compromising other immune functions. Experimental induction of transplantation tolerance by dendritic cells (DCs) and/or T regulatory (Treg) cells can efficiently prevent graft-versus-host disease and organ graft rejection in animal models, and there is much hope that similar strategies in transplanted patients will provide an alternative to immunosuppression. Photodynamic therapy (PDT) is a therapeutic treatment for graft versus host disease and organ rejection that may operate via induction of tolerance. We investigated whether a new PDT therapy, based on exposure of cells to 4,5-dibromorhodamine methyl ester (TH9402), may operate via induction of tolerogenic DC. We developed an in vitro model to mimic the in vivo effect of re-infusing peripheral blood mononuclear cells (PBMCs) treated with PDT based on TH9402 (TH-PDT). TH-PDT-treated PBMCs were co-cultured with allogeneic immature monocyte-derived DCs. After 24 h, the phenotype and T-cell stimulatory capacity of the DCs was assessed. Following phagocytosis of TH-PDT PBMCs, DCs maintained an immature phenotype, produced significantly increased amounts of interleukin-10, and had a reduced allostimulatory capacity in comparison to mature DCs. In the context of transplantation, these data suggest that repeated exposure of circulating DCs to TH-PDT PBMCs may result in presentation of alloantigens under anti-inflammatory conditions and induction of antigen-specific tolerance.

CD4+ T‐regulatory cells: toward therapy for human diseases

“…Increased levels of tolerogenic DCs and Tregs could then suppress inflammation and result in the welldocumented clinical improvement in GVHD. In support of this hypothesis, activated DCs produce reduced levels of proinflammatory cytokines, such as IL-12, and increased levels of suppressive cytokines such as IL-10 and TGF-b upon in vitro exposure to ECP-treated cells (185,186). Moreover, infusion of ECP-treated cells inhibits the immune response in a murine model of contact hypersensitivity (184).…”

Dye Sensitizers for Photodynamic Therapy

“…The presence of halogen atoms increases the efficiency of intersystem crossing to the triplet state and yields singlet oxygen. This sensitizer has been evaluated for PDT treatment of graft-versus-host disease and it destroys lymphocytes via apoptosis [86,87]. It has also entered clinical trials involving allogeneic stem cell transplantation [9].…”

The immunosuppressive side of PDT

“…64 The resulting inhibition of complex I function induces the production of ROS from the mitochondria, which oxidizes a key cysteine residue in HMGB1, neutralizing its ability to promote immune responses. 51 It is therefore entirely possible that the abundance of different ROS during PDT may act in the same manner on HMGB1 and on occasion induce tolerance.…”