ABSTRACT
Photodynamic therapy (PDT) is frequently accompanied by induction of systemic immunosuppression. Photochemical mechanisms underlying this effect are not completely understood. Here, we demonstrate the immunosuppressive activity of photooxidation products of protoporphyrin IX dimethyl ester (PPIX) in a murine model of contact hypersensitivity (CHS) to 2,4-dinitrofluorobenzene (DNFB). Intravenous injection of the preirradiated solution of PPIX to mice resulted in fluence-dependent suppression of the CHS. The samples of photodecomposed PPIX with suppressive effect on the CHS contained chlorin-type products, namely, two isomers of photoprotoporphyrin (pPP1 and pPP2) as main photoproducts. Concentration-dependent suppression of the CHS was also induced when purified pPP1 or pPP2 were injected to mice intravenously. These purified photoproducts exerted equal immunosuppressive activity. The highest suppression of the CHS was induced when pPP1 was injected 20 h before sensitization with DNFB. The lowest suppression was at its injection time 24 h before challenge. The pPP1-induced suppression of the CHS was adoptively transferable and was associated with generation of cells with suppressive functions. These suppressor cells inhibited the efferent phase of the CHS. Our results strongly indicate that induction of systemic immunosuppression by PDT with PPIX may proceed through photobleaching of photosensitizer and generation of photoprotoporphyrins, which can affect T cell immunity.
Subject(s)
Dermatitis, Contact/immunology , Dermatitis, Contact/prevention & control , Immunosuppression Therapy/methods , Protoporphyrins/pharmacology , Adoptive Transfer , Animals , Immunosuppressive Agents/chemistry , Immunosuppressive Agents/pharmacology , Male , Mice , Oxidation-Reduction , Photochemistry , Photosensitizing Agents/chemistry , Photosensitizing Agents/pharmacology , Porphyrins/chemistry , Porphyrins/pharmacology , Protoporphyrins/chemistry , Protoporphyrins/radiation effects , T-Lymphocytes/immunology , Time FactorsABSTRACT
Photodynamic therapy is frequently accompanied by the induction of immunosuppression. The photochemical mechanisms behind the induction of this immunosuppression are not clear. The purpose of this study was to evaluate the potential of photoproducts of merocyanine 540 (MC540), protoporphyrin IX (PPIX) and hematoporphyrin derivative (HpD) to cause modulation (suppression/activation) of the T cell immune response in vivo. The approach that we have adopted is the pre-irradiation of a photosensitizer solution with the subsequent application of the products of photosensitizer photodegradation in animals. In this approach the photochemical mechanisms of type I and II are not involved in the photosensitized modification of biological targets in vivo. Using the model of delayed type hypersensitivity (DTH) reaction to sheep red blood cells in mice, we have demonstrated that the photoproducts of three essentially different photosensitizers affect T-cell immunity. The HpD photoproducts had a suppressive effect on the DTH, while products of PPIX photodegradation enhanced the DTH nearly twice. Pre-irradiated MC540 strongly modulated the DTH response, i.e. the DTH was enhanced at low doses and inhibited at higher doses. Our results strongly indicate that at least part of the photodynamic therapy-induced immunomodulation may occur via the photobleaching of photosensitizers accompanied by the generation of photoproducts, which can affect T cell immunity.
