Evaluation of the immunomodulatory mechanisms of photochemotherapy in transplantation

Legitimo, Annalisa; Consolini, Rita; Stefano, Rossella Di; Bencivelli, W.; Calleri, Alberto; Mosca, Franco

doi:10.1016/s0041-1345(01)01985-6

Cited by 8 publications

(9 citation statements)

References 8 publications

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“…An intravenous formulation of 8-MOP, UVADEX, allows for direct addition of the photosensitizing agent to the collected plasma and buffy coat ex vivo prior to UVA exposure. ECP was originally introduced for the treatment of cutaneous T-cell lymphoma by Edelson et al [1]; thereafter it was shown that ECP reduces the incidence of acute and chronic heart rejection [2][3][4] and alloreactive T-cell responses in graft versus host diseases (GvHD) [5]. In heart transplant patients, ECP reduces cardiac rejection episodes, decreases the frequency of cytomegalovirus infections [2], and decreases coronary artery intimal thickness [6].…”

Section: Introductionmentioning

confidence: 99%

Extracorporeal photochemotherapy

Maeda

2009

Journal of Dermatological Science

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Although extracorporeal photochemotherapy (ECP) is reported to be effective for a wide variety of diseases, such as cutaneous T cell lymphoma, autoimmune diseases, organ graft rejection, and graft versus host disease, its mechanism of action remains unclear. The basis of extracorporeal photopheresis is the reinfusion of leukocytes previously exposed to 8-methoxypsoralen (8-MOP) and ultraviolet A radiation. Although only 5-10% of circulating mononuclear cells is treated during one ECP procedure, the treatment has long-lasting immunomodulatory effects. The advantage of photopheresis treatment is the low frequency of side effects related to treatment. The disadvantages, however, are the practical efforts required and the high treatment cost. Recent studies demonstrated that ECP downregulates the immune response and induces tolerance by regulatory T cells. Other studies suggest that the mechanism of ECP also involves the recruitment and involvement of additional immune cells. Although immune tolerance induced by ECP is the most likely mechanism of the clinical efficacy of ECP it is not clear how ECP, both activates tumor immunity against cutaneous T-cell lymphoma and induces tolerance in autoreactive disorders. Further studies are necessary to determine the details of the underlying mechanisms of action.

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Section: Introductionmentioning

confidence: 99%

Extracorporeal photochemotherapy

Maeda

2009

Journal of Dermatological Science

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“…In heart transplantation, ECP prevents chronic rejection (3,4), reduces acute rejection episodes (5), and is associated with an increased number of apoptotic cells infiltrating the transplanted heart (4). In patients with graft-versus-host-disease, ECP reduces alloreactive T-cell responses (6,7); a partial success has also been reported in type 1 diabetes (8) but ECP had no beneficial effect in multiple sclerosis (9).…”

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confidence: 99%

The Immunological Effects of Extracorporeal Photopheresis Unraveled: Induction of Tolerogenic Dendritic Cells In Vitro and Regulatory T Cells In Vivo

Parisi²,

et al. 2005

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Extracorporeal photopheresis (ECP) may represent an alternative to immunosuppression, as a means of reducing rejection after thoracic organ transplantation. The mechanism by which ECP exerts its protective effects has, until now, remained elusive. We analyzed peripheral blood mononuclear cells of four children with chronic heart and lung transplant rejection, who received ECP in addition to conventional immunosuppressive treatment. The effects of ECP were evaluated at each cycle, comparing blood samples from the same patient collected before and after treatment. In vitro, peripheral blood mononuclear cells treated with ECP undergo apoptosis and are phagocytosed by immature dendritic cells, which, in turn, acquire a tolerogenic phenotype. The frequency of T cells, with a regulatory phenotype and strong suppressive activity, was significantly increased in the blood of ECP-treated patients. The immunomodulatory effects of ECP may be explained by its ability to increase the frequency of regulatory T cells with inhibitory action on transplant immune rejection.

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“…We have previously demonstrated that PUVA treatment induced in vitro leukocyte hyporesponsiveness and a decrease in expression of costimulatory and adhesion molecules as well as of cytokine levels; it also induced apoptosis in both mononuclear cells and purified monocytes [9, 10]. …”

Section: Discussionmentioning

confidence: 99%

“…Stromal cells are easily defined in culture, forming the nonhematopoietic adherent cell component, composed of a variety of cell types, from long-term cultures [9]. …”

Section: Methodsmentioning

confidence: 99%

“…The main direct effects of ECP on treated circulating T cells are the consequence of the covalent interaction between DNA and 8-MOP under UVA light [7]. Treated cells become unable to proliferate in vitro and undergo modification of membrane antigenicity and apoptosis after several hours [8,9,10,11]. Recently, it has been demonstrated that ECP acts not only on T cells but also on other cells, such as accessory cells: the collection of peripheral mononuclear cells during ECP procedure may induce an increase in monocyte activation and a conversion of monocytes to dendritic cells [12,13,14,15,16].…”

Section: Introductionmentioning

confidence: 99%

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Assessment of 8-Methoxypsoralen and Ultraviolet A Light Effects on Human Stroma Generation and Function

Legitimo

Consolini

Bencivelli³

et al. 2006

Acta Haematol

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Photopheresis or extracorporeal photochemotherapy (ECP) is a new immunomodulatory therapy in which a patient’s leukocytes are exposed extracorporeally to 8-methoxypsoralen (8-MOP) and ultraviolet A (UVA) light. Although it is used for the treatment of cutaneous T cell lymphoma, graft-versus-host disease, and several autoimmune diseases, with efficacy and safety reported in almost all studies, the mechanisms by which ECP exerts its beneficial effects are still unclear. As cellular targets of this procedure are numerous, we investigated the effects of 8-MOP and UVA light on stromal precursors and mature stromal layers. Human bone marrow stromal cell layers were established in long-term bone marrow culture medium from normal marrow mononuclear cells. Normal marrow mononuclear cells were incubated with 8-MOP and/or exposed to UVA light (PUVA treatment) before culturing. A control without 8-MOP and UVA was also included in the study. Apoptosis induction was evaluated using annexin V following 7 days after PUVA. After 4–6 weeks of culture, stromal layers were examined under a phase-contrast microscope to identify structural differences between PUVA-treated and control stroma. To determine whether PUVA treatment affected stromal regulation of adherent hematopoietic cell survival, mature stromal layers, incubated with 8-MOP and exposed to UVA light, were cocultured with nonadherent mononuclear cells from normal marrow. After 24 h, the percentage of apoptotic hematopoietic cell precursors was quantified by flow cytometry. This study provides evidences that the in vitro exposure of human stromal cell precursors to UVA light, in the presence of 8-MOP, inhibits stromal layer generation by inducing apoptosis, as evidenced by annexin V staining following 7 days of culture. Here, we show an additional cell target for this psoralen following UVA irradiation. However, in a second set of experiments, PUVA treatment did not affect the stromal capacity to support hematopoiesis in culture. Our results can contribute to a better definition of ECP mechanisms of action for future development of experimental designs and clinical applications of this intriguing procedure.

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Evaluation of the immunomodulatory mechanisms of photochemotherapy in transplantation

Cited by 8 publications

References 8 publications

Extracorporeal photochemotherapy

Extracorporeal photochemotherapy

The Immunological Effects of Extracorporeal Photopheresis Unraveled: Induction of Tolerogenic Dendritic Cells In Vitro and Regulatory T Cells In Vivo

Assessment of 8-Methoxypsoralen and Ultraviolet A Light Effects on Human Stroma Generation and Function

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