Extracorporeal photochemotherapy induces apoptosis of infiltrating lymphoid cells in patients with mycosis fungoides in early stages. A quantitative histological study

Abstract

Extracorporeal photochemotherapy (ExP) is a well-tolerated new form of chemoimmunotherapy, which is considered to be effective for cutaneous T-cell lymphoma (CTCL) and the treatment of choice for Sézary syndrome. Improvements have also been seen in patients with non-erythrodermic mycosis fungoides (MF) in the early stages, even when tumour cells are not detectable in the peripheral blood. In this study, we used ExP as a monotherapy in seven patients who had early stage (Ib) MF, and who were no longer responsive to or had contraindications for other therapies. We observed a clinical improvement in the disease after 12 months of treatment: one patient showed a complete response, five a partial response, and one remained stable. In each patient we compared skin biopsies of large plaque lesions before and after the treatment. We undertook a histological evaluation of the infiltrate. The lymphoid cell proliferation and death rates were quantified using the following parameters; lymphoid cell density (LCD), Ki67 + lymphoid cell nuclei percentage (Ki67 + Lcn percentage), and apoptotic index (AI). Significant decreases in the lymphoid cell infiltrate and in cell proliferation, and a significant increase in AI were observed after therapy. The mean LCD decreased from 187 +/- 33 to 34 +/- 17.7, Ki67 + Lcn mean percentage decreased from 16.9 +/- 3.9 to 4.9 +/- 2.4, and the AI mean value increased from 0.05 +/- 0.03 to 2.41 +/- 1.54. Our results suggest a role for apoptosis in the improvement of the skin lesions and are in line with some reports on the mode of action of ExP. Although the way in which ExP works needs to be clarified further, it does seem to stimulate a CD8+ cell-mediated anticlonotypic activity against circulating pathogenic clones. Furthermore, a release of tumour necrosis factor alpha (TNF-alpha) by circulating monocytes has been demonstrated after ExP. Both are known to induce cell death by apoptosis.

Mycosis fungoides – a review of the management of 28 patients and of the recent literature

“…The lymphocytes are then irradiated with UVA and subsequently transferred back to the patient. The mode of action is unclear, but it is suggested that 8‐methoxypsoralen (8‐MOP) forms covalent photoadducts with the nuclear DNA, thereby affecting the antigenicity and immunogenicity of the neoplastic cells which have been exposed to UVA 44 . These antigenetically altered lymphocytes are then felt to stimulate the host's immune system, mediated by CD8+ lymphocytes that target the malignant clone 45 .…”

GVHD: Complication and Challenge to Successful Allogeneic Hematopoietic Cell Transplantation

“…Pheresis and treatment of patient leukocytes with a photo-sensitizing compound (ex, methoxypsoralen) followed by UVA exposure to delete reactive cells and re-infusion has shown promise in some HCT transplants [224][225][226]. The mechanisms involved in the ECP therapy are not understood but may include apoptosis, modulation of CD8, NK as well as antigen presenting cell activity [227][228][229][230][231]. The potential to selectively delete reactive cells in situ, for example, in the skin during cutaneous GVHD by exposure to some level of UVA may also show promise [232,233].…”

Immunbiologische Effekte der extrakorporalen Photopherese

“…B. die Translokation von Phosphatidylseringruppen von der inneren zur äuûeren Zellmembranseite, Veränderungen der Chromatintextur mit Hilfe von DNA-bindenden Farbstoffen und eine intrazelluläre Verringerung des pHWertes am Tag 2 der ECP-Behandlung, konnte in dieser Untersuchung nachgewiesen werden. Auch eine Reihe von weiteren Untersuchungen konnten die ECP-Effekte bestätigen; ApoptoseMarker steigen nach 24 Stunden und nach 48 Stunden signifikant an und auch in Hautläsionen von CTCL-Patienten zeigt sich Apoptose von Lymphozyten [26]. Osella-Abate u. Mitarb.…”