Mechanisms of lymphocytotoxicity induced by extracorporeal photochemotherapy for cutaneous T cell lymphoma.

Abstract

Extracorporeal photochemotherapy is an effective treatment for cutaneous T cell lymphoma but its mode of action is uncertain. The reduction in viability of patients' photoirradiated buffy coat lymphocytes was correlated with a 35% increase in DNA single-strand breaks and marked decreases in cellular ATP and NAD levels (to 58 and 34% of control, respectively) immediately after photoirradiation. Complementary in vitro studies were conducted with normal human peripheral blood lymphocytes using a Therakos ultraviolet A (UVA) light box. UVA light was cytotoxic on its own but was potentiated by 8-methoxypsoralen. 3-aminobenzamide, a poly (ADP-ribose) synthetase inhibitor, mitigated the cytotoxic effect of ultraviolet A light in the presence of 8-methoxypsoralen in lymphocytes and reduced the amount of nucleotide depletion they caused. 10 J/cm2 of UVA light in the presence of 300 ng/ml 8-methoxypsoralen increased the poly (ADP-ribose) synthetase activity of peripheral blood lymphocytes. Exposing lymphocytes to deoxycoformycin and deoxyadenosine was found to induce biochemical and physical effects similar to those of photochemotherapy. In summary, we have shown that the lymphocytotoxic effect of extracorporeal photochemotherapy for cutaneous T cell lymphoma is apparently mediated by DNA damage, subsequent poly (ADP-ribosyl)ation and adenine nucleotide depletion. It is not known how the DNA damage and resultant biochemical effects relate to the possible immunological mechanism of extracorporeal photochemotherapy; however, it is possible that its effects can be mimicked by other DNA-damaging agents. (J. Clin.

A prospective interventional study on the use of extracorporeal photopheresis in patients with bronchiolitis obliterans syndrome after lung transplantation

“…5 More recently, ECP has been successfully used to treat acute heart allograft rejection 6,7 and chronic allograft dysfunction after lung transplantation, 8 -11,24 without increasing infectious complications. This therapy is thought to control these diseases at least partly through direct induction of lymphocyte apoptosis 12 and subsequent production of regulatory T cells (Treg). 13,14 However, the clear indications for use of ECP are not yet established.…”

Extracorporeal Photopheresis for the Treatment of Cutaneous T-Cell Lymphoma

“…On the other hand, ECP added to bexarotene oral therapy was also shown to improve the response to that agent, which is approved as a monotherapy for the cutaneous manifestations of CTCL. 26 Although the mechanisms of photopheresis action were unknown for years, the UVA treatment has been shown to induce DNA damage 29 and cytokine release, including TNF-a, IL-6, and IL-10. 30 Phagocytosis of tumor cells by activated dendritic cells, so-called ''transimmunization,'' is hypothesized to invoke a cytotoxic CD8+ or NK) response against the T-cell clone.…”

Immunbiologische Effekte der extrakorporalen Photopherese

“…Dieser unmittelbare Bestrahlungseffekt bei der ECP ist bereits von Marks u. Mitarb. näher untersucht worden [24]. Sie konnten zeigen, dass es durch die Photophereseprozedur zur Apoptose von lymphoiden Zellen kommt, die anhand der apoptotischen Zellmorphologie und einer DNAFragmentierung nachgewiesen wurde.…”