Stahnke et al1 discussed the mechanisms associated with the apoptosis of lymphoid cells following in vivo chemotherapy. Their observations showed striking similarities to those of early apoptotic lymphocytes induced by extracorporeal photopheresis (ECP). ECP therapy involves exposing cells, separated by leukapheresis, to 8-methoxypsoralen (8-MOP) and ultraviolet A (UVA). Treated cells are subsequently reinfused.2 Like in vivo chemotherapy, ECP induces a rapid increase in lymphocyte apoptosis following treatment.1,3 The apoptosis is independent of subtype: CD4+ and CD8+ lymphocytes are similarly affected.1,4 As early as 12 hours following in vivo chemotherapy, an increase in Bax expression was observed, but p53 remained undetectable.1 Immediately following ECP, exposed lymphocytes also demonstrate no increase in p53 expression but do show a reduction in Bcl-2/Bax ratio.5 Early loss in mitochondrial function also links the 2 treatment modalities: both therapies demonstrated early loss of mitochondrial membrane potential (Δψm).1,6 Immediately after ECP the apoptosis was caspase independent,6 and Stahnke et al also indicate that, in some patients, apoptosis was independent of caspase activation.1 Only after prior in vitro stimulation did chemotherapy induce apoptosis by a CD95- or p53-dependent mediated pathway,1 2 mechanisms not observed in the early stages after ECP; these pathways are only observed after a prolonged incubation in culture after ECP (Yoo et al7 and J.B., P.T., manuscript submitted, November 2001).
These observations may indicate a common pathway for the early induction of apoptosis in lymphocytes following treatment with DNA-damaging agents. Rather than an arrest of cell cycle and an increase in p53 expression, these cells become apoptotic immediately and are subsequently removed by the reticular endothelial system. The different environmental conditions, required by both treatment regimens to activate p53 and CD95, may indicate that lymphocyte apoptosis induced by these mechanisms involves a different phase. With regard to UVA-induced apoptosis, these 2 phases have previously been termed immediate- and delayed-type apoptosis.8
The beneficial, clinical effects of ECP are thought not only to be due to the apoptosis induced in treated lymphocytes. ECP is believed also to induce a “vaccination-type” immunomodulatory response, whereby nontreated, but clonal T cells are also removed.9In patients with cutaneous T-cell lymphoma (CTCL), ECP reduces the number of malignant CD4+ T cells in “responders” while CD8+ levels remain constant,10 a response we have also observed in patients with CTCL treated at Rotherham Photopheresis unit (P.T., unpublished data, December 2001). But in vivo chemotherapy causes a pan–T-cell depletion and lymphopenia.1 This difference may provide further evidence that the ECP effect is not purely linked to the induction of T-cell apoptosis. Monocytes do not become apoptotic following ECP.7 Conversely, ECP-treated monocytes demonstrate increased secretion of TNFα,11 enhanced ability to phagocytose apoptotic T cells,7 and unlike with other UV therapies, retain the adhesion markers required for the presentation of processed antigens to T cells (J.B., P.T., manuscript submitted, November 2001).
The similar mechanisms, but differing outcomes, of the apoptosis induced by in vivo chemotherapy and ECP may help reinforce the importance of the monocytes in this immunomodulatory response. Further research may center on the manipulation of these antigen-presenting cells as a useful tool in the treatment of other clonal conditions.
