Blood, 15 April 2002, Vol. 99, No. 8, pp. 3071-3072
CORRESPONDENCE
To the editor:
The common pathways, but different outcomes, of
apoptosis induced by extracorporeal photopheresis and in vivo
chemotherapy may reinforce the important immunomodulatory effect of
monocytes
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 (
m).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.9 In 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 TNF
,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.
John Bladon and Peter Taylor
Correspondence: John Bladon, Photopheresis Unit, Rotherham
General Hospital, South Yorkshire, S60 2UD United Kingdom
References
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Activation of apoptosis pathways in peripheral blood lymphocytes by in vivo chemotherapy.
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Treatment of cutaneous T cell lymphoma by Extracorporeal photochemotherapy: preliminary results.
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Bladon J, Taylor P.
Extracorporeal photopheresis induces apoptosis in the lymphocytes of cutaneous T cell lymphoma and graft versus host disease patients.
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