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Blood, 1 June 2002, Vol. 99, No. 11, pp. 4053-4062
IMMUNOBIOLOGY
Defective T-helper cell function after T-cell-depleting
therapy affecting naive and memory populations
Andreas Heitger,
Patricia Winklehner,
Petra Obexer,
Johannes Eder,
Claudia Zelle-Rieser,
Gabriele Kropshofer,
Martin Thurnher, and
Wolfgang Holter
From the University Children's Hospital Innsbruck;
Department of Urology, University Innsbruck, Austria; Children's
Cancer Research Institute, St Anna Children's Hospital Vienna,
Austria.
Impaired T-cell function after T-cell- depleting (TCD) therapy
has been hypothesized to be related to a transient predominance of
extrathymically expanding memory T cells. To test whether after TCD
therapy the naive T-helper cell population is functionally intact, the
in vitro immune response of CD4+CD45RA+ (naive)
and of CD4+CD45RA (memory) cells to
polyclonal mitogens (immobilized anti-CD3, phytohemagglutinin) was
analyzed by flow cytometry in 22 pediatric patients after high-dose
chemotherapy (including 5 after autologous and 5 after allogeneic stem
cell support). At 1 to 3 months after TCD therapy, patient samples
showing decreased lymphoproliferative responses also showed a reduced
induction of the early activation marker CD69 by CD4+ T
cells from 4 to 72 hours after stimulation even when supplemented with
exogenous interleukin-2. This defect affected
CD4+CD45RA cells, but, strikingly, also
CD4+CD45RA+ cells, including samples in which
CD4+CD45RA+ cells were more than 90/µL, thus
indicating ongoing thymopoiesis. Histogram analyses showed the median
peak channel of CD69 in control CD4+CD45RA+
cells rising 98-fold (median) but only 28-fold in patient cells (P < .0001). Apoptosis as detected by annexin V staining
was increased in resting patient CD4+ T cells (25% versus
6%) and also affected CD4+CD45RA+ cells (12%
versus 5%, P < .01). When peripheral blood mononuclear cells (PBMCs) were enriched for T cells, stimulatory responses of
CD4+ cells and of CD4+CD45RA+ cells
markedly improved. Thus, after TCD therapy suppressor factors contained
in the non-T-cell fraction of PBMCs may affect T-helper cells
irrespective of their naive or memory phenotype thus extending T-cell
dysfunction to the presumably thymus-dependently regenerated T cells.
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