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In vivo induction of gamma interferon and tumor necrosis factor by
interleukin-2 infusion following intensive chemotherapy or autologous
marrow transplantation
HE Heslop, DJ Gottlieb, AC Bianchi, A Meager, HG Prentice, AB Mehta, AV Hoffbrand and MK Brenner
Department of Haematology, Royal Free Hospital, London, England.
Interleukin-2 (IL-2) therapy may improve immune reconstitution and reduce
the risk of leukemic relapse in the setting of minimal residual disease by
augmenting cytotoxic effector mechanisms directed at residual malignant
cells. In addition, IL-2 in vitro promotes the release of cytokines
including gamma-interferon (gamma-IFN) and tumor necrosis factor (TNF),
which also possess antileukemic activity and can enhance granulocyte
function. To determine if IL-2 infusion induces release of gamma-IFN and
TNF in vivo in sufficient quantity to mediate these effects, we have
measured serum levels of these cytokines and secretion by lymphocytes
obtained from patients receiving this cytokine in a phase 1 trial. Serum
gamma-IFN was undetectable pre-IL-2 and increased to 1.5 to 17 U/mL during
IL-2 infusion (P less than .05). Culture of patient lymphocytes for 48
hours produced 1.2 U gamma-IFN/2 x 10(6) cells/mL pre-IL-2 rising to 50 U/2
x 10(6) cells/mL when the lymphocytes were obtained during therapy (P less
than .05). Lymphocyte subset analysis showed that both CD3+ and CD16+ cells
secreted gamma- IFN in response to IL-2. TNF secretion by lymphocytes also
rose during IL-2 infusion from a mean of 5 U/mL to 14.4 U/mL (P less than
.01) although no rise was seen in serum levels. The material secreted by
IL- 2-stimulated lymphocytes is bioactive as addition of supernatants from
lymphocytes obtained during IL-2 therapy to cultures of myeloid blasts
significantly inhibited clonogenic growth. IL-2-induced secretion of these
cytokines mediated this inhibition as it could be partially blocked by
either anti-gamma-IFN or anti-TNF antibodies. Preincubation of granulocytes
with the same supernatants produced enhanced oxidative metabolism, measured
by chemiluminescence in response to N-formyl-
methionyl-leucyl-phenylalanine (FMLP). This effect also could be partially
abrogated by anti-gamma-IFN and anti-TNF antibodies. Therefore, secondary
cytokine secretion may boost granulocyte function and contribute to the
antileukemic effects of IL-2 infusion in patients following bone marrow
transplantation or chemotherapy.
Volume 74,
Issue 4,
pp. 1374-1380,
09/01/1989
Copyright © 1989 by The American Society of Hematology
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