I. Dussault et Sc. Miller, STIMULATION OF NATURAL-KILLER-CELL NUMBERS BUT NOT FUNCTION IN LEUKEMIC INFANT MICE - A SYSTEM PRIMED IN INFANCY ALLOWS SURVIVAL IN ADULTHOOD, Natural immunity, 12(2), 1993, pp. 66-78
Infant mice (< 3-4 weeks) demonstrate no detectable natural killer (NK
)-cell-mediated immunity. The aim of the present work was to assess, q
uantitatively and functionally, the possibility that prostaglandin E2,
(PGE2), an NK cell inhibitor, may be responsible for the absence of N
K-cell-mediated activity in normal and/or erythroleukemia-bearing infa
nt DBA/2 mice prior to the normal age-related onset of NK-cell-mediate
d lytic capacity. Infants (7 days after birth) were exposed daily to i
ndomethacin via intraperitoneal injection for 10 days and/or recombina
nt interleukin-2 (rIL-2) daily for 4 days. Significant increases in th
e number of NK cells in both the spleen and bone marrow were found aft
er 10 days of indomethacin or 4 days of rIL-2 in normal mice. The sple
ens but not the bone marrow of infants treated with indomethacin from
tumor onset (7 days after birth) contained significantly more NK cells
10 days later than did control (tumor + vehicle) infants. Infants tre
ated with rIL-2 during the last 4 days of tumor bearing, i.e., days 13
-16 after birth, contained significantly more NK cells in both their s
pleen and bone marrow, while combined administration of rIL-2 and indo
methacin to tumor-bearing, but not normal, infants resulted in a more
than additive increase in the NK cell numbers in both organs relative
to control (tumor + vehicle or vehicle alone). However, in neither nor
mal nor tumor-bearing infants, could indomethacin, rIL-2, or a combina
tion of both, induce the development of NK-cell-mediated functional (l
ytic) activity in spite of the generation, in nearly all instances, of
high levels of NK cells in the presence of these agents. The observat
ions collectively suggest that the lack of functional (lytic) reactivi
ty of infant-source NK cells, in the presence of agents which potently
enhance adult-source NK cells, reflects (1) the innate immaturity of
infant NK lineage cells, or (2) the presence in infant NK-cell-contain
ing organs of a function-suppressive mechanism which is indomethacin i
nsensitive, i.e., not PGE2-mediated. The significantly prolonged survi
val, and even cure, of infant leukemic mice treated with indomethacin
and/or rIL-2 may result from the agent-mediated elevated levels of pre
cursor NK cells coming under the influence of some age-related, as yet
unidentified, endogenous factor imbuing them with functional capacity
.