Stimulation of natural killer cell numbers but not function in leukemic infant mice: a system primed in infancy allows survival in adulthood.

ABSTRACT

Infant mice (< 3-4 weeks) demonstrate no detectable natural killer (NK)-cell-mediated immunity. The aim of the present work was to assess, quantitatively and functionally, the possibility that prostaglandin E2, (PGE2), an NK cell inhibitor, may be responsible for the absence of NK-cell-mediated activity in normal and/or erythroleukemia-bearing infant DBA/2 mice prior to the normal age-related onset of NK-cell-mediated lytic capacity. Infants (7 days after birth) were exposed daily to indomethacin via intraperitoneal injection for 10 days and/or recombinant interleukin-2 (rIL-2) daily for 4 days. Significant increases in the number of NK cells in both the spleen and bone marrow were found after 10 days of indomethacin or 4 days of rIL-2 in normal mice. The spleens 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 treated 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 spleen and bone marrow, while combined administration of rIL-2 and indomethacin 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 normal nor tumor-bearing infants, could indomethacin, rIL-2, or a combination of both, induce the development of NK-cell-mediated functional (lytic) activity in spite of the generation, in nearly all instances, of high levels of NK cells in the presence of these agents. The observations collectively suggest that the lack of functional (lytic) reactivity 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-containing organs of a function-suppressive mechanism which is indomethacin insensitive, i.e., not PGE2-mediated. The significantly prolonged survival, and even cure, of infant leukemic mice treated with indomethacin and/or rIL-2 may result from the agent-mediated elevated levels of precursor NK cells coming under the influence of some age-related, as yet unidentified, endogenous factor imbuing them with functional capacity.