Development of hyporesponsiveness to augmentation of natural killer cell activity after multiple doses of maleic anhydride divinyl ether: Association with decreased numbers of large granular lymphocytes

Augmentation of Organ-Associated NK Activity by BRMs: Association of NK Activity with Mononuclear Cell Infiltration

“…If this hypothesis is correct, then the depressed NK activity in blood and spleen should be paralleled by a decrease in the number of LGL in those sites. Recent studies support this hypothesis since the hyporesponsiveness of NK activity induced by multiple injections with MVE-2 in blood and spleen correlated with a significant decrease in the number of LGL isolated from those sites [80]. Further, recent studies from our laboratory have demonstrated that this de crease in LGL at sites of hyporesponsiveness following multiple treatment with MVE-2 was associated with an increase in total LGL isolable from the liver [52], Overall, these results support, but do not prove, that BRMinduced redistribution of NK-active cells may contribute to the unequal distribution of NK activity in various anatomical com partments following single or repeated BRM administration.…”

“…This has been particularly perplexing in situations where the repeated administration of var ious BRMs, including IFN and pyran copo lymer, has resulted in depressed levels of NK activity [77,79,80]. One explanation for this effect would be the redistribution of NKactive cells from the NK-depressed sites (blood and spleen) to NK-augmented sites (lung and liver).…”

NK Cell Hyporesponsiveness: More Is Not Always Better

“…Since the 1980′s, impact of treatments with IFNα, IL-2, IL-12 or IL-15, on NK cells have been examined in mice. Unexpectedly, while a single treatment with one of the above-mentioned cytokines leads to an increased NK cell cytotoxic activity, multiple treatments with one cytokine was shown to be negatively correlated with NK cell cytotoxic activity [142,143,144,145,146,147,148]. This NK cell hyporesponsiveness driven by cytokines was shown to be systemic [144,148], indicating that the origin of this phenomenon was not linked to a redistribution to other organs.…”

“…Moreover, regulatory T cells, immunosuppressive cytokines such as IL-10 or TGFβ, and also IFNγ, were shown not to be involved in IL-15 repeated treatment [146,148]. Studies from Saito and colleagues in 1985 have shown that NK cell hyporesponsiveness following repeated treatment with cytokine was linked to a decreased percentage of large granular lymphocytes (LGL), the effector cell population responsible for NK cell-mediated cytotoxicity [142,143]. However, despite initial characterization of LGL as NK cells, LGL are now shown to contain T cells and NK cells, which therefore prevents us from supporting their hypothesis.…”

“…The reversibility of this phenomenon is, furthermore, unclear. Indeed, only two studies pointed out that, in mice, after a first cycle of treatment with IL-2 or IFNα a second injection using a different cytokine restores NK cell responsiveness [143,144]. In contrast, after a first cycle of treatment with IL-15, a second cycle of treatment using a different cytokines does not restore NK cell responsiveness [146,148].…”