Blackwell Publishing Journal Backfiles 1879-2005
We have shown that acute (GVH) reactions produced in the parental Kt hybrid combination. A/J→(C57BL/6 × A/J) F1 result in the activation of two cytotoxic cell populations: a host-derived Thy-1+/- natural killer (NK) cell with a lytic spectrum confined to YAC-1 targets, and a donor-derived Thy-1+ NK-like cell that has the ability to lyse target cells that are normally insensitive to lysis by NK cells. Cold-target inhibition (CTI) experiments have shown that the greater range of target cell killing seen in the NK-like population is mediated by a single effector cell with a broadened lytic repertoire. Percoll density fractionation studies have revealed that NK and NK-like cell co-fractionate, suggesting that btith are large granular lymphocytes. We have also shown that NK-like cells do not express either Lyt-2 or L3T4 markers. We have also observed that there is a close temporal relationship between elevated levels of mterleukin-2 (IL-2) secretion by spleen cell cultures from mice with GVH disease and the subsequent emergence of splenic NK activity in both acute [A/J→(C57BL/6×A/J)F1] and chronic (A/J→ CBA×A/J)F1 GVH reactions. We have also noted that, despite high levels of IL-2 secretion, mice with chronic GVH reactions do not generate NK-like activity. Interferon (IFN) measurements have shown that, although increased IFN activity can be detected in both acute and chronic models, a preponderance of IFN-α/β and some IFN-γ is produced in the acute reaction, whereas only IFN-γ can be detected in the chronic model. These results suggest that, although IL-2 may participate in augmenting conventional NK activity. IL-2 by itself does not generate NK-like activity. We suggest that IFN-α/β may be the cytokinc that, either alone or in concert with IL-2, triggers the NK-like cell response. The NK-like cell described in our study resembles a phenotypically identical, donor-derived large granular lymphocyte, identified by others, in close proximity to dead or dying epithelial cells in mice with GVH disease . It has been suggested that these cells may mediate tissue injury. If in fact these graft-derived NK-like cells are involved in the pathogenesis of acute GVH disease, our present findings suggest that they must first be activated by an appropriate complement of cytokines that includes IFN-α/β. We postulate that whether or not a GVH reaction pursues an acute, rapidly lethal, course depends not only on the cohort of effector cells in the graft, but also on the stimulatory cytokines released during the early, lymphoproliferative phase of the reaction.
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