DEPLETION OF NATURAL-KILLER-CELLS FROM THE GRAFT REDUCES INTERFERON-GAMMA LEVELS AND LIPOPOLYSACCHARIDE-INDUCED TUMOR-NECROSIS-FACTOR-ALPHARELEASE IN F-1 HYBRID MICE WITH ACUTE GRAFT-VERSUS-HOST DISEASE

Background We wished to determine whether removal of NK1.1(+) cells fr om the graft provides protection against acute graft-versus-host disea se (GVHD) by obviating the Th1 immune response that underlies the deve lopment of this disease.Methods. Graft-versus-host (GVH) reactions wer e induced in two groups of (C57BL/6 x DBA/2)F-1 hybrid mice. The first received grafts harvested from polyinosinic:polycytidylic acid-stimul ated, C57BL/6 donors and depleted in vitro of NK1.1(+) cells. This tre atment provides protection against GVHD-associated mortality and cache xia. The second received unmodified grafts. We compared interferon-gam ma and interleukin-10 production as well as the levels of engraftment in these two groups. Lipopolysaccharide-induced tumor necrosis factor- alpha (TNF-alpha) release was also compared since TNF-alpha levels in GVH mice following injection of a sublethal dose of endotoxin provide an index of macrophage priming by Th1 cytokines. Results. Interferon-g amma production was absent in recipients of NR1.1-depleted grafts at t he time when high levels were seen in recipients of unmodified grafts. Following lipopolysaccharide injection, high levels of TNF-alpha were observed in recipients of unmodified grafts, whereas negligible amoun ts were present in recipients of NK1.1-depleted grafts. The use of NK1 .1-depleted grafts did not result in a reduced level of engraftment of CD4(+) or CD8(+) cells. Conclusions. These results suggest that NK1.1 depletion of the graft confers protection against mortality by interf ering with an immunoregulatory mechanism that results in the developme nt of a Th1 response in GVH mice, and does not result in abortion of t he graft. Because macrophage priming is prevented, recipients are also protected from the exaggerated sensitivity to endotoxin seen in mice with acute GVHD.