Lipoxygenase pathway inhibition impairs the allograft response.

The inflammatory response may play a critical role in determining the ultimate fate of the allograft. Certain inflammatory mediators derived from the arachidonic acid lipoxygenase pathway (e.g., leukotriene B4), stimulate T cell function in vitro, but their role in allograft rejection is unknown. Nordihydroguaiaretic acid (NDGA) inhibits both the lipoxygenase (LO) pathway and T cell function in vitro. In this study, we investigated the effects of systemic LO inhibition with NDGA on the in vivo generation of allospecific and natural killer (NK) effector cells and arachidonic acid metabolites from sponge matrix allografts in mice. In control animals, generation of both allospecific cytolytic and NK cells increased progressively up to 12 days after grafting. Sponge cell synthesis of both leukotriene B4 (LTB4) and the cyclooxygenase product prostaglandin E2 (PGE2) could also be detected over this period. Recipient NDGA treatment (50 mg/kg/day) impaired both the accumulation and the specific cytotoxic potential of lymphocytes in allograft. Compared with control animals (1196 +/- 30 pg/10(6) cells), cells from recipients of NDGA produced significantly less LTB4 (55 +/- 10 pg/10(6) cells, p less than 0.01) but produced normal amounts of PGE2 (340 +/- /255 +/- 22 pg/10(6) cells, p = NS), thus proving the specificity of the NDGA treatment on LO pathway function. We conclude that cells capable of metabolizing arachidonic acid by both pathways accumulate in sponge allografts, but LO activity is specifically suppressed by systemic NDGA. Furthermore, systemic LO inhibition reduces the nonspecific inflammatory component, as well as allospecific cytolytic and NK generation, without compromising animal survival. These studies suggest that suppression of specific components of the inflammatory response associated with allograft rejection by LO inhibition may be a useful approach to selective immunosuppression.