Changes in liver glycogen and lipid metabolism during transient graft-versus-host (GvH) and graft-versus-leukemia (GvL) reactivity

We investigated the influence of transient graft-versus-leukemia (GvL) and graft-versus-host reactivity (GvH) following allogeneic immune cell transfer on the glycogen and lipid metabolism in the liver of affected mice to better understand the underlying mechanism of these phenomena. As model we used a well established adoptive cellular immunotherapy (ADI) system. This involves transfer of in situ activated anti-tumor immune spleen lymphocytes (ISPL) from the tumor-resistant mouse strain B10.D2 (H-2(d), M1s(b)) into 5 Gy sublethally irradiated syngeneic ESb-MP lymphoma-bearing DBA/2 (H-2(d), M1s(a)) mice. Experiments were performed by transfer of ISPL from B10.D2 into DBA/2 tumor-bearing mice (GvL effect on liver metabolism) and into DBA/2 non-tumor-bearing mice (GvH effect on liver metabolism). Our results show that glycogen in hepatocytes decreased dramatically 5 days after ISPL transfer, which coincided with a high increase of large fat granules. 8 days after ISPL transfer, livers started to re-express glycogen and to decrease their lipid content. Normalization of both parameters was seen after day 30. These changes were qualitatively similar in both GvL and GvH. Measurement of activity of the liver marker enzymes, GOT and GPT, in the sera of animals subjected to GvL or GvH, showed peak values also at day 5, coinciding with the loss of glycogen. Quantitative differences were seen, however, in that much higher levels were reached in GvL than in GvH. Immune system recovery from irradiation damage and liver regeneration after immune cell mediated liver damage are likely explanations for the reversibility of the metabolic changes and for the lack of GVH disease and mortality in this new and effective cellular cancer immunotherapy model.