Rosiglitazone prevents graft-versus-host disease (GVHD)

The effect of rosiglitazone, an agonist of peroxisome proliferator-activated receptor-γ (PPARγ), was investigated in a mouse parent-to-F1 GVHD model. Rosiglitazone inhibited mixed lymphocyte reactions, inducing enhanced apoptosis in CD4+, CD8+, and B220 + cells, but not in NK1.1+, Mac-1+, CD4 +/CD25 + and CD3 +/NK1.1 + cells. Rosiglitazone administration prevented GVHD in the liver, skin, spleen and intestine. Rosiglitazone inhibited GVHD-induced increases in serum levels of tumor necrosis factor-alpha, interferon-gamma, interleukin (IL)-6, and IL-12, and the GVHD-induced decreases in transforming growth factor-beta and IL-10. Immunophenotyping of splenic leukocytes demonstrated that while rosiglitazone treatment increased the population percentages of both donor and host CD4 +/CD25 + and CD3 +/NK1.1 + cells, the treatment resulted in lower fractions of both donor and host CD8 + cells. Rosiglitazone inhibited the GVHD-induced decreases in the expression of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), as well as the GVHD-induced increase in the splenic p-Akt and nuclear factor-kappa B expression. These results indicate that rosiglitazone and PPARγ activation may be useful in protecting the host from GVHD.

► The effect of rosiglitazone (PPARγ agonist) was investigated in a mouse GVHD model.
► Rosiglitazone inhibited MLR, inducing differential apoptosis among leukocyte subsets.
► Rosiglitazone inhibited GVHD-induced changes in serum cytokine levels.
► Rosiglitazone inhibited GVHD-induced changes in leukocyte immunophenotypes.
► Rosiglitazone prevented GVHD histologically in GVHD target organs.