Butyric Acid Derivative Induces Allospecific T Cell Anergy and Prevents Graft-Versus-Host Disease

Abstract

Graft-versus-host-disease (GVHD) is a common and potentially fatal complication following bone marrow transplantation. This study was initiated to test whether MEB [n-butyrate 2-(4-morpholinyl) ethyl butyrate hydrochloride], a derivative of the G1 blocker butyric acid, could specifically inactivate the alloantigen-specific T cells that mediate GVHD. MEB was shown to inhibit proliferation in a one-way mixed lymphocyte reaction (MLR) in which spleen cells from C57BL/6 mice (H-2b) were stimulated with spleen cells from DBA/2 mice (H-2d). The addition of MEB to the MLR prevented the expansion of alloantigen-stimulated CD8+ and CD4+ T cells in association with decreased IL-2 production. In addition, MEB inhibited the CTL activity of CD8+ T cells from the MLR. Most importantly, T cells from the MEB-treated MLR, unlike T cells from an untreated MLR, were unable to induce the splenomegaly and increased serum TNF-α levels characteristic of acute GVHD when injected into B6D2F1 mice. The splenomegaly found in the B6D2F1 mice injected with T cells from an untreated MLR encompassed the expansion and activation of CD8+ T cells, CD4+ T cells, B cells and macrophages. In contrast, the spleens of mice injected with T cells from MEB-treated MLR looked essentially identical to those of control B6D2F1 mice in terms of the numbers and activation state of the spleen cell populations. Similarly, the increase in IFN-γ and TNF-α production by CD4+ and CD8+ T cells from the spleens of mice undergoing acute GVHD was not observed if the mice were injected with T cells from an MEB-treated MLR instead of an untreated MLR. The use of MEB to inactivate host-specific T cells ex vivo underlines the potential clinical importance of this compound in the prevention and treatment of unwanted immune responses such as GVHD.