Butyric acid derivative induces allospecific T cell anergy and prevents graft-versus-host disease.
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-alpha 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-gamma and TNF-alpha 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.
Gilbert
Kathleen M
KM
Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA. gilbertkathleenm@uams.edu
Boger
Susan
S
Fifer
E Kim
EK
D000818:Animals; D002087:Butyrates / Q000494:pharmacology / Q000627:therapeutic use*; D015704:CD4 Antigens / Q000187:drug effects / Q000378:metabolism; D016827:CD8 Antigens / Q000187:drug effects / Q000378:metabolism; D017690:Cell Transplantation; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000187:drug effects*; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D007519:Isoantigens / Q000187:drug effects* / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use*; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects
C412896:2-(4-morpholinyl)ethyl butyrate; D002087:Butyrates; D015704:CD4 Antigens; D016827:CD8 Antigens; D016207:Cytokines; D007519:Isoantigens; D009025:Morpholines; D014409:Tumor Necrosis Factor-alpha