Deletion of AMPK minimizes graft-versus-host disease through an early impact on effector donor T cells

Abstract

Study approval. All animal studies were approved and carried out according to Institutional Animal Care and Use Committee guidelines from the University of Pittsburgh. All studies on human cells were designated exempt status by the University of Pittsburgh Institutional Review Board. Author contributionsDAM, KJB, and PC designed and performed experiments, analyzed data, and reviewed the manuscript. KP designed and performed experiments and analyzed data. NJM, AKD, and RAB performed experiments and analyzed data. JAO reviewed pathology slides, assigned scores in a blinded fashion, and reviewed the manuscript. CAB drafted the manuscript with assistance from DAM. BRB and CAB designed the studies, interpreted and analyzed data, and critically revised the final manuscript. Authorship order among coauthors was assigned based on percentage contribution to the final manuscript, intellectual involvement, and role in responding to reviewers' inquiries.

Recent Metabolic Advances for Preventing and Treating Acute and Chronic Graft Versus Host Disease

“…In vivo metformin administration increased the ratio of Treg/ Th17, enhanced autophagy and reduced mTOR/STAT3 signaling (59) resulting in the amelioration of murine aGVHD severity (59). In contrast, a recent study reported that the loss of AMPK in donor T cells attenuated aGVHD (60), suggesting a pAMPK independent mechanism of GVHD amelioration by metformin (60). Allogeneic murine and human T cells upregulated pAMPK during early aGVHD and xenogeneic GVHD respectively.…”

Kinase Inhibition as Treatment for Acute and Chronic Graft-Versus-Host Disease

“…The investigators established AMPK double knockout (AMPK-dKO) mice lacking AMPKa1 and AMPKa2 in all peripheral T-cells. AMPK is a heterotrimeric molecule with the a subunit as kinase domain and the b/g subunits being important for stability and substrate specificity (175,(178)(179)(180). Although T-cell development and in vitro proliferation in a MLR was not different between AMPK-dKO and WT T-cells, AMPK-deficient T-cells caused less severe GvHD after transplantation into lethally irradiated recipient mice.…”

“…Co-transplantation experiments revealed that AMPK-dKO T-cells stimulated an increase of WT Tregs. Given the importance of Tregs to reduce GvHD severity, increased Treg numbers due to accompanying AMPK-dKO cells were named as a major mechanism to suppress GvHD severity (175,(182)(183)(184). Although there are no AMPK inhibitors available yet, inhibition of AMPK in T-cells could serve as novel target for GvHD treatment; however, more detailed analysis is needed to better understand the role of AMPK after allo-HCT (175).…”

“…GvHD following allo-HCT is predominantly driven by alloreactive donor T-cells which cause severe tissue damage ( 4 ). Novel therapeutic options aim to impair T-cell functions to reduce life-threatening GvHD without affecting GvL activity, including the idea to metabolically re-program T-cells after allo-HCT ( 175 ). Following transplantation, T-cells increase oxidative phosphorylation and fatty acid oxidation ( 176 , 177 ).…”

“…Following transplantation, T-cells increase oxidative phosphorylation and fatty acid oxidation ( 176 , 177 ). Since it is known that allogeneic effector T-cells require fatty acid oxidation (FAO) during GvHD, it was hypothesized that AMP kinase (AMPK) activation plays a major role in regulating T-cell activity after allo-HCT ( 175 , 177 ).…”