α-1-Antitrypsin (AAT)–modified donor cells suppress GVHD but enhance the GVL effect: a role for mitochondrial bioenergetics

Abstract

• Donor treatment with AAT suppresses GVHD in the transplant recipient while enhancing the GVL effect.• AAT effects are mediated via cell type-specific alterations of mitochondrial bioenergetics.Hematopoietic cell transplantation is curative in many patients. However, graft-versus-host disease (GVHD), triggered by alloreactive donor cells, has remained a major complication. Here, we show an inverse correlation between plasma a-1-antitrypsin (AAT) levels in human donors and the development of acute GVHD in the recipients (n 5 111; P 5 .0006). In murine models, treatment of transplant donors with human AAT resulted in an increase in interleukin-10 messenger RNA and CD8

Alpha-1-antitrypsin in cell and organ transplantation

“…Marcondes et al reported that AAT alters the cellular redox state and improves mitochondrial membrane potential while also increasing expression of antioxidant enzymes such as heme oxygenase 1 (Figure 1). 4, 5, 6, 7 Oxidative stress is important in inflammation and IRI, so these activities may contribute to the ability of AAT to promote cell and tissue survival and modulate inflammatory damage 10, 11, 13, 14, 15, 16, 17, 18, 19, 20. Because different types of lymphocytes, and cells in different activation states, differ in dependence on glycolysis vs oxidative phosphorylation, modulation of mitochondrial function may influence the balance between sensitization and tolerance 6…”

“…Increased cell survival may result not only from stabilization of mitochondrial membranes, but also likely involves direct inhibition of caspases (Figure 1). 4, 5, 6, 7, 10, 11, 13, 14, 15, 16, 17, 18, 19, 20 The molecular mechanism(s) of this inhibition have not been elucidated; caspases are cysteine proteases, while elastase and other canonical targets of AAT depend on serine. However, immunofluorescence studies have shown colocalization of AAT and activated caspase 3 in apoptotic but not in viable cells 11.…”

“…The precise mechanism(s) by which AAT inhibits NFKB activation is unclear, but likely includes dampened activation of pro‐inflammatory signaling cascades 5, 20, 21, 22, 23 as well as protection of IKB from degradation in proteasomes (Figure 1). 4, 5, 6, 7, 20 Besides proinflammatory cytokines, several NFKB‐induced genes, such as Bcl‐2, promote cell survival, so most compounds that inhibit NFKB are pro‐apoptotic. In contrast, AAT may be unique in inhibiting both NFKB and apoptosis (by separate mechanisms).…”

“…These include stabilization of mitochondrial membranes and inhibition of caspases, which together inhibit apoptosis and increase cellular resistance to ischemia (Figure 1). 4, 5, 6, 7 Inhibition of degradation of the inhibitor of NFKB (IKB), and therefore, nuclear factor kappa B (NFKB) activation, and activation of protein phosphatases alter the balance between pro‐ and anti‐inflammatory cytokines and may modulate adaptive as well as innate immunity and promote tolerance 4, 6, 7. Evidence from cellular and animal models suggests that these novel activities may be beneficial in transplantation.…”

“…Major intracellular effects of alpha‐1‐antitrypsin and how they interrelate to achieve physiologic effects 4, 5, 6, 7…”