Alpha-1-antitrypsin monotherapy reduces graft-versus-host disease after experimental allogeneic bone marrow transplantation

Abstract

Acute graft-versus-host disease (GvHD) is a major complication that prevents successful outcomes after allogeneic bone marrow transplantation (BMT), an effective therapy for hematological malignancies. Several studies demonstrate that donor T cells and host antigen-presenting cells along with several proinflammatory cytokines are required for the induction of GvHD and contribute to its severity. Increasing evidence demonstrates that human serumderived αalpha-1-anti-trypsin (AAT) reduces production of proinflammatory cytokines, induces anti-inflammatory cytokines, and interferes with maturation of dendritic cells. Using well-characterized mouse models of BMT, we have studied the effects of AAT on GvHD severity. Administration of AAT early after BMT decreased mortality in three models of GvHD and reduced serum levels of proinflammatory cytokines in the allogeneic recipients compared with vehicle (albumin) treated animals. AAT treatment reduced the expansion of alloreactive T effector cells but enhanced the recovery of T regulatory T cells, (Tregs) thus altering the ratio of donor T effector to T regulatory cells in favor of reducing the pathological process. However, despite altering the ratio in vivo, AAT had no direct effects on either the donor T effector cells or T regulatory cells Tregs in vitro. In contrast, AAT suppressed LPSinduced in vitro secretion of proinflammatory cytokines such as TNF-α and IL-1β, enhanced the production of the anti-inflammatory cytokine IL-10, and impaired NF-κB translocation in the host dendritic cells. In light of its long history of safety in humans, these findings suggest that administration of AAT represents a novel unique and viable strategy to mitigate clinical GvHD.inflammation | interleukin

α-Linoleic Acid Enhances the Capacity of α1-Antitrypsin to Inhibit Lipopolysaccharide-Induced IL-1β in Human Blood Neutrophils

“…In brief, increasing diabetes, gouty arthritis, and ischemia-reperfusion injuries. (11)(12)(13)(14)(15)(16)(17) Despite growing reports on the anti inflammatory properties demonstrated for A1AT, the mechanism of a direct effect of A1AT on cells remains to be defined. Both in vitro and in vivo studies provide evidence that the beneficial effects of A1AT are mostly related to suppression of Toll-like receptor (TLR) agonist-induced innate immune cell activation.…”

Anti-inflammatory and immunomodulatory properties of α1-antitrypsin without inhibition of elastase

“…Plasma-derived AAT (Aralast) monotherapy prolongs survival of islet allograft transplants (11), induces immune tolerance to allografts (14), and prevents the development of diabetes in the nonobese diabetic mouse (12). We incubated LPS-stimulated mouse pancreatic islets with AAT (Aralast) as well as rAAT and determined the surface expression of MHC II, TLR4, and TLR2 on islet macrophages.…”

“…For example, the addition of exogenous AAT in vitro inhibits the release of IL-8 by monocytes (9) and the expression of HIV-1 (10). In animal models, the administration of AAT prevents murine islet cell allografts from rejection (11), blocks β-cell apoptosis (12), and suppresses alloreactivity in allogeneic marrow transplantation models (13,14). In other models, AAT therapy reduces TNF-α-or endotoxin-induced lethality, cigarette smoke-induced emphysema and inflammation, and suppresses bacterial proliferation during infections (15)(16)(17).…”

Trypsin-antitrypsin Imbalance in Immune Escape and Clonal Proliferation of Pancreatic Cancer

“…Corresponding research results were published in Digestive Diseases & Science and Chinese Medical Journal [30,31]. Meanwhile, it also has been confirmed that the theory of AAT compensatory increase is to neutralize and inhibit the activation of trypsin and other proteolytic enzymes so to inhibit the proliferation and spread of tumor cells [23][24][25][26][27]. And another hot issue is that trypsin is a kind of lymphocyte stimulation and its inhibitor-AAT has the function of immune suppression, and the confrontation of them plays an important role in immune surveillance of mutant cells.…”

“…In addition, AAT also can regulate immune response, affect the removal of antigen-antibody immune complex, and activate the complement and inflammatory response [25][26][27][28][29]. AAT can be synthesized by mononuclear cells, alveolar macrophages and epithelial cells and those synthesized by extrahepatic cells play an important role in the regulation of local tissue injury.…”