Inhibition of IL-32 activation by {alpha}-1 antitrypsin suppresses alloreactivity and increases survival in an allogeneic murine marrow transplantation model.

Publication Type:

Journal Article

Source:

Blood, Volume 118, Issue 18, p.5031-5037 (2011)

Keywords:

2011, Adolescent, Adult, Aged, alpha 1-Antitrypsin, Animals, Bone Marrow Transplantation, Cells, Cultured, Center-Authored Paper, Child, Clinical Research Division, Comparative Medicine Core Facility, Disease Models, Animal, Flow Cytometry Core Facility, Genomics Core Facility, Graft vs Host Disease, Humans, Interleukins, Leukocytes, Mononuclear, MICE, Mice, Inbred C57BL, Middle Aged, October 2011, Shared Resources, Specimen Processing, Survival Analysis, Transplantation Conditioning, Transplantation Tolerance, Transplantation, Homologous, Young Adult

Abstract:

Interleukin-32 (IL32) was originally identified in NK cells and IL-2-activated human T-lymphocytes. As T-cells are activated in allogeneic transplantation, we determined the role of IL-32 in human mixed lymphocyte cultures (MLC) and graft-versus-host-disease (GVHD). In allogeneic MLC, IL-32 increased 2-fold in responding T-cells, accompanied by 5-fold increases of TNFα, IL-6 and IL-8. After allogeneic hematopoietic cell transplantation, IL-32 mRNA levels in blood leukocytes were statistically significantly higher in patients with acute GVHD (n=10) than in serial samples from patients who did not develop acute GVHD (n=5; p=0.02). No significant changes in IL-32 levels were present in patients with treated (n=14) or untreated (n=8) chronic GVHD, compared to healthy controls (n=8) (p=0.5 and p=0.74, respectively). As IL-32 is activated by proteinase-3 (PR3), we determined the effect of the serine protease inhibitor α-1 antitrypsin (AAT) on IL-32 levels and showed suppression of IL-32 and T-lymphocyte proliferation in MLC. In an MHC-minor antigen disparate murine transplant model, pre- and post-conditioning treatment with AAT resulted in attenuation or prevention of GVHD and superior survival compared to albumin-treated controls (80% versus 44%; p=0.04). These findings suggest that AAT modulates immune and inflammatory functions and may represent a novel approach to prevent or treat GVHD.