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

Abstract:

:Interleukin (IL)-32 was originally identified in natural killer 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 (MLCs) and GVHD. In allogeneic MLCs, IL-32 increased two-fold in responding T cells, accompanied by five-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 = .02). No significant changes in IL-32 levels were present in patients with treated (n = 14) or untreated (n = 8) chronic GVHD, compared with healthy controls (n = 8; P = .5, and P = .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 MLCs. In an MHC-minor antigen disparate murine transplant model, preconditioning and postconditioning treatment with AAT resulted in attenuation or prevention of GVHD and superior survival compared with albumin-treated controls (80% vs 44%; P = .04). These findings suggest that AAT modulates immune and inflammatory functions and may represent a novel approach to prevent or treat GVHD.

journal_name

Blood

journal_title

Blood

authors

Marcondes AM,Li X,Tabellini L,Bartenstein M,Kabacka J,Sale GE,Hansen JA,Dinarello CA,Deeg HJ

doi

10.1182/blood-2011-07-365247

subject

Has Abstract

pub_date

2011-11-03 00:00:00

pages

5031-9

issue

18

eissn

0006-4971

issn

1528-0020

pii

blood-2011-07-365247

journal_volume

118

pub_type

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