title: 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.
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. mmarcond@fhcrc.org
authors: A Mario
authors: AM
authors: Marcondes
authors: Xiang
authors: X
authors: Li
authors: Laura
authors: L
authors: Tabellini
authors: Matthias
authors: M
authors: Bartenstein
authors: Julia
authors: J
authors: Kabacka
authors: George E
authors: GE
authors: Sale
authors: John A
authors: JA
authors: Hansen
authors: Charles A
authors: CA
authors: Dinarello
authors: H Joachim
authors: HJ
authors: Deeg
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects* / Q000276:immunology / Q000401:mortality; D002478:Cells, Cultured; D002648:Child; D004195:Disease Models, Animal; D006085:Graft Survival / Q000187:drug effects*; D006086:Graft vs Host Disease / Q000097:blood / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007378:Interleukins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D016019:Survival Analysis; D019172:Transplantation Conditioning / Q000379:methods; D023001:Transplantation Tolerance / Q000187:drug effects*; D014184:Transplantation, Homologous; D055815:Young Adult; D000515:alpha 1-Antitrypsin / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C496971:IL32 protein, human; D007378:Interleukins; D000515:alpha 1-Antitrypsin; C569037:interleukin-32, mouse