title: Modulation of heme oxygenase-1 by metalloporphyrins increases anti-viral T cell responses.
abstract: Heme oxygenase (HO)-1, the inducible isoform of HO, has immunomodulatory functions and is considered a target for therapeutic interventions. In the present study, we investigated whether modulation of HO-1 might have regulatory effects on in-vitro T cell activation. The study examined whether: (i) HO-1 induction by cobalt-protoporphyrin (CoPP) or inhibition by tin-mesoporphyrin (SnMP) can affect expansion and function of virus-specific T cells, (ii) HO-1 modulation might have a functional effect on other cell populations mediating effects on proliferating T cells [e.g. dendritic cells (DCs), regulatory T cells (T(regs)) and natural killer cells] and (iii) HO-1-modulated anti-viral T cells might be suitable for adoptive immunotherapy. Inhibition of HO-1 via SnMP in cytomegalovirus (CMV)pp65-peptide-pulsed peripheral blood mononuclear cells (PBMCs) led to increased anti-viral T cell activation and the generation of a higher proportion of effector memory T cells (CD45RA(-) CD62L(-)) with increased capability to secrete interferon (IFN)-γ and granzyme B. T(reg) depletion and SnMP exposure increased the number of anti-viral T cells 15-fold. To test the possibility that HO-1 modulation might be clinically applicable in conformity with good manufacturing practice (GMP), SnMP was tested in isolated anti-viral T cells using the cytokine secretion assay. Compared to control, SnMP treatment resulted in higher cell counts and purity without negative impact on quality and effector function [CD107a, IFN-γ and tumour necrosis factor (TNF)-α levels were stable]. These results suggest an important role of HO-1 in the modulation of adaptive immune responses. HO-1 inhibition resulted in markedly more effective generation of functionally active T cells suitable for adoptive T cell therapy.
authors.affiliation: Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany; Integrated Research and Treatment Centre Transplantation - IFB-Tx, Hannover Medical School, Hannover, Germany.
authors.forename: C E
authors.initials: CE
authors.lastname: Bunse
authors.forename: V
authors.initials: V
authors.lastname: Fortmeier
authors.forename: S
authors.initials: S
authors.lastname: Tischer
authors.forename: E
authors.initials: E
authors.lastname: Zilian
authors.forename: C
authors.initials: C
authors.lastname: Figueiredo
authors.forename: T
authors.initials: T
authors.lastname: Witte
authors.forename: R
authors.initials: R
authors.lastname: Blasczyk
authors.forename: S
authors.initials: S
authors.lastname: Immenschuh
authors.forename: B
authors.initials: B
authors.lastname: Eiz-Vesper
mesh_terms: D019264:Adoptive Transfer; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D051547:Heme Oxygenase-1 / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000276:immunology; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology*; D010750:Phosphoproteins / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D014763:Viral Matrix Proteins / Q000276:immunology
chemical_list: C573415:IFNG protein, human; D008665:Metalloporphyrins; D010750:Phosphoproteins; D014409:Tumor Necrosis Factor-alpha; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa; D007371:Interferon-gamma; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1
keywords: HO-1 modulation; antigen-specific T cells; immunotherapy; metalloporphyrins