Modulation of heme oxygenase‐1 by metalloporphyrins increases anti‐viral T cell responses

Summary 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 ( DC s), 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 ( PBMC s) led to increased anti‐viral T cell activation and the generation of a higher proportion of effector memory T cells ( CD 45 RA − CD 62 L − ) 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 [ CD 107a, 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.