Vaccinia vaccine–based immunotherapy arrests and reverses established pulmonary fibrosis

Collins, Samuel; Chan‐Li, Yee; Oh, Min Hee; Vigeland, C.L.; Limjunyawong, Nathachit; Mitzner, Wayne; Powell, Jonathan D.; Horton, Maureen R.

doi:10.1172/jci.insight.83116

Cited by 28 publications

(46 citation statements)

References 62 publications

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“…Key investigations have implicated aberrant STAT3 signaling and T H 17 cells in murine models of pulmonary fibrosis pathogenesis (9, 28, 29). Here, we report that PD-1 up-regulation on human T H 17 cells creates not only an immunosuppressive microenvironment but also a profibrotic one.…”

Section: Discussionmentioning

confidence: 99%

PD-1 up-regulation on CD4 ⁺ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production

et al. 2018

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Pulmonary fibrosis is a progressive inflammatory disease with high mortality and limited therapeutic options. Previous genetic and immunologic investigations suggest common intersections between idiopathic pulmonary fibrosis (IPF), sarcoidosis, and murine models of pulmonary fibrosis. To identify immune responses that precede collagen deposition, we conducted molecular, immunohistochemical, and flow cytometric analysis of human and murine specimens. Immunohistochemistry revealed programmed cell death-1 (PD-1) up-regulation on IPF lymphocytes. PD-1+CD4+ T cells with reduced proliferative capacity and increased transforming growth factor–β (TGF-β)/interleukin-17A (IL-17A) expression were detected in IPF, sarcoidosis, and bleomycin CD4+T Cells. PD-1+ T helper 17 cells are the predominant CD4+T cell subset expressing TGF-β. Coculture of PD-1+CD4+ T cells with human lung fibroblasts induced collagen-1 production. Strikingly, ex vivo PD-1 pathway blockade resulted in reductions in TGF-β and IL-17A expression from CD4+ T cells, with concomitant declines in collagen-1 production from fibroblasts. Molecular analysis demonstrated PD-1 regulation of the transcription factor STAT3 (signal transducer and activator of transcription 3). Chemical blockade of STAT3, using the inhibitor STATTIC, inhibited collagen-1 production. Both bleomycin administration to PD-1 null mice or use of antibody against programmed cell death ligand 1 (PD-L1) demonstrated significantly reduced fibrosis compared to controls. This work identifies a critical, previously unrecognized role for PD-1+CD4+ T cells in pulmonary fibrosis, supporting the use of readily available therapeutics that directly address interstitial lung disease pathophysiology.

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Section: Discussionmentioning

confidence: 99%

PD-1 up-regulation on CD4 ⁺ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production

et al. 2018

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“…All mice were treated with 0.8 units of bleomycin (Bleomycin for Injection USP, Hospira, Lake Forest, IL) intraperitoneally (IP) on days 1, 3, 7, 10, 14, and 21 [15]. Mice (randomly assigned) were simultaneously treated subcutaneously (sc) with MIA-602 (5 μg/day) or its vehicle (100 μL/day) [14].…”

Section: Methodsmentioning

confidence: 99%

Growth Hormone-Releasing Hormone Receptor Antagonist Modulates Lung Inflammation and Fibrosis due to Bleomycin

Zhang

Cai

Lazerson

et al. 2019

Lung

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PurposeGrowth hormone-releasing hormone (GHRH) is a 44-amino acid peptide that regulates growth hormone (GH) secretion. We hypothesized that a GHRH receptor (GHRH-R) antagonist, MIA-602, would inhibit bleomycin-induced lung inflammation and/or fibrosis in C57Bl/6J mice.MethodsWe tested whether MIA-602 (5 μg or vehicle given subcutaneously [SC] on days 1–21) would decrease lung inflammation (at day 14) and/or fibrosis (at day 28) in mice treated with intraperitoneal (IP) bleomycin (0.8 units on days 1, 3, 7, 10, 14, and 21). Bleomycin resulted in inflammation and fibrosis around airways and vessels evident histologically at days 14 and 28.ResultsInflammation (histopathologic scores assessed blindly) was visibly less evident in mice treated with MIA-602 for 14 days. After 28 days, lung hydroxyproline (HP) content increased significantly in mice treated with vehicle; in contrast, lung HP did not increase significantly compared to naïve controls in mice treated with GHRH-R antagonist. GHRH-R antagonist increased basal and maximal oxygen consumption of cultured lung fibroblasts. Multiple genes related to chemotaxis, IL-1, chemokines, regulation of inflammation, and extracellular signal–regulated kinases (ERK) were upregulated in lungs of mice treated with bleomycin and MIA-602. MIA-602 also prominently suppressed multiple genes related to the cellular immune response including those for T-cell differentiation, receptor signaling, activation, and cytokine production.ConclusionsMIA-602 reduced lung inflammation and fibrosis due to bleomycin. Multiple genes related to immune response and T-cell functions were downregulated, supporting the view that MIA-602 can modulate the cellular immune response to bleomycin lung injury.

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“…Vaccination would need specifically to target CD8 T-cell responses; inducing cytotoxic activity against target microbes may eliminate them from the microbiota, thus preventing pathology. The concept that immunization to induce CD8 T-cell responses can suppress inflammatory pathology may be counterintuitive, but proof of principle for this was demonstrated in mouse models of airway disease 52,53 . Such vaccination could provide long-lasting effects on the highly plastic DCs that direct immune responses into pathways associated with health or disease.…”

Section: Target Cd8 T-cell Proliferation Assayed After 4 Days Revealementioning

confidence: 99%

Deficient Resident Memory T Cell and CD8 T Cell Response to Commensals in Inflammatory Bowel Disease

Noble

Durant

Hoyles

et al. 2019

Journal of Crohn's and Colitis

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Background and Aims The intestinal microbiota is closely associated with resident memory lymphocytes in mucosal tissue. We sought to understand how acquired cellular and humoral immunity to the microbiota differ in health versus inflammatory bowel disease [IBD]. Methods Resident memory T cells [Trm] in colonic biopsies and local antibody responses to intraepithelial microbes were analysed. Systemic antigen-specific immune T and B cell memory to a panel of commensal microbes was assessed. Results Systemically, healthy blood showed CD4 and occasional CD8 memory T cell responses to selected intestinal bacteria, but few memory B cell responses. In IBD, CD8 memory T cell responses decreased although B cell responses and circulating plasmablasts increased. Possibly secondary to loss of systemic CD8 T cell responses in IBD, dramatically reduced numbers of mucosal CD8+ Trm and γδ T cells were observed. IgA responses to intraepithelial bacteria were increased. Colonic Trm expressed CD39 and CD73 ectonucleotidases, characteristic of regulatory T cells. Cytokines/factors required for Trm differentiation were identified, and in vitro-generated Trm expressed regulatory T cell function via CD39. Cognate interaction between T cells and dendritic cells induced T-bet expression in dendritic cells, a key mechanism in regulating cell-mediated mucosal responses. Conclusions A previously unrecognised imbalance exists between cellular and humoral immunity to the microbiota in IBD, with loss of mucosal T cell-mediated barrier immunity and uncontrolled antibody responses. Regulatory function of Trm may explain their association with intestinal health. Promoting Trm and their interaction with dendritic cells, rather than immunosuppression, may reinforce tissue immunity, improve barrier function, and prevent B cell dysfunction in microbiota-associated disease and IBD aetiology.

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Vaccinia vaccine–based immunotherapy arrests and reverses established pulmonary fibrosis

Cited by 28 publications

References 62 publications

PD-1 up-regulation on CD4 ⁺ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production

PD-1 up-regulation on CD4 ⁺ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production

Growth Hormone-Releasing Hormone Receptor Antagonist Modulates Lung Inflammation and Fibrosis due to Bleomycin

Deficient Resident Memory T Cell and CD8 T Cell Response to Commensals in Inflammatory Bowel Disease

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Vaccinia vaccine–based immunotherapy arrests and reverses established pulmonary fibrosis

Cited by 28 publications

References 62 publications

PD-1 up-regulation on CD4 + T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production

PD-1 up-regulation on CD4 + T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production

Growth Hormone-Releasing Hormone Receptor Antagonist Modulates Lung Inflammation and Fibrosis due to Bleomycin

Deficient Resident Memory T Cell and CD8 T Cell Response to Commensals in Inflammatory Bowel Disease

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PD-1 up-regulation on CD4 ⁺ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production

PD-1 up-regulation on CD4 ⁺ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production