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Combined GM-CSF and G-CSF administration mobilizes CD4⁺ CD25^hi Foxp3^hi Treg in leukapheresis products of rhesus monkeys.

ABSTRACT: Early phase clinical trials are evaluating the feasibility, safety, and therapeutic potential of ex vivo expanded regulatory T cells (Treg) in transplantation. A limitation is the paucity of naturally occurring Treg numbers in peripheral blood. Hence, protracted ex vivo expansion is required to obtain sufficient Treg in order to meet target cell doses. Because cytokine administration has been used successfully to mobilize immune cells to the peripheral blood in experimental and clinical studies, we hypothesized that granulocyte macrophage-colony-stimulating factor (GM-CSF) and granulocyte-CSF (G-CSF) administration would enhance Treg percentages in leukapheresis products of rhesus monkeys. Following combined GM-CSF and G-CSF administration, the incidence of Treg in peripheral blood and leukapheresis products was elevated significantly, where approximately 3.7 × 10⁶ /kg CD4⁺ CD25^hi Foxp3^hi or 6.8 × 10⁶ /kg CD4⁺ CD25^hi CD127^lo Treg can be collected from individual products. Mobilized Treg expressed a comparable repertoire of surface markers, chemokine receptors, and transcription factors to naïve monkey peripheral blood Treg. Furthermore, when expanded ex vivo, mobilized leukapheresis product and peripheral blood Treg exhibited similar ability to suppress autologous CD4⁺ and CD8⁺ T cell proliferation. These observations indicate that leukapheresis products from combined GM-CSF- and G-CSF-mobilized individuals are a comparatively rich source of Treg and may circumvent long-term ex vivo expansion required for therapeutic application.

SUBMITTER: Sasaki K

PROVIDER: S-EPMC7768825 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAllergic rhinitis (AR) is one of the most widespread immune conditions worldwide. However, common treatments often present with significant side effects or are cost-prohibitive for much of the population. A plethora of treatments have been used for the treatment of AR including antihistamines, steroids, and immune modulators. Among the treatments which have shown potential for efficacy in treating AR with a minimum of side effects but remains understudied is the conditionally essential amino acid taurine. Taurine has been previously shown to reduce AR symptoms. Here, we examine the role of taurine in modulating T regulatory cells, modulating the cytokine response in AR, and restoring healthy nasal mucosa.MethodsBlood samples from 20 healthy donors and 20 AR patients were compared for CD4+CD25+FoxP3+ T regulatory (Treg) cell population percentage, cytokine release, and STAT1 signaling with and without taurine treatment or IL-35 neutralization. An OVA-induced AR mouse model was administered vehicle, taurine, or taurine plus an IL-35 neutralizing antibody and assayed for sneezing frequency, inflammatory cytokine response, nasal mucosa goblet cell density, and T regulatory cell percentage. CD4+ cells were further examined for cytokine release, STAT1 phosphorylation, and response to an anti-IL-35 antibody with and without a STAT1 inhibitor.ResultsComparison of blood from normal donors and AR patients showed a reduction in CD4+CD25+FoxP3+ Treg cells in AR patients and a strong correlation between Treg percentage and IL-35 release. A similar pattern of Treg suppression was found in untreated AR mice when compared to normal control mice wherein there was a reduction in Treg percentage and a corresponding decrease in IL-35 release. AR mice also demonstrated increased sneezing frequency, an infiltration of goblet cell in nasal mucosa, and a reduction in IL-35 release from CD4+ cells. Conversely, IL-4, IL-5, and IL-13 secretion from CD4+ cells were increased in AR model mice, as was STAT1 phosphorylation. When AR mice were treated with taurine, sneezing frequency and nasal mucosa goblet cell content were reduced while Treg abundance was increased to that of normal mice. Accordingly, IL-35 release was restored, while IL-4, IL-5, and IL-13 secretion from CD4+ cells were suppressed. Likewise, STAT1 phosphorylation was inhibited with taurine treatment. Taurine-treated mice also given an IL-35 neutralizing antibody exhibited AR pathology including frequent sneezing and high nasal goblet cell content while retaining a restoration of Tregs. Furthermore, murine AR model CD4+ cells exposed to recombinant IL-35 responded with a reduction in inflammatory cytokine release and a decrease in STAT1 phosphorylation, mimicking the effect of taurine treatment.ConclusionsTaurine induces release of IL-35 in AR; IL-35 promotes the production of CD4+CD25+FoxP3+ Treg cells via a STAT1-dependent pathway. The restoration of Treg populations by taurine normalizes the inflammatory response, reduces AR symptomology, and reduces histopathologic signs of AR.

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Combined GM-CSF and G-CSF administration mobilizes CD4⁺ CD25^hi Foxp3^hi Treg in leukapheresis products of rhesus monkeys.

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Combined GM-CSF and G-CSF administration mobilizes CD4+ CD25hi Foxp3hi Treg in leukapheresis products of rhesus monkeys.

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OmicsDI is part of the ELIXIR infrastructure

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Combined GM-CSF and G-CSF administration mobilizes CD4⁺ CD25^hi Foxp3^hi Treg in leukapheresis products of rhesus monkeys.