Ruxolitinib synergizes with regulatory T cells to improve inflammation but has no added benefits in decreasing albuminuria in SLE
BackgroundUmbilical cord blood (UCB)-derived CD4+CD25+CD127low regulatory T cells (Tregs) can decrease albuminuria and anti-dsDNA IgG in systemic lupus erythematosus (SLE). Ruxolitinib, a JAK/STAT inhibitor, has been shown to improve cutaneous manifestations of SLE. We hypothesize that the addition...
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Frontiers Media S.A.
2025-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1449693/full |
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| author | Mi-Ae Lyu Ximing Tang Maria Gabriela Raso Meixian Huang Ke Zeng Tara Sadeghi Christopher R. Flowers Simrit Parmar |
| author_facet | Mi-Ae Lyu Ximing Tang Maria Gabriela Raso Meixian Huang Ke Zeng Tara Sadeghi Christopher R. Flowers Simrit Parmar |
| author_sort | Mi-Ae Lyu |
| collection | DOAJ |
| description | BackgroundUmbilical cord blood (UCB)-derived CD4+CD25+CD127low regulatory T cells (Tregs) can decrease albuminuria and anti-dsDNA IgG in systemic lupus erythematosus (SLE). Ruxolitinib, a JAK/STAT inhibitor, has been shown to improve cutaneous manifestations of SLE. We hypothesize that the addition of ruxolitinib to UCB-Tregs may improve SLE outcomes.MethodsIn vitro cell suppression, phenotype change, IL-10 secretion, and cytokine levels in coculture supernatants were determined to quantify the impact of adding ruxolitinib to UCB-Tregs. A xenogeneic SLE model was utilized to study their in vivo combination.ResultsIn a dose-dependent manner, ruxolitinib addition synergizes with UCB-Tregs to suppress SLE-PBMC proliferation, inhibit CD8+ T cells, and reduce phosphorylation of STAT3/STAT5/AKT in CD8+ T cells. UCB-Treg and ruxolitinib combination also downregulates the soluble form of inflammatory cytokines including IFN-γ, IP-10, TNF-α, IL-6, sCD40L, IL-17A, IL-17F, IL-1α, and LIF in cocultures. The addition of ruxolitinib increases UCB-Treg cell persistence in peripheral blood in vivo and decreases the soluble form of human inflammatory cytokines including IFN-γ, TNF-α, and sCD40L in plasma along with improvement of skin lesions in SLE xenografts. Compared to control, significantly lesser CD3+, CD4+, CD8+, and Ki-67+ infiltrates are observed in the lung and kidney of UCB-Tregs and/or ruxolitinib recipients. No added benefit of addition of ruxolitinib is observed on the significant improvement in the urine albumin/creatinine ratio and the anti-dsDNA IgG levels induced by UCB-Tregs.ConclusionsOur results demonstrate that the addition of ruxolitinib to UCB-Tregs increases UCB-Tregs suppressor function and their persistence in vivo, downregulates systemic inflammation, and controls cutaneous SLE but does not add to UCB-Treg-mediated improvement in renal manifestations. |
| format | Article |
| id | doaj-art-b9f5bb5f93e54c6b847f7b2195c8b1e2 |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj-art-b9f5bb5f93e54c6b847f7b2195c8b1e22025-02-05T07:32:59ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-02-011610.3389/fimmu.2025.14496931449693Ruxolitinib synergizes with regulatory T cells to improve inflammation but has no added benefits in decreasing albuminuria in SLEMi-Ae Lyu0Ximing Tang1Maria Gabriela Raso2Meixian Huang3Ke Zeng4Tara Sadeghi5Christopher R. Flowers6Simrit Parmar7Department of Lymphoma/Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United StatesDepartment of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United StatesDepartment of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United StatesDepartment of Lymphoma/Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United StatesDepartment of Lymphoma/Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United StatesCellenkos Inc., Houston, TX, United StatesDepartment of Lymphoma/Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United StatesDepartment of Microbial Pathogenesis & Immunology, Texas A&M University, Bryan, TX, United StatesBackgroundUmbilical cord blood (UCB)-derived CD4+CD25+CD127low regulatory T cells (Tregs) can decrease albuminuria and anti-dsDNA IgG in systemic lupus erythematosus (SLE). Ruxolitinib, a JAK/STAT inhibitor, has been shown to improve cutaneous manifestations of SLE. We hypothesize that the addition of ruxolitinib to UCB-Tregs may improve SLE outcomes.MethodsIn vitro cell suppression, phenotype change, IL-10 secretion, and cytokine levels in coculture supernatants were determined to quantify the impact of adding ruxolitinib to UCB-Tregs. A xenogeneic SLE model was utilized to study their in vivo combination.ResultsIn a dose-dependent manner, ruxolitinib addition synergizes with UCB-Tregs to suppress SLE-PBMC proliferation, inhibit CD8+ T cells, and reduce phosphorylation of STAT3/STAT5/AKT in CD8+ T cells. UCB-Treg and ruxolitinib combination also downregulates the soluble form of inflammatory cytokines including IFN-γ, IP-10, TNF-α, IL-6, sCD40L, IL-17A, IL-17F, IL-1α, and LIF in cocultures. The addition of ruxolitinib increases UCB-Treg cell persistence in peripheral blood in vivo and decreases the soluble form of human inflammatory cytokines including IFN-γ, TNF-α, and sCD40L in plasma along with improvement of skin lesions in SLE xenografts. Compared to control, significantly lesser CD3+, CD4+, CD8+, and Ki-67+ infiltrates are observed in the lung and kidney of UCB-Tregs and/or ruxolitinib recipients. No added benefit of addition of ruxolitinib is observed on the significant improvement in the urine albumin/creatinine ratio and the anti-dsDNA IgG levels induced by UCB-Tregs.ConclusionsOur results demonstrate that the addition of ruxolitinib to UCB-Tregs increases UCB-Tregs suppressor function and their persistence in vivo, downregulates systemic inflammation, and controls cutaneous SLE but does not add to UCB-Treg-mediated improvement in renal manifestations.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1449693/fulladoptive cell therapyregulatory T cells (Tregs)allogeneicumbilical cord blood (UCB)ruxolitinibJAK/STAT pathway |
| spellingShingle | Mi-Ae Lyu Ximing Tang Maria Gabriela Raso Meixian Huang Ke Zeng Tara Sadeghi Christopher R. Flowers Simrit Parmar Ruxolitinib synergizes with regulatory T cells to improve inflammation but has no added benefits in decreasing albuminuria in SLE Frontiers in Immunology adoptive cell therapy regulatory T cells (Tregs) allogeneic umbilical cord blood (UCB) ruxolitinib JAK/STAT pathway |
| title | Ruxolitinib synergizes with regulatory T cells to improve inflammation but has no added benefits in decreasing albuminuria in SLE |
| title_full | Ruxolitinib synergizes with regulatory T cells to improve inflammation but has no added benefits in decreasing albuminuria in SLE |
| title_fullStr | Ruxolitinib synergizes with regulatory T cells to improve inflammation but has no added benefits in decreasing albuminuria in SLE |
| title_full_unstemmed | Ruxolitinib synergizes with regulatory T cells to improve inflammation but has no added benefits in decreasing albuminuria in SLE |
| title_short | Ruxolitinib synergizes with regulatory T cells to improve inflammation but has no added benefits in decreasing albuminuria in SLE |
| title_sort | ruxolitinib synergizes with regulatory t cells to improve inflammation but has no added benefits in decreasing albuminuria in sle |
| topic | adoptive cell therapy regulatory T cells (Tregs) allogeneic umbilical cord blood (UCB) ruxolitinib JAK/STAT pathway |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1449693/full |
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