Regulatory T cells expressing CD19-targeted chimeric antigen receptor restore homeostasis in Systemic Lupus Erythematosus
Abstract Systemic Lupus Erythematosus (SLE) is a progressive disease leading to immune-mediated tissue damage, associated with an alteration of lymphoid organs. Therapeutic strategies involving regulatory T (Treg) lymphocytes, which physiologically quench autoimmunity and support long-term immune to...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-46448-9 |
| _version_ | 1797233470563418112 |
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| author | M. Doglio A. Ugolini C. Bercher-Brayer B. Camisa C. Toma R. Norata S. Del Rosso R. Greco F. Ciceri F. Sanvito M. Casucci A. A. Manfredi C. Bonini |
| author_facet | M. Doglio A. Ugolini C. Bercher-Brayer B. Camisa C. Toma R. Norata S. Del Rosso R. Greco F. Ciceri F. Sanvito M. Casucci A. A. Manfredi C. Bonini |
| author_sort | M. Doglio |
| collection | DOAJ |
| description | Abstract Systemic Lupus Erythematosus (SLE) is a progressive disease leading to immune-mediated tissue damage, associated with an alteration of lymphoid organs. Therapeutic strategies involving regulatory T (Treg) lymphocytes, which physiologically quench autoimmunity and support long-term immune tolerance, are considered, as conventional treatment often fails. We describe here a therapeutic strategy based on Tregs overexpressing FoxP3 and harboring anti-CD19 CAR (Fox19CAR-Tregs). Fox19CAR-Tregs efficiently suppress proliferation and activity of B cells in vitro, which are relevant for SLE pathogenesis. In an humanized mouse model of SLE, a single infusion of Fox19CAR-Tregs restricts autoantibody generation, delay lymphopenia (a key feature of SLE) and restore the human immune system composition in lymphoid organs, without detectable toxicity. Although a short survival, SLE target organs appear to be protected. In summary, Fox19CAR-Tregs can break the vicious cycle leading to autoimmunity and persistent tissue damage, representing an efficacious and safe strategy allowing restoration of homeostasis in SLE. |
| first_indexed | 2024-04-24T16:16:41Z |
| format | Article |
| id | doaj.art-8ebf6bb78c644d3087b4ecb41f2e463d |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-24T16:16:41Z |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-8ebf6bb78c644d3087b4ecb41f2e463d2024-03-31T11:25:27ZengNature PortfolioNature Communications2041-17232024-03-0115112110.1038/s41467-024-46448-9Regulatory T cells expressing CD19-targeted chimeric antigen receptor restore homeostasis in Systemic Lupus ErythematosusM. Doglio0A. Ugolini1C. Bercher-Brayer2B. Camisa3C. Toma4R. Norata5S. Del Rosso6R. Greco7F. Ciceri8F. Sanvito9M. Casucci10A. A. Manfredi11C. Bonini12Experimental Hematology Unit, Division of Immunology Transplantation and Infectious Diseases (DITID), IRCCS San Raffaele Scientific InstituteExperimental Hematology Unit, Division of Immunology Transplantation and Infectious Diseases (DITID), IRCCS San Raffaele Scientific InstituteExperimental Hematology Unit, Division of Immunology Transplantation and Infectious Diseases (DITID), IRCCS San Raffaele Scientific InstituteExperimental Hematology Unit, Division of Immunology Transplantation and Infectious Diseases (DITID), IRCCS San Raffaele Scientific InstituteExperimental Hematology Unit, Division of Immunology Transplantation and Infectious Diseases (DITID), IRCCS San Raffaele Scientific InstituteGLP Test Facility, San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific InstituteAutoimmunity Lab, IRCCS San Raffaele HospitalHematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele HospitalHematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele HospitalGLP Test Facility, San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific InstituteInnovative Immunotherapies Unit, Division of Immunology Transplantation and Infectious Diseases (DITID), IRCCS San Raffaele Scientific InstituteAutoimmunity and Vascular Inflammation Unit, Division of Immunology Transplantation and Infectious Diseases (DITID), IRCCS San Raffaele Scientific InstituteExperimental Hematology Unit, Division of Immunology Transplantation and Infectious Diseases (DITID), IRCCS San Raffaele Scientific InstituteAbstract Systemic Lupus Erythematosus (SLE) is a progressive disease leading to immune-mediated tissue damage, associated with an alteration of lymphoid organs. Therapeutic strategies involving regulatory T (Treg) lymphocytes, which physiologically quench autoimmunity and support long-term immune tolerance, are considered, as conventional treatment often fails. We describe here a therapeutic strategy based on Tregs overexpressing FoxP3 and harboring anti-CD19 CAR (Fox19CAR-Tregs). Fox19CAR-Tregs efficiently suppress proliferation and activity of B cells in vitro, which are relevant for SLE pathogenesis. In an humanized mouse model of SLE, a single infusion of Fox19CAR-Tregs restricts autoantibody generation, delay lymphopenia (a key feature of SLE) and restore the human immune system composition in lymphoid organs, without detectable toxicity. Although a short survival, SLE target organs appear to be protected. In summary, Fox19CAR-Tregs can break the vicious cycle leading to autoimmunity and persistent tissue damage, representing an efficacious and safe strategy allowing restoration of homeostasis in SLE.https://doi.org/10.1038/s41467-024-46448-9 |
| spellingShingle | M. Doglio A. Ugolini C. Bercher-Brayer B. Camisa C. Toma R. Norata S. Del Rosso R. Greco F. Ciceri F. Sanvito M. Casucci A. A. Manfredi C. Bonini Regulatory T cells expressing CD19-targeted chimeric antigen receptor restore homeostasis in Systemic Lupus Erythematosus Nature Communications |
| title | Regulatory T cells expressing CD19-targeted chimeric antigen receptor restore homeostasis in Systemic Lupus Erythematosus |
| title_full | Regulatory T cells expressing CD19-targeted chimeric antigen receptor restore homeostasis in Systemic Lupus Erythematosus |
| title_fullStr | Regulatory T cells expressing CD19-targeted chimeric antigen receptor restore homeostasis in Systemic Lupus Erythematosus |
| title_full_unstemmed | Regulatory T cells expressing CD19-targeted chimeric antigen receptor restore homeostasis in Systemic Lupus Erythematosus |
| title_short | Regulatory T cells expressing CD19-targeted chimeric antigen receptor restore homeostasis in Systemic Lupus Erythematosus |
| title_sort | regulatory t cells expressing cd19 targeted chimeric antigen receptor restore homeostasis in systemic lupus erythematosus |
| url | https://doi.org/10.1038/s41467-024-46448-9 |
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