Constitutive reduction in the checkpoint inhibitor, CTLA-4, does not accelerate SLE in NZM 2328 mice
Background/objective Treatment with immune checkpoint inhibitors (ICIs) in oncology patients is increasing. Although ICIs trigger rheumatic immune-related adverse events, development of SLE features has been rare. Whether long-term treatment with ICIs would promote SLE features remains unknown. To b...
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BMJ Publishing Group
2019-12-01
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| Series: | Lupus Science and Medicine |
| Online Access: | https://lupus.bmj.com/content/6/1/e000313.full |
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| author | William Stohl Chaim Putterman Ning Yu Samantha A Chalmers Chaim O Jacob |
| author_facet | William Stohl Chaim Putterman Ning Yu Samantha A Chalmers Chaim O Jacob |
| author_sort | William Stohl |
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| description | Background/objective Treatment with immune checkpoint inhibitors (ICIs) in oncology patients is increasing. Although ICIs trigger rheumatic immune-related adverse events, development of SLE features has been rare. Whether long-term treatment with ICIs would promote SLE features remains unknown. To begin to address this, we generated SLE-prone NZM 2328 mice with lifelong reduction in CTLA-4 expression.Methods Since CTLA-4-deficient (Ctla4−/−) NZM mice developed a lethal lymphoproliferative disorder by 3–6 weeks of age, development of SLE in these mice could not be studied. Ctla4 haploinsufficient NZM.Ctla4+/− mice were assessed in parallel with littermate female NZM.Ctla4+/+ mice. Evaluations included CTLA-4 expression and lymphocyte profiles, assessed by fluorescence-activated cell sorting; serological profiles, assessed by ELISA; renal immunopathology, assessed by histology and immunofluorescence; and clinical courses, assessed by mortality.Results CTLA-4 expression was lower in NZM.Ctla4+/− mice than in NZM.Ctla4+/+ mice. Spleen mononuclear cells, B cells, plasma cells, CD4+ cells, recently activated CD4+ cells and CD4+ T regulatory (Treg) cells were increased in NZM.Ctla4+/− mice (p≤0.042). The serological profile, degree of renal immunopathology and mortality in NZM.Ctla4+/− mice remained unaffected.Conclusion Lifelong reduction in CTLA-4 expression in NZM mice neither accelerated nor aggravated SLE. Expansion in Treg cells may have played a protective role. Our observations raise the hope that long-term treatment of patients with SLE with an anti-CTLA-4 agent, should the need arise, would not adversely affect SLE disease activity. |
| format | Article |
| id | doaj-art-a1d8e02464494d6fa06e7561ad5b1ec2 |
| institution | OA Journals |
| issn | 2053-8790 |
| language | English |
| publishDate | 2019-12-01 |
| publisher | BMJ Publishing Group |
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| series | Lupus Science and Medicine |
| spelling | doaj-art-a1d8e02464494d6fa06e7561ad5b1ec22025-08-20T01:56:48ZengBMJ Publishing GroupLupus Science and Medicine2053-87902019-12-016110.1136/lupus-2018-000313Constitutive reduction in the checkpoint inhibitor, CTLA-4, does not accelerate SLE in NZM 2328 miceWilliam Stohl0Chaim Putterman1Ning Yu2Samantha A Chalmers3Chaim O Jacob46 University of Southern California Keck School of Medicine, Los Angeles, California, USA3 Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA1 Division of Rheumatology, University of Southern California, Los Angeles, California, USA2 Division of Rheumatology, Albert Einstein College of Medicine, Bronx, New York, USA1 Division of Rheumatology, University of Southern California, Los Angeles, California, USABackground/objective Treatment with immune checkpoint inhibitors (ICIs) in oncology patients is increasing. Although ICIs trigger rheumatic immune-related adverse events, development of SLE features has been rare. Whether long-term treatment with ICIs would promote SLE features remains unknown. To begin to address this, we generated SLE-prone NZM 2328 mice with lifelong reduction in CTLA-4 expression.Methods Since CTLA-4-deficient (Ctla4−/−) NZM mice developed a lethal lymphoproliferative disorder by 3–6 weeks of age, development of SLE in these mice could not be studied. Ctla4 haploinsufficient NZM.Ctla4+/− mice were assessed in parallel with littermate female NZM.Ctla4+/+ mice. Evaluations included CTLA-4 expression and lymphocyte profiles, assessed by fluorescence-activated cell sorting; serological profiles, assessed by ELISA; renal immunopathology, assessed by histology and immunofluorescence; and clinical courses, assessed by mortality.Results CTLA-4 expression was lower in NZM.Ctla4+/− mice than in NZM.Ctla4+/+ mice. Spleen mononuclear cells, B cells, plasma cells, CD4+ cells, recently activated CD4+ cells and CD4+ T regulatory (Treg) cells were increased in NZM.Ctla4+/− mice (p≤0.042). The serological profile, degree of renal immunopathology and mortality in NZM.Ctla4+/− mice remained unaffected.Conclusion Lifelong reduction in CTLA-4 expression in NZM mice neither accelerated nor aggravated SLE. Expansion in Treg cells may have played a protective role. Our observations raise the hope that long-term treatment of patients with SLE with an anti-CTLA-4 agent, should the need arise, would not adversely affect SLE disease activity.https://lupus.bmj.com/content/6/1/e000313.full |
| spellingShingle | William Stohl Chaim Putterman Ning Yu Samantha A Chalmers Chaim O Jacob Constitutive reduction in the checkpoint inhibitor, CTLA-4, does not accelerate SLE in NZM 2328 mice Lupus Science and Medicine |
| title | Constitutive reduction in the checkpoint inhibitor, CTLA-4, does not accelerate SLE in NZM 2328 mice |
| title_full | Constitutive reduction in the checkpoint inhibitor, CTLA-4, does not accelerate SLE in NZM 2328 mice |
| title_fullStr | Constitutive reduction in the checkpoint inhibitor, CTLA-4, does not accelerate SLE in NZM 2328 mice |
| title_full_unstemmed | Constitutive reduction in the checkpoint inhibitor, CTLA-4, does not accelerate SLE in NZM 2328 mice |
| title_short | Constitutive reduction in the checkpoint inhibitor, CTLA-4, does not accelerate SLE in NZM 2328 mice |
| title_sort | constitutive reduction in the checkpoint inhibitor ctla 4 does not accelerate sle in nzm 2328 mice |
| url | https://lupus.bmj.com/content/6/1/e000313.full |
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