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Constitutive reduction in the checkpoint inhibitor, CTLA-4, does not accelerate SLE in NZM 2328 mice
  1. William Stohl1,
  2. Ning Yu1,
  3. Samantha A Chalmers2,
  4. Chaim Putterman3 and
  5. Chaim O Jacob1
  1. 1 Division of Rheumatology, University of Southern California, Los Angeles, California, USA
  2. 2 Division of Rheumatology, Albert Einstein College of Medicine, Bronx, New York, USA
  3. 3 Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA
  1. Correspondence to Dr William Stohl; stohl{at}usc.edu

Abstract

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.

  • CTLA-4
  • lupus
  • animal model
  • checkpoint protein

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Footnotes

  • Contributors WS designed the study and wrote the first draft. NY performed most of the experiments. SC performed some of the experiments. All authors analysed the data, contributed intellectually to the final draft and approved the final version.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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