Constitutive reduction in the checkpoint inhibitor, CTLA-4, does not accelerate SLE in NZM 2328 mice

William Stohl, Ning Yu, Samantha A. Chalmers, Chaim Putterman, Chaim O. Jacob

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number000313
JournalLupus Science and Medicine
Volume6
Issue number1
DOIs
StatePublished - Feb 1 2019

Keywords

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

ASJC Scopus subject areas

  • Immunology

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