BTK inhibition modulates multiple immune cell populations involved in the pathogenesis of immune mediated nephritis

Samantha A. Chalmers, Sayra J. Garcia, Deborah Webb, Leal Herlitz, Jay Fine, Elliott Klein, Meera Ramanujam, Chaim Putterman

Research output: Contribution to journalArticlepeer-review

Abstract

Lupus nephritis (LN) is a serious end organ complication of systemic lupus erythematosus. Nephrotoxic serum nephritis (NTN) is an inducible model of LN, which utilizes passive transfer of pre-formed nephrotoxic antibodies to initiate disease. In previous studies, we demonstrated that the Bruton's tyrosine kinase inhibitor, BI-BTK-1, prevents the development of nephritis in NTN when treatment was started prior to nephrotoxic serum transfer, and reverses established proteinuria as well. We manipulated the initiation and duration of BI-BTK-1 therapy in NTN to study its delayed therapeutic effects when treatment is given later in the disease course, as well as to further understand what effect BI-BTK-1 is having to prevent initiation of nephritis with early treatment. Early treatment and remission induction each correlated with decreased inflammatory macrophages, CD4+ and CD8+ T cells, and decreased B220+ B cells. Additionally, an increased proportion of resident macrophages within the CD45+ population favored a delay of disease onset and remission induction. We also studied the cellular processes involved in reactivation of nephritis by withdrawing BI-BTK-1 treatment at different time points. Treatment cessation led to either early or later onset of renal flares inversely dependent on the initial duration of BTK inhibition, as assessed by increased proteinuria and BUN levels and worse renal pathology. These flares were associated with an increase in kidney CD45+ infiltrates, including myeloid cell populations. IL-6, CD14, and CCL2 were also increased in mice developing late flares. These analyses point to the role of macrophages as an important contributor to the pathogenesis of immune mediated nephritis, and further support the therapeutic potential of BTK inhibition in this disease and related conditions.

Original languageEnglish
Article number108640
JournalClinical Immunology
Volume223
DOIs
StatePublished - Feb 2021

Keywords

  • BTK
  • BTK inhibitors
  • Immune cell infiltration
  • Lupus nephritis

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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