EGFR-ErbB2 dual kinase inhibitor lapatinib decreases autoantibody levels and worsens renal disease in Interferon α-accelerated murine lupus

被引:2
作者
Gallo, Paul M. [1 ,5 ]
Chain, Robert W. [1 ,6 ]
Xu, Jun [1 ,7 ]
Whiteman, Leah M. [2 ]
Palladino, Annette [1 ,8 ]
Caricchio, Roberto [3 ,9 ]
Costa-Reis, Patricia [4 ,10 ]
Sullivan, Kathleen E. [1 ,2 ,3 ,4 ,11 ]
Gallucci, Stefania [1 ,2 ,12 ]
机构
[1] Temple Univ, Lewis Katz Sch Med, Dept Microbiol & Immunol, Lab Dendrit Cell Biol, Philadelphia, PA 19140 USA
[2] UMass Chan Med Sch, Dept Med, Div Innate Immun, Worcester, MA USA
[3] Temple Univ, Lewis Katz Sch Med, Sect Rheumatol, Philadelphia, PA 19140 USA
[4] Univ Penn, Childrens Hosp Philadelphia, Perelman Sch Med, Div Allergy Immunol,Dept Pediat, Philadelphia, PA 19104 USA
[5] Childrens Hosp Philadelphia, Div Hematol, Philadelphia, PA USA
[6] CRISPR Therapeut, Boston, MA USA
[7] Verismo Therapeut, Philadelphia, PA USA
[8] St Lukes Univ Hosp, Bethlehem Campus, Blackwood, NJ USA
[9] UMass Chan Med Sch, Dept Med, Div Rheumatol, Worcester, MA USA
[10] Univ Lisbon, Hosp Santa Maria, Fac Med, Pediat Rheumatol Unit,Pediat Dept, Lisbon, Portugal
[11] Univ Penn, Perelman Sch Med, Childrens Hosp Philadelphia, Div Allergy Immunol,Dept Pediat, Philadelphia, PA 19104 USA
[12] UMass Chan Med Sch, Dept Med, Div Innate Immun, Lab Dendrit Cell Biol, Worcester, MA USA
关键词
Autoantibodies; Nephrotoxicity; EGFR/HER2; inhibitor; Fibrosis; Lupus; type I IFN; GROWTH-FACTOR RECEPTOR; I INTERFERON; PHASE-II; MICE; NEPHRITIS; CELLS; ERYTHEMATOSUS; EXPRESSION; THERAPY; EGF;
D O I
10.1016/j.intimp.2024.112692
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Glomerulonephritis remains a major cause of morbidity and mortality in systemic lupus erythematosus (SLE). We have reported that expression of HER2/ErbB2, a member of the EGFR family, is increased in kidneys of patients and mice with lupus nephritis. We therefore asked if EGFR-family inhibition could ameliorate murine lupus nephritis. We used lapatinib, an EGFR-ErbB2 dual kinase inhibitor in female lupus-prone NZBxW/F1 mice, in which lupus onset was accelerated by injecting an IFN-alpha-expressing adenovirus. Mice received lapatinib (75 mg/Kg) or vehicle from the beginning of the acceleration or after the mice developed severe proteinuria (>300 mg/dL). Autoantibodies, kidney disease and markers of fibrosis and wound healing were analyzed. Exposure to IFN alpha induced ErbB2 expression in the kidney of lupus prone mice. Lapatinib, administered before but not after renal disease onset, lowered autoantibody titers and lessened immune complex deposition in the kidney. However, lapatinib increased proteinuria, kidney fibrosis and mouse mortality. Lapatinib also inhibited an in vitro wound healing assay testing renal cells. Our results suggest that EGFR-ErbB2 dual kinase inhibitor lapatinib decreases autoimmunity but worsens renal disease in IFN alpha-accelerated lupus, by increasing fibrosis and inhibiting wound healing. Type I Interferons are highlighted as important regulators of HER2/ErbB2 expression in the kidney. Further studies are required to parse the beneficial aspects of EGFR inhibition on autoimmunity from its negative effects on wound healing in lupus nephritis.
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页数:11
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