Imatinib Suppresses Cryoglobulinemia and Secondary Membranoproliferative Glomerulonephritis

Abstract

Imatinib is a receptor tyrosine kinase inhibitor that blocks the activity of c-Abl, c-Kit, and PDGF receptors. We tested the protective effects of imatinib in thymic stromal lymphopoietin transgenic mice, a model of cryoglobulinemia and associated membranoproliferative glomerulonephritis (MPGN), in which some glomerular manifestations likely result from PDGF receptor activation. Surprising, administration of imatinib beginning at weaning suppressed production of cryoglobulin, attenuating both the renal injury and systemic features of cryoglobulinemia. Flow cytometry suggested that inhibition of B cell development in the bone marrow likely caused the reduction in cryoglobulin production. In addition, administration of imatinib to thymic stromal lymphopoietin transgenic mice with established MPGN also diminished cryoglobulin production and reversed the renal and systemic lesions. These data suggest that treatment with imatinib may be a novel therapeutic approach for cryoglobulinemia and MPGN in humans.

Imatinib

“…A transgenic mouse model with constitutively active thymic stromal lymphopoietin resulted in cryoglobulin production and renal histologic lesions consistent with membranoproliferative GN caused by cryoglobulinemia. 55 Imatinib treatment in this mouse model reduces the cryocrit, serum levels of all immunoglobulins, mature and immature B cells, systemic manifestations of the disease, and C3 glomerular deposition. To highlight the immunomodulatory role of imatinib, the same thymic stromal lymphopoietin tg mouse model was treated with angiotensinconverting enzyme inhibition or angiotensin-receptor blocker therapy alone and showed no improvement in markers of immunologic activation.…”

“…[53][54][55] In the two LN models, imatinib reduced anti-double-stranded DNA levels and decreased immune complex deposition. 53,54 This resulted in improved survival, creatinine, and proteinuria.…”

“…Imatinib also markedly reduced ECM deposition and fibrosis in most of these murine models of kidney disease. 11,49,50,53,55,[58][59][60][61] PDGF signaling was disrupted by imatinib, as shown by decreased levels of PDGF-A, 58 PDGF-B, 50,58,59 , and PDGFR-b. 50,54,57,58 Imatinib also decreased levels of TGF-b 50,53,54,58,59 and TGF-b type I receptor 58 as well.…”

A Spleen Tyrosine Kinase Inhibitor Reduces the Severity of Established Glomerulonephritis

“…23 Tyrosine kinases are important therapeutic targets; for example, imatinib, an inhibitor of tyrosine kinase downstream of platelet-derived growth factor receptor, has been shown to reduce the severity of established experimental glomerulonephritis, including NTN, in association with reduction of glomerular IL-1␤ and MCP-1. 18,26 Our results suggested that Syk inhibition has potential in the treatment of patients with glomerulonephritis.…”

Deletion of Activating Fcγ Receptors Does Not Confer Protection in Murine Cryoglobulinemia-Associated Membranoproliferative Glomerulonephritis

“…As previously described, the liver and lung inflammation was scored semiquantitatively on a scale of 0 to 3: 0, no inflammation; 1, mild; 2, moderate; 3, severe, with regard to the extent and density of leukocytic infiltration. 15,17 All data are expressed as mean Ϯ SEM. Statistical analysis of the data for multiple groups was performed by TSLPtg mice developed typical features of cryoglobulin-associated MPGN as described previously.…”