B-cell depletion with anti-CD20 ameliorates autoimmune cholangitis but exacerbates colitis in transforming growth factor-β receptor II dominant negative mice

Yuki Moritoki, Zhe Xiong Lian, Keith Lindor, Joseph Tuscano, Koichi Tsuneyama, Weici Zhang, Yoshiyuki Ueno, Robert Dunn, Marilyn Kehry, Ross L. Coppel, Ian R. Mackay, M. Eric Gershwin

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Abstract

The treatment of primary biliary cirrhosis (PBC) with conventional immunosuppressive drugs has been relatively disappointing and there have been few efforts in defining a role for the newer biological agents useful in rheumatoid arthritis and other systemic autoimmune diseases. In this study we took advantage of transforming growth factor-β (TGF-β) receptor II dominant negative (dnTGF-βRII) mice, a mouse model of autoimmune cholangitis, to address the therapeutic efficacy of B-cell depletion using anti-CD20. Mice were treated at either 4-6 weeks of age or beginning at 20-22 weeks of age with intraperitoneal injections of anti-CD20 every 2 weeks. We quantitated B-cell levels in all mice as well as antimitochondrial antibodies (AMA), serum and hepatic levels of proinflammatory cytokines, and histopathology of liver and colon. In mice whose treatment was initiated at 4-6 weeks of age, anti-CD20 therapy demonstrated a significantly lower incidence of liver inflammation associated with reduced numbers of activated hepatic CD8 + T cells. However, colon inflammation was exacerbated. In contrast, in mice treated at 20-22 weeks of age, anti-CD20 therapy had relatively little effect on either liver or colon disease. As expected, all treated animals had reduced levels of B cells, absence of AMA, and increased levels in sera of tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and chemokine (C-C motif) ligand (CCL2) (monocyte chemoattractant protein 1 [MCP-1]). Conclusion: These data suggest potential usage of anti-CD20 in early PBC resistant to other modalities, but raise a cautionary note regarding the use of anti-CD20 in inflammatory bowel disease.

Original languageEnglish (US)
Pages (from-to)1893-1903
Number of pages11
JournalHepatology
Volume50
Issue number6
DOIs
StatePublished - 2009
Externally publishedYes

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Cholangitis
Growth Factor Receptors
Transforming Growth Factors
Colitis
B-Lymphocytes
Liver
Colon
Biliary Liver Cirrhosis
Inflammation
Therapeutics
CC Chemokines
Antibodies
Chemokine CCL2
Biological Factors
Immunosuppressive Agents
Intraperitoneal Injections
Serum
Inflammatory Bowel Diseases
Autoimmune Diseases
Interleukin-6

ASJC Scopus subject areas

  • Hepatology

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B-cell depletion with anti-CD20 ameliorates autoimmune cholangitis but exacerbates colitis in transforming growth factor-β receptor II dominant negative mice. / Moritoki, Yuki; Lian, Zhe Xiong; Lindor, Keith; Tuscano, Joseph; Tsuneyama, Koichi; Zhang, Weici; Ueno, Yoshiyuki; Dunn, Robert; Kehry, Marilyn; Coppel, Ross L.; Mackay, Ian R.; Gershwin, M. Eric.

In: Hepatology, Vol. 50, No. 6, 2009, p. 1893-1903.

Research output: Contribution to journalArticle

Moritoki, Y, Lian, ZX, Lindor, K, Tuscano, J, Tsuneyama, K, Zhang, W, Ueno, Y, Dunn, R, Kehry, M, Coppel, RL, Mackay, IR & Gershwin, ME 2009, 'B-cell depletion with anti-CD20 ameliorates autoimmune cholangitis but exacerbates colitis in transforming growth factor-β receptor II dominant negative mice', Hepatology, vol. 50, no. 6, pp. 1893-1903. https://doi.org/10.1002/hep.23238
Moritoki, Yuki ; Lian, Zhe Xiong ; Lindor, Keith ; Tuscano, Joseph ; Tsuneyama, Koichi ; Zhang, Weici ; Ueno, Yoshiyuki ; Dunn, Robert ; Kehry, Marilyn ; Coppel, Ross L. ; Mackay, Ian R. ; Gershwin, M. Eric. / B-cell depletion with anti-CD20 ameliorates autoimmune cholangitis but exacerbates colitis in transforming growth factor-β receptor II dominant negative mice. In: Hepatology. 2009 ; Vol. 50, No. 6. pp. 1893-1903.
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abstract = "The treatment of primary biliary cirrhosis (PBC) with conventional immunosuppressive drugs has been relatively disappointing and there have been few efforts in defining a role for the newer biological agents useful in rheumatoid arthritis and other systemic autoimmune diseases. In this study we took advantage of transforming growth factor-β (TGF-β) receptor II dominant negative (dnTGF-βRII) mice, a mouse model of autoimmune cholangitis, to address the therapeutic efficacy of B-cell depletion using anti-CD20. Mice were treated at either 4-6 weeks of age or beginning at 20-22 weeks of age with intraperitoneal injections of anti-CD20 every 2 weeks. We quantitated B-cell levels in all mice as well as antimitochondrial antibodies (AMA), serum and hepatic levels of proinflammatory cytokines, and histopathology of liver and colon. In mice whose treatment was initiated at 4-6 weeks of age, anti-CD20 therapy demonstrated a significantly lower incidence of liver inflammation associated with reduced numbers of activated hepatic CD8 + T cells. However, colon inflammation was exacerbated. In contrast, in mice treated at 20-22 weeks of age, anti-CD20 therapy had relatively little effect on either liver or colon disease. As expected, all treated animals had reduced levels of B cells, absence of AMA, and increased levels in sera of tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and chemokine (C-C motif) ligand (CCL2) (monocyte chemoattractant protein 1 [MCP-1]). Conclusion: These data suggest potential usage of anti-CD20 in early PBC resistant to other modalities, but raise a cautionary note regarding the use of anti-CD20 in inflammatory bowel disease.",
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AU - Lindor, Keith

AU - Tuscano, Joseph

AU - Tsuneyama, Koichi

AU - Zhang, Weici

AU - Ueno, Yoshiyuki

AU - Dunn, Robert

AU - Kehry, Marilyn

AU - Coppel, Ross L.

AU - Mackay, Ian R.

AU - Gershwin, M. Eric

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AB - The treatment of primary biliary cirrhosis (PBC) with conventional immunosuppressive drugs has been relatively disappointing and there have been few efforts in defining a role for the newer biological agents useful in rheumatoid arthritis and other systemic autoimmune diseases. In this study we took advantage of transforming growth factor-β (TGF-β) receptor II dominant negative (dnTGF-βRII) mice, a mouse model of autoimmune cholangitis, to address the therapeutic efficacy of B-cell depletion using anti-CD20. Mice were treated at either 4-6 weeks of age or beginning at 20-22 weeks of age with intraperitoneal injections of anti-CD20 every 2 weeks. We quantitated B-cell levels in all mice as well as antimitochondrial antibodies (AMA), serum and hepatic levels of proinflammatory cytokines, and histopathology of liver and colon. In mice whose treatment was initiated at 4-6 weeks of age, anti-CD20 therapy demonstrated a significantly lower incidence of liver inflammation associated with reduced numbers of activated hepatic CD8 + T cells. However, colon inflammation was exacerbated. In contrast, in mice treated at 20-22 weeks of age, anti-CD20 therapy had relatively little effect on either liver or colon disease. As expected, all treated animals had reduced levels of B cells, absence of AMA, and increased levels in sera of tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and chemokine (C-C motif) ligand (CCL2) (monocyte chemoattractant protein 1 [MCP-1]). Conclusion: These data suggest potential usage of anti-CD20 in early PBC resistant to other modalities, but raise a cautionary note regarding the use of anti-CD20 in inflammatory bowel disease.

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