B-cell depletion with anti-CD20 ameliorates autoimmune cholangitis but exacerbates colitis in transforming growth factor-beta receptor II dominant negative mice.
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-beta (TGF-beta) receptor II dominant negative (dnTGF-betaRII) 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-alpha), interleukin 6 (IL-6), and chemokine (C-C motif) ligand (CCL2) (monocyte chemoattractant protein 1 [MCP-1]).


CONCLUSIONS
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.
Moritoki
Yuki
Y
Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA 95616, USA.
Lian
Zhe-Xiong
ZX
Lindor
Keith
K
Tuscano
Joseph
J
Tsuneyama
Koichi
K
Zhang
Weici
W
Ueno
Yoshiyuki
Y
Dunn
Robert
R
Kehry
Marilyn
M
Coppel
Ross L
RL
Mackay
Ian R
IR
Gershwin
M Eric
ME
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D018951:Antigens, CD20 / Q000276:immunology*; D001327:Autoimmune Diseases / Q000628:therapy*; D001402:B-Lymphocytes / Q000502:physiology*; D002761:Cholangitis / Q000628:therapy*; D003092:Colitis / Q000209:etiology*; D016207:Cytokines / Q000032:analysis; D008105:Liver Cirrhosis, Biliary / Q000628:therapy; D008212:Lymphocyte Depletion; D051379:Mice; D008928:Mitochondria / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D016207:Cytokines; D018125:Receptors, Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II