Control of spontaneous B lymphocyte autoimmunity with adenovirus-encoded soluble TACI

Arthritis Rheum. 2004 Jun;50(6):1884-96. doi: 10.1002/art.20290.

Abstract

Objective: Serum B lymphocyte stimulator (BLyS) is increased in autoimmune diseases, both in animal models and in humans. This study examined the effect of BLyS blockade in 3 animal models of lupus.

Methods: Antibodies and lupus-like disease manifestations were examined in mice after administration of a single injection of an adenoviral construct for the transmembrane activator and CAML interactor receptor (AdTACI) that produces high serum levels of TACI-Fc fusion protein.

Results: In C57BL/6 (B6) lpr/lpr mice (B6.lpr/lpr), which were used to model autoimmunity in the absence of severe disease, treatment of younger mice with AdTACI prevented the development of hypergammaglobulinemia. In contrast, use of AdTACI for BLyS blockade had only transient effects on the levels of IgG in normal B6 mice. AdTACI blocked the development of autoantibodies in younger B6.lpr/lpr mice and reversed the production of autoantibodies in older B6.lpr/lpr mice, and also reduced the numbers of splenic plasma cells. In MRL.lpr/lpr mice, which were used to examine disease manifestations, AdTACI reduced the extent of glomerulonephritis and proteinuria and improved survival, but had little effect on T cell infiltration and interstitial nephritis. However, in (NZB x NZW)F(1) mice, AdTACI induced neutralizing anti-TACI antibodies and failed to reduce the numbers of B cells.

Conclusion: BLyS blockade has little effect on IgG levels in normal mice, but reverses the production of spontaneously produced IgM and IgG autoantibodies in the setting of established autoimmunity. Blockade of BLyS ameliorates B cell-dependent disease manifestations even in the MRL.lpr/lpr model, but its effectiveness on autonomous T cell aspects of the disease is limited. Moreover, its effectiveness is neutralized by anti-TACI antibodies when present. These results provide a basis for understanding the potential effects of BLyS blockade in human disease.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Autoantibodies / blood
  • Autoimmunity / immunology
  • B-Lymphocytes / immunology*
  • COS Cells
  • Female
  • Genetic Therapy
  • Hypergammaglobulinemia / immunology
  • Hypergammaglobulinemia / therapy
  • Immunoglobulin Fc Fragments / genetics
  • Lupus Nephritis / immunology*
  • Lupus Nephritis / pathology
  • Lupus Nephritis / therapy*
  • Membrane Proteins / genetics*
  • Membrane Proteins / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred MRL lpr
  • Mice, Inbred NZB
  • Receptors, Tumor Necrosis Factor / genetics*
  • Receptors, Tumor Necrosis Factor / immunology
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / immunology
  • Transmembrane Activator and CAML Interactor Protein

Substances

  • Autoantibodies
  • Immunoglobulin Fc Fragments
  • Membrane Proteins
  • Receptors, Tumor Necrosis Factor
  • Recombinant Fusion Proteins
  • Tnfrsf13b protein, mouse
  • Transmembrane Activator and CAML Interactor Protein