Long-term inhibition of murine lupus by brief simultaneous blockade of the B7/CD28 and CD40/gp39 costimulation pathways

J Immunol. 1997 Oct 1;159(7):3104-8.

Abstract

Murine lupus in NZB/NZW F1 (B/W) mice can be retarded by sustained administration of CTLA4Ig and by brief treatment early in life with mAb that block CD40/gp39 interactions. We sought to determine whether brief therapy with CTLA4Ig could provide sustained benefit in B/W mice and whether a synergistic effect could be derived by blockade of both the B7/CD28 and the CD40/gp39 pathways. We found that a short course of CTLA4Ig at the onset of disease produced only short-term benefit. However, when CTLA4Ig was combined with anti-gp39, there was long-lasting inhibition of autoantibody production and renal disease. Ten months after the 2-wk course of therapy, 70% of these mice were alive, compared with only 18% and 0% of those that received only anti-gp39 or CTLA4Ig, respectively. These findings demonstrate that brief simultaneous blockade of the B7/CD28 and CD40/gp39 costimulation pathways can produce benefit that lasts long after treatment has been discontinued.

Publication types

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

MeSH terms

  • Abatacept
  • Animals
  • Antibodies, Blocking / pharmacology
  • Antibodies, Blocking / therapeutic use
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal / therapeutic use
  • Antigens, CD
  • Antigens, Differentiation / pharmacology
  • Antigens, Differentiation / therapeutic use
  • B7-1 Antigen / immunology*
  • B7-1 Antigen / metabolism
  • CD28 Antigens / immunology*
  • CD28 Antigens / metabolism
  • CD40 Antigens / immunology*
  • CD40 Antigens / metabolism
  • CD40 Ligand
  • CTLA-4 Antigen
  • Drug Synergism
  • Female
  • Immunoconjugates*
  • Immunosuppressive Agents / pharmacology*
  • Immunosuppressive Agents / therapeutic use
  • Ligands
  • Lupus Nephritis / etiology*
  • Lupus Nephritis / immunology*
  • Lupus Nephritis / prevention & control
  • Lymphocyte Activation
  • Membrane Glycoproteins / immunology*
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred NZB
  • Time Factors

Substances

  • Antibodies, Blocking
  • Antibodies, Monoclonal
  • Antigens, CD
  • Antigens, Differentiation
  • B7-1 Antigen
  • CD28 Antigens
  • CD40 Antigens
  • CTLA-4 Antigen
  • Ctla4 protein, mouse
  • Immunoconjugates
  • Immunosuppressive Agents
  • Ligands
  • Membrane Glycoproteins
  • CD40 Ligand
  • Abatacept