Antibody-mediated depletion of lymphocyte-activation gene-3 (LAG-3(+) )-activated T lymphocytes prevents delayed-type hypersensitivity in non-human primates

Clin Exp Immunol. 2011 May;164(2):265-74. doi: 10.1111/j.1365-2249.2011.04329.x. Epub 2011 Feb 24.


Lymphocyte-activation gene-3 (LAG-3, CD223) is a marker for recently activated effector T cells. Activated T lymphocytes are of major importance in many autoimmune diseases and organ transplant rejection. Therefore, specifically depleting LAG-3(+) T cells might lead to targeted immunosuppression that would spare resting T cells while eliminating pathogenic activated T cells. We have shown previously that anti-LAG-3 antibodies sharing depleting as well as modulating activities inhibit heart allograft rejection in rats. Here, we have developed and characterized a cytotoxic LAG-3 chimeric antibody (chimeric A9H12), and evaluated its potential as a selective therapeutic depleting agent in a non-human primate model of delayed-type hypersensitivity (DTH). Chimeric A9H12 showed a high affinity to its antigen and depleted both cytomegalovirus (CMV)-activated CD4(+) and CD8(+) human T lymphocytes in vitro. In vivo, a single intravenous injection at either 1 or 0·1 mg/kg was sufficient to deplete LAG-3(+) -activated T cells in lymph nodes and to prevent the T helper type 1 (Th1)-driven skin inflammation in a tuberculin-induced DTH model in baboons. T lymphocyte and macrophage infiltration into the skin was also reduced. The in vivo effect was long-lasting, as several weeks to months were required after injection to restore a positive reaction after antigen challenge. Our data confirm that LAG-3 is a promising therapeutic target for depleting antibodies that might lead to higher therapeutic indexes compared to traditional immunosuppressive agents in autoimmune diseases and transplantation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal / therapeutic use*
  • Antibody-Dependent Cell Cytotoxicity / drug effects
  • Antigens, CD / immunology*
  • BCG Vaccine / immunology
  • Cells, Cultured / drug effects
  • Cells, Cultured / immunology
  • Chemotaxis, Leukocyte / drug effects
  • Cytomegalovirus Infections / immunology
  • Cytomegalovirus Infections / pathology
  • Humans
  • Hypersensitivity, Delayed / etiology
  • Hypersensitivity, Delayed / prevention & control*
  • Immunosuppressive Agents / pharmacology
  • Immunosuppressive Agents / therapeutic use*
  • Intradermal Tests
  • Lymphocyte Activation
  • Lymphocyte Activation Gene 3 Protein
  • Lymphocyte Depletion*
  • Macrophages / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Papio
  • Recombinant Fusion Proteins / pharmacology
  • Recombinant Fusion Proteins / therapeutic use*
  • Skin / immunology*
  • Skin / pathology
  • T-Lymphocyte Subsets / immunology*
  • Th1 Cells / drug effects
  • Th1 Cells / immunology
  • Tuberculin / toxicity


  • Antibodies, Monoclonal
  • Antigens, CD
  • BCG Vaccine
  • Immunosuppressive Agents
  • Recombinant Fusion Proteins
  • Tuberculin
  • Lymphocyte Activation Gene 3 Protein