CTLA-4: a negative regulator of autoimmune disease.

• DOI: 10.1084/jem.184.2.783
• Publication Date: 2004-06-24T07:56:10Z
• Authors: N J Karandikar; C L Vanderlugt; T L Walunas; S D Miller; J A Bluestone
• Keywords: Multiple Sclerosis; Encephalomyelitis, Autoimmune, Experimental; Immunoconjugates; Immunology; Molecular Sequence Data; Inbred Strains; Mice, Inbred Strains; Neurodegenerative; Passive; Lymphocyte Activation; Autoimmune Disease; Medical and Health Sciences; Autoantigens; Abatacept; Experimental; Interferon-gamma; Mice; 03 medical and health sciences; 0302 clinical medicine; Antigens, CD; 616; 2.1 Biological and endogenous factors; Animals; CTLA-4 Antigen; Amino Acid Sequence; Aetiology; Antigens; Encephalomyelitis; Inflammatory and immune system; Neurosciences; Immunization, Passive; Myelin Basic Protein; Antigens, Differentiation; Brain Disorders; CD; 3. Good health; Differentiation; Interleukin-2; Immunization; Female; Peptides; Autoimmune

CTLA-4, a CD28 homologue expressed on activated T cells, binds with high affinity to the CD28 ligands, B7-1 (CD80) and B7-2 (CD86). This study was designed to examine the role of CTLA-4 in regulating autoimmune disease. Murine relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE) is a demyelinating disease mediated by PLP139-151-specific CD4+ T cells in SJL/J mice. Anti-CTLA-4 mAbs (or their F(ab) fragments) enhanced in vitro proliferation and pro-inflammatory cytokine production by PLP139-151-primed lymph node cells. Addition of either reagent to in vitro activation cultures potentiated the ability of T cells to adoptively transfer disease to naive recipients. In vivo administration of anti-CTLA-4 mAb to recipients of PLP139-151-specific T cells resulted in accelerated and exacerbated disease. Finally, anti-CTLA-4 treatment of mice during disease remission resulted in the exacerbation of relapses. Collectively, these results suggest that CTLA-4 mediates the downregulation of ongoing immune responses and plays a major role in regulating autoimmunity.