CTLA-4 - A NEGATIVE REGULATOR OF AUTOIMMUNE-DISEASE

CTLA-4, a CD28 homologue expressed on activated T cells, binds with hi gh affinity to the CD28 ligands, B7-1 (CD80) and B7-2 (CD86). This stu dy was designed to examine the role of CTLA-4 in regulating autoimmune disease. Murine relapsing-remitting experimental autoimmune encephalo myelitis (R-EAE) is a demyelinating disease mediated by PLP139-151-spe cific CD4(+) T cells in SJL/J mice. Anti-CTLA-4 mAbs (or their F(ab) f ragments) enhanced in vitro proliferation and pro-inflammatory cytokin e production by PLP139-151-primed lymph node cells. Addition oi either reagent to in vitro activation cultures potentiated the ability of T cells to adoptively transfer disease to naive recipients. In vivo admi nistration of anti-CTLA-4 mAb to recipients of PLP139-151-specific cel ls resulted in accelerated and exacerbated disease. Finally, anti-CTLA -4 treatment of mice during disease remission resulted in tile exacerb ation of relapses. Collectively, these results suggest that CTLA-4 med iates the downregulation of ongoing immune responses and plays a major role in regulating autoimmunity.