Blockade of CD28 during in vitro activation of encephalitogenic T cells orafter disease onset ameliorates experimental autoimmune encephalomyelitis

Previous studies have shown complex roles for the B7 receptors in providing both positive and negative regulation of experimental autoimmune encephalo myelitis (EAE). B7 blockade can ameliorate clinical EAE by indirectly inter fering with CD28 signaling. However, B7 blockade can also result in disease exacerbation, presumably by interfering with regulatory B7:CTLA-4 interact ions, Therefore, we have directly targeted T cell CD28 with specific mAbs b oth during initial Ag priming and after the onset of clinical signs of EAE, We found that CD28 blockade ameliorated EAE during the efferent and affere nt limbs of the immune response, Disease amelioration at disease onset was associated with suppression of TNF-alpha production. Finally, Ab blockade o f T cell CD28 during the first disease episode resulted in significant atte nuation of the subsequent disease course, with no significant relapses. In contrast to previous studies targeting APC B7 with CTLA4-Ig, reagents targe ting CD28 can block ongoing disease. Therefore, the present results suggest a clinically relevant therapeutic scenario for human diseases, such as mul tiple sclerosis.