Blockade of CD28 during in vitro activation of encephalitogenic T cells or after 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 encephalomyelitis (EAE). B7 blockade can ameliorate clinical EAE by indirectly interfering with CD28 signaling. However, B7 blockade can also result in disease exacerbation, presumably by interfering with regulatory B7:CTLA-4 interactions. Therefore, we have directly targeted T cell CD28 with specific mAbs both during initial Ag priming and after the onset of clinical signs of EAE. We found that CD28 blockade ameliorated EAE during the efferent and afferent limbs of the immune response. Disease amelioration at disease onset was associated with suppression of TNF-alpha production. Finally, Ab blockade of T cell CD28 during the first disease episode resulted in significant attenuation of the subsequent disease course, with no significant relapses. In contrast to previous studies targeting APC B7 with CTLA4-Ig, reagents targeting CD28 can block ongoing disease. Therefore, the present results suggest a clinically relevant therapeutic scenario for human diseases, such as multiple sclerosis.
Perrin
P J
PJ
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104, USA. perrinpj@mail.med.upenn.edu
June
C H
CH
Maldonado
J H
JH
Ratts
R B
RB
Racke
M K
MK
D000818:Animals; D019138:Antibodies, Blocking / Q000378:metabolism / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism; D001666:Binding Sites, Antibody; D018106:CD28 Antigens / Q000276:immunology* / Q000378:metabolism; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000276:immunology* / Q000517:prevention & control*; D005260:Female; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D018122:B7-1 Antigen; D018106:CD28 Antigens; D007376:Interleukin-2; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; D014409:Tumor Necrosis Factor-alpha