Selective targeting of regulatory T cells with CD28 superagonists allows effective therapy of experimental autoimmune encephalomyelitis.
CD4+CD25+ regulatory T cells (T reg cells) play a key role in controlling autoimmunity and inflammation. Therefore, therapeutic agents that are capable of elevating numbers or increasing effector functions of this T cell subset are highly desirable. In a previous report we showed that a superagonistic monoclonal antibody specific for rat CD28 (JJ316) expands and activates T reg cells in vivo and upon short-term in vitro culture. Here we demonstrate that application of very low dosages of the CD28 superagonist into normal Lewis rats is sufficient to induce T reg cell expansion in vivo without the generalized lymphocytosis observed with high dosages of JJ316. Single i.v. administration of a low dose of the CD28 superagonist into Dark Agouti (DA) rats or Lewis rats that suffered from experimental autoimmune encephalomyelitis (EAE) proved to be highly and equally efficacious as high-dose treatment. Finally, we show that T reg cells that were isolated from CD28-treated animals displayed enhanced suppressive activity toward myelin basic protein-specific T cells in vitro, and, upon adoptive transfer, protected recipients from EAE. Our data indicate that this class of CD28-specific monoclonal antibodies targets CD4+CD25+ T reg cells and provides a novel means for the effective treatment of multiple sclerosis and other autoimmune diseases.
Beyersdorf
Niklas
N
Institute for Virology and Immunobiology, University of Würzburg, D-97078 Würzburg, Germany.
Gaupp
Stefanie
S
Balbach
Karen
K
Schmidt
Jens
J
Toyka
Klaus V
KV
Lin
Chia-Huey
CH
Hanke
Thomas
T
Hünig
Thomas
T
Kerkau
Thomas
T
Gold
Ralf
R
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004306:Dose-Response Relationship, Immunologic; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D007165:Immunosuppression Therapy; D007275:Injections, Intravenous; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D015375:Receptors, Interleukin-2
D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D015375:Receptors, Interleukin-2