Superagonist CD28 antibody preferentially expanded Foxp3-expressing nTreg cells and prevented graft-versus-host diseases.
Regulatory lymphocytes play a pivotal role in preventing organ-specific autoimmune disease and in induction and maintenance of tolerance in various experimental transplantation models. The enhancement of the number and activity of peripheral CD4(+)CD25(+) Treg cells is an obvious goal for the treatment of autoimmunity and for the suppression of alloreactions. The present study demonstrates that naturally occurring CD4(+)CD25(+) Treg (nTreg) cells preferentially proliferate to a fourfold increase within 3 days in response to the administration of a single superagonistic CD28-specific monoclonal antibody (supCD28 mAb). The appearance of increased Foxp3 molecules was accompanied with polarization toward a Th2 cytokine profile with decreased production of IFN-gamma and increased production of IL-4 and IL-10 in the expanded Treg subset. Adoptive transfer of supCD28 mAb-expanded cells in a graft-versus-host disease (GvHD) model induced a potent inhibition of lethality. These results suggest that this therapeutic effect is mediated by the in vivo expansion of nTreg cells. Taken together, these data demonstrate that supCD28-mAb may target nTreg cells in vivo and maintain and enhance their potent regulatory functions for the treatment GvHD.
Laboratory of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
Yusuke
Y
Kitazawa
Masayuki
M
Fujino
Xiao-Kang
XK
Li
Lin
L
Xie
Naotsugu
N
Ichimaru
Masayoshi
M
Okumi
Norio
N
Nonomura
Akira
A
Tsujimura
Yoshitaka
Y
Isaka
Hiromitsu
H
Kimura
Thomas
T
Hünig
Shiro
S
Takahara
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D018106:CD28 Antigens / Q000276:immunology*; D049109:Cell Proliferation; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051381:Rats; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D051858:Forkhead Transcription Factors; C500522:Foxp3 protein, rat; D007376:Interleukin-2; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma