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.
Kitazawa
Yusuke
Y
Laboratory of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
Fujino
Masayuki
M
Li
Xiao-Kang
XK
Xie
Lin
L
Ichimaru
Naotsugu
N
Okumi
Masayoshi
M
Nonomura
Norio
N
Tsujimura
Akira
A
Isaka
Yoshitaka
Y
Kimura
Hiromitsu
H
Hünig
Thomas
T
Takahara
Shiro
S
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