Anti-human CD4 induces peripheral tolerance in a human CD4+, murine CD4-, HLA-DR+ advanced transgenic mouse model

被引:13
作者
Laub, R [1 ]
Brecht, R
Dorsch, M
Valey, U
Wenk, K
Emmrich, F
机构
[1] Univ Leipzig, Inst Clin Immunol & Transfus Med, Max Burger Forsch Zentrum, Johannisallee 30, D-04103 Leipzig, Germany
[2] Hannover Med Sch, Inst Lab Anim Sci, Hannover, Germany
关键词
D O I
10.4049/jimmunol.169.6.2947
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Selection in vivo of potent mAbs to human CD4 useful for immunotherapy, e.g., for the induction of immunological tolerance, is restricted for ethical reasons. We therefore used multiple transgenic mice that lack murine CD4, but express human CD4 specifically on Th cells, and HLA-DR3 as its natural counterligand (CD4/DR3 mice). The injection of CD4/DR3 mice with anti-human CD4 (mAb Max.16H5) before immunization with tetanus toxoid (TT, day 0) totally blocked the formation of specific Abs. This state of unresponsiveness persisted a subsequent boost again performed in the presence of anti-human CD4. When these mice were left untreated for at least 40 days, and were then re-exposed with TT, but in the absence of anti-human CD4, they consistently failed to induce specific Abs (long-term unresponsiveness). Exposure to second party Ags (hen egg lysozyme, human acetylcholine receptor) induced specific Abs comparable with control mice, demonstrating that the anti-CD4-induced unresponsiveness was Ag specific (immunological tolerance). Importantly, the concurrent injection of TT and anti-human CD4 at day 0, followed by another two anti-CD4 treatments, also led to tolerant animals, indicating that tolerance was inducible at the same day as the Ag exposure is provided. We finally demonstrate a limited ability of spleen cells to respond to TT in vitro, indicating that T cells are essentially involved in the maintenance of TT-specific tolerance. These data show for the first time that the human CD4 coreceptor mediates tolerance-inducing signals when triggered by an appropriate ligand in vivo.
引用
收藏
页码:2947 / 2955
页数:9
相关论文
共 50 条
[41]   EXPRESSION OF HUMAN CD4 BY 2 HUMAN MOUSE INTERLINEAGE HYBRIDS [J].
TAYLOR, GM ;
MORTEN, JEN ;
MORTEN, H ;
DODGE, AB ;
RIDWAY, JC ;
JONES, PM ;
HARRIS, R .
JOURNAL OF IMMUNOGENETICS, 1988, 15 (04) :197-208
[42]   EXPRESSION OF CD4 BY HUMAN MEGAKARYOCYTES [J].
BASCH, RS ;
KOURI, YH ;
KARPATKIN, S .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1990, 87 (20) :8085-8089
[43]   HUMAN CD4 BINDS IMMUNOGLOBULINS [J].
LENERT, P ;
KROON, D ;
SPIEGELBERG, H ;
GOLUB, ES ;
ZANETTI, M .
SCIENCE, 1990, 248 (4963) :1639-1643
[44]   Molecular Mechanotransduction in Human CD4 [J].
Jimenez, Raul Perez ;
Berkovich, Ronen ;
Richard, Patricia ;
Badilla, Carmen ;
Fernandez, Julio .
BIOPHYSICAL JOURNAL, 2012, 102 (03) :384A-384A
[45]   CD4+ cells in human ejaculates [J].
Gil, T ;
Castilla, JA ;
Hortas, ML ;
Molina, J ;
Redondo, M ;
Samaniego, F ;
Garrido, F ;
Vergara, F ;
Herruzo, A .
HUMAN REPRODUCTION, 1995, 10 (11) :2923-2927
[46]   Induction of CD4(+) T cell depletion in mice doubly transgenic for HIV gp120 and human CD4 [J].
Finco, O ;
Nuti, S ;
DeMagistris, MT ;
Mangiavacchi, L ;
Aiuti, A ;
Forte, P ;
Fantoni, A ;
vanderPutten, H ;
Abrignani, S .
EUROPEAN JOURNAL OF IMMUNOLOGY, 1997, 27 (06) :1319-1324
[47]   CD4 AND CD8 EXPRESSION BY HUMAN AND MOUSE THYMIC DENDRITIC CELLS [J].
WINKEL, K ;
SOTZIK, F ;
VREMEC, D ;
CAMERON, PU ;
SHORTMAN, K .
IMMUNOLOGY LETTERS, 1994, 40 (02) :93-99
[48]   CD4/CD8 ratio in human ageing [J].
Rea, IM ;
Stewart, M ;
Campbell, P ;
Alexander, HD ;
Morris, TCM .
BRITISH JOURNAL OF HAEMATOLOGY, 1996, 93 :190-190
[49]   HLA-DR POLYMORPHISM AFFECTS THE INTERACTION WITH CD4 [J].
SEKALY, RP ;
THIBODEAU, J ;
CROTEAU, G ;
LABRECQUE, N ;
ARONSON, HE ;
CANTIN, C ;
LONG, EO ;
FLEURY, S .
FASEB JOURNAL, 1995, 9 (04) :A1055-A1055
[50]   Modulation of the CD4 molecule on T helper cells by specific anti-human CD4 antibodies does not impair graft-versus-leukemia effect [J].
Schmidt, F. ;
Hilger, N. ;
Svanidze, E. ;
Emmrich, F. ;
Fricke, S. .
ONKOLOGIE, 2013, 36 :219-219