Prevention of Graft-Versus-Host Diseases by in Vivo supCD28mAb-Expanded Antigen-Specific nTreg Cells

• Published in: Cell transplantation Vol. 19; no. 6-7; pp. 765 - 774
• Main Authors: Kitazawa, Yusuke, Li, Xiao-Kang, Liu, Zhong, Kimura, Hiromitsu, Isaka, Yoshitaka, Hünig, Thomas, Takahara, Shiro
• Format: Journal Article
• Language: English
• Published: Los Angeles, CA SAGE Publications 01.06.2010; SAGE Publishing
• Subjects: Animals; Antibodies, Monoclonal - therapeutic use; CD28 Antigens - immunology; Cell Proliferation; Cytokines - blood; Epitopes - immunology; Forkhead Transcription Factors - metabolism; Graft vs Host Disease - blood; Graft vs Host Disease - drug therapy; Graft vs Host Disease - immunology; Graft vs Host Disease - prevention & control; Interleukin-2 Receptor alpha Subunit - immunology; Kinetics; Rats; Rats, Inbred Lew; Spleen - cytology; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - immunology; Graft-versus-host disease; Antigen-specific nTregs; nTregs
• ISSN: 0963-6897; 1555-3892
• DOI: 10.3727/096368910X508870

Naturally occurring CD4+CD25+ Treg cells (nTregs) can be exploited to establish an immunologic tolerance to non-self-antigens. The in vivo administration of a single superagonistic CD28-specific monoclonal antibody (supCD28mAb) to naive rat preferentially expanded the nTregs, which induced a potent inhibition of lethality of the graft-versus-host (GvH) diseases. The appearance of increased Foxp3 molecules was accompanied with a polarization towards a Th2 cytokine profile with a decreased production of IFN-γ and increased production of IL-4 and IL-10 in the serum of the antibody-treated rat. The peripheral Foxp3 nTregs are decreased in acute GvHD, while supCD28mAb administration showed that nTregs were preferentially proliferating in vivo, thus resulting in the significant prevention of the GvH disease. Furthermore, antigen-specific nTregs could suppress conventional T-cell proliferation stimulated with alloantigen in vitro. Taken together, our findings demonstrate that the potent regulatory functions of the Tregs for the treatment of GvHD are antigen specific. These data also provide evidence that GvHD is associated with decrease of Tregs in the periphery of the host. The determination of the Foxp3 Tregs can be a helpful tool to discriminate GvHD severity and lethality after allogeneic stem cell transplantation.