Regulation of rat and human T-cell immune response by pharmacologically modified dendritic cells.
BACKGROUND
The central function of dendritic cells (DC) in inducing and preventing immune responses makes them ideal therapeutic targets for the induction of immunologic tolerance. In a rat in vivo model, we showed that dexamethasone-treated DC (Dex-DC) induced indirect pathway-mediated regulation and that CD4+CD25+ T cells were involved in the observed effects. The aim of the present study was to investigate the mechanisms underlying the acquired immunoregulatory properties of Dex-DC in the rat and human experimental systems.


METHODS
After treatment with dexamethasone (Dex), the immunogenicity of Dex-DC was analyzed in T-cell proliferation and two-step hyporesponsiveness induction assays. After carboxyfluorescein diacetate succinimidyl ester labeling, CD4+CD25+ regulatory T-cell expansion was analyzed by flow cytometry, and cytokine secretion was measured by ELISA.


RESULTS
In this study, we demonstrate in vitro that rat Dex-DC induced selective expansion of CD4+CD25+ regulatory T cells, which were responsible for alloantigen-specific hyporesponsiveness. The induction of regulatory T-cell division by rat Dex-DC was due to secretion of interleukin (IL)-2 by DC. Similarly, in human studies, monocyte-derived Dex-DC were also poorly immunogenic, were able to induce T-cell anergy in vitro, and expand a population of T cells with regulatory functions. This was accompanied by a change in the cytokine profile in DC and T cells in favor of IL-10.


CONCLUSIONS
These data suggest that Dex-DC induced tolerance by different mechanisms in the two systems studied. Both rat and human Dex-DC were able to induce and expand regulatory T cells, which occurred in an IL-2 dependent manner in the rat system.
Fazekasova
Henrieta
H
Immunoregulation Laboratory, MRC Centre of Transplantation DIIID, King's College London, Guy's Campus, London, United Kingdom.
Golshayan
Dela
D
Read
Joseph
J
Tsallios
Aristotle
A
Tsang
Julia Yuen-Shan
JY
Dorling
Anthony
A
George
Andrew J T
AJ
Lechler
Robert I
RI
Lombardi
Giovanna
G
Mirenda
Vincenzo
V
D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology; D015704:CD4 Antigens / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D003907:Dexamethasone / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D055633:Immune System Phenomena / Q000276:immunology*; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*
D015704:CD4 Antigens; D016207:Cytokines; D003907:Dexamethasone