Human regulatory T cells control xenogeneic graft-versus-host disease induced by autologous T cells in RAG2-/-gammac-/- immunodeficient mice.
OBJECTIVE
Effective prevention of graft-versus-host disease (GvHD) is a major challenge to improve the safety of allogeneic stem cell transplantation for leukemia treatment. In murine transplantation models, administration of naturally occurring CD4+CD25+ regulatory T cells (Treg) can prevent GvHD. Toward understanding the role of human Treg in stem cell transplantation, we studied their capacity to modulate T-cell-dependent xenogeneic (x)-GvHD in a new model where x-GvHD is induced in RAG2-/-gammac-/- mice by i.v. administration of human peripheral blood mononuclear cells (PBMC).


METHODS
Human PBMC, depleted of or supplemented with autologous CD25+ Tregs, were administered in mice at different doses. The development of x-GvHD, in vivo expansion of human T cells, and secretion of human cytokines were monitored at weekly intervals.


RESULTS
Depletion of CD25+ cells from human PBMC significantly exacerbated x-GvHD and accelerated its lethality. In contrast, coadministration of Treg-enriched CD25+ cell fractions with autologous PBMC significantly reduced the lethality of x-GvHD. Treg administration significantly inhibited the explosive expansion of effector CD4+ and CD8+ T cells. Interestingly, protection from x-GvHD after Treg administration was associated with a significant increase in plasma levels of interleukin-10 and IFN-gamma, suggesting the de novo development of TR1 cells.


CONCLUSIONS
These results show, for the first time, the potent in vivo capacity of naturally occurring human Tregs to control GvHD-inducing autologous T cells, and indicate that this xenogeneic in vivo model may provide a suitable platform to further explore the in vivo mechanisms of T-cell down-regulation by naturally occurring human Tregs.
Mutis
Tuna
T
Department of Hematology, University Medical Center Utrecht and Faculty of Pharmaceutical Sciences, the Netherlands. t.mutis@azu.nl
van Rijn
Rozemarijn S
RS
Simonetti
Elles R
ER
Aarts-Riemens
Tineke
T
Emmelot
Maarten E
ME
van Bloois
Louis
L
Martens
Anton
A
Verdonck
Leo F
LF
Ebeling
Saskia B
SB
D000818:Animals; D015478:Antigens, Heterophile / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D001804:Blood Transfusion, Autologous / Q000662:veterinary; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology* / Q000401:mortality; D006801:Humans; D007142:Immunoglobulin gamma-Chains / Q000235:genetics*; D007371:Interferon-gamma / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D017708:Leukocyte Transfusion; D007962:Leukocytes / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016019:Survival Analysis; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*
D015478:Antigens, Heterophile; D001324:Autoantigens; D004268:DNA-Binding Proteins; D007142:Immunoglobulin gamma-Chains; D053645:Interleukin-2 Receptor alpha Subunit; C499308:Rag2 protein, mouse; D016753:Interleukin-10; D007371:Interferon-gamma