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Human Regulatory T Cells Control Xenogeneic Graft-versus-Host Disease Induced by Autologous T Cells in RAG2^–/–c^–/– Immunodeficient Mice

Authors' Affiliations: ¹ Department of Hematology, University Medical Center Utrecht and ² Faculty of Pharmaceutical Sciences, Department of Pharmaceutics, University of Utrecht, Utrecht, the Netherlands

Requests for reprints: T. Mutis, Department of Hematology (G.03.647), University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands. Phone: 31-30-2506504; Fax: 31-30-2511893; E-mail: t.mutis{at}azu.nl.

Purpose: 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^–/–c^–/– mice by i.v. administration of human peripheral blood mononuclear cells (PBMC).

Experimental Design: 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-, 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.

Commentary

Studying Human Regulatory T Cells In vivo

Emmanuel Zorn and Jerome Ritz
Clin. Cancer Res. 2006 12: 5265-5267. [Full Text] [PDF]

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