Recipient-type specific CD4+CD25+ regulatory T cells favor immune reconstitution and control graft-versus-host disease while maintaining graft-versus-leukemia
Aurélie Trenado, … , Benoît L. Salomon, José L. Cohen
Aurélie Trenado, … , Benoît L. Salomon, José L. Cohen
Published December 1, 2003
Citation Information: J Clin Invest. 2003;112(11):1688-1696. https://doi.org/10.1172/JCI17702.
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Article Immunology

Recipient-type specific CD4+CD25+ regulatory T cells favor immune reconstitution and control graft-versus-host disease while maintaining graft-versus-leukemia

Abstract

CD4+CD25+ regulatory T cells (Treg’s) play a pivotal role in preventing organ-specific autoimmune diseases and in inducing tolerance to allogeneic organ transplants. We and others recently demonstrated that high numbers of Treg’s can also modulate graft-versus-host disease (GVHD) if administered in conjunction with allogeneic hematopoietic stem cell transplantation in mice. In a clinical setting, it would be impossible to obtain enough freshly purified Treg’s from a single donor to have a therapeutic effect. Thus, we performed regulatory T cell expansion ex vivo by stimulation with allogeneic APCs, which has the additional effect of producing alloantigen-specific regulatory T cells. Here we show that regulatory T cells specific for recipient-type alloantigens control GVHD while favoring immune reconstitution. Irrelevant regulatory T cells only mediate a partial protection from GVHD. Preferential survival of specific regulatory T cells, but not of irrelevant regulatory T cells, was observed in grafted animals. Additionally, the use of specific regulatory T cells was compatible with some form of graft-versus-tumor activity. These data suggest that recipient-type specific Treg’s could be preferentially used in the control of GVHD in future clinical trials.

Authors

Aurélie Trenado, Frédéric Charlotte, Sylvain Fisson, Micael Yagello, David Klatzmann, Benoît L. Salomon, José L. Cohen

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Increased survival of sTreg’s as compared to irTreg’s in the spleen of g...
Increased survival of sTreg’s as compared to irTreg’s in the spleen of grafted mice. The injected Treg’s were detected in the spleen of animals grafted as described in Figure 1 by the expression of the Thy-1.1 congenic marker 45 days after transplantation. (a) Upper panels show proportions of Thy-1.1+ cells after they received either sTreg’s (n = 5) or irTreg’s (n = 5). Values indicate mean ± SEM of the absolute number of Thy-1.1+ cells. P < 0.05 between the two groups. Lower panels show the CD4 CD25 phenotype of cells gated on Thy-1.1+ cells. FSC, forward scatter. (b and c) The presence of injected Thy-1.1+ Treg’s was also evaluated in the spleen of grafted animals by immunohistochemistry. (b) Arrows indicate Thy-1.1–positive cells. (c) Each spleen was scored for the presence of injected Treg’s (Thy-1.1) or other T cells (Thy-1.2) in grafted mice receiving either sTreg’s (n = 8) or irTreg’s (n = 7). The y-axis indicates the intensity of staining ranging from 0 to 3. Each point corresponds to the histopathological score of an individual mouse; histograms indicate the mean histopathological score for each group. P < 0.05 between sTreg’s versus irTreg’s for Thy-1.1.