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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Figure 4

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Comparison of in vitro and in vivo properties of cultured sTreg’s and ir...
Comparison of in vitro and in vivo properties of cultured sTreg’s and irTreg’s. (a and b) 1 × 106 sTreg’s or irTreg’s were labeled with CFSE and injected into semiallogeneic, nonirradiated [BALB/c × C3H]F1. At days 3, 10, and 28, splenocytes from grafted animals were collected. The injected Treg’s were detected in the spleen of grafted animals by the expression of the Thy-1.1 congenic marker. Cell proliferation was measured as the sequential loss of CFSE within the Thy-1.1+ cell population by flow cytometry (a) and by the count of the absolute number of Thy-1.1+ cells in the spleen (magnitude ×100) (b). (c) 1 × 106 sTreg’s or irTreg’s were labeled with CFSE and injected into semiallogeneic irradiated [BALB/c × C3H]F1. At day 3, splenocytes from grafted animals were collected and cell division of donor cells was evaluated. (d) The in vitro suppressive properties of cultured Treg’s were tested after 3 weeks of culture. BALB/c CD25-depleted cells (effector T cells, white bar) were stimulated either by C3H APCs (left panel) or B6 APCs (right panel). Cells were cocultured with BALB/c sTreg’s (black bar) or irTreg’s (gray bar) in order to assess their suppressive activity. This figure is representative of three independent experiments.