Research ArticleGraft-Versus-Host Disease

Massive ex Vivo Expansion of Human Natural Regulatory T Cells (Tregs) with Minimal Loss of in Vivo Functional Activity

Science Translational Medicine  18 May 2011:
Vol. 3, Issue 83, pp. 83ra41
DOI: 10.1126/scitranslmed.3001809

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Cross-Checking Graft-Versus-Host Disease

Fighting in hockey is a long-standing tradition: Stitches and gap-toothed smiles are badges of honor among these aggressive athletes. Yet, a balance must be maintained between the occasional high stick and an all-out melee. Black-and-white striped referees serve to uphold this balance, breaking up fights and preventing the bench-clearing brawl. Regulatory T cells (Tregs) are the referees of the adaptive immune system. They prevent the enforcers, cytotoxic T cells, from an overly exuberant response and, in the case of a bone marrow transplant, from attacking the patient’s own tissues. This process, called graft-versus-host disease (GVHD), is one of the risks of transplantation and differs from organ rejection. However, using Tregs to prevent GVHD has been limited by low Treg numbers and altered function after expansion in vitro. Hippen et al. now report a new way to expand Tregs to numbers much larger than those previously achieved while maintaining their ability to selectively suppress self-attacking cytotoxic T cells in vivo.

Umbilical cord blood can be used to expand functional natural Tregs (nTregs); however, the initial number of nTregs in cord blood is limited. Therefore, the authors used peripheral blood as a source of nTregs for expansion. Using good manufacturing practice conditions and artificial antigen-presenting cells designed to stimulate T cell expansion, Hippen et al. expanded nTregs 80-fold after only one stimulation; they then showed that these multiplied cells maintained suppressor function. Stimulation of the nTreg population up to four times expanded the numbers of functional cells ~50 million–fold. When injected into mice at the same time as human T cells, these expanded Tregs significantly reduced mortality resulting from GVHD. Such large numbers of functional nTregs could be used to establish donor banks that would keep human GVHD and autoimmunity in check.


  • Citation: K. L. Hippen, S. C. Merkel, D. K. Schirm, C. M. Sieben, D. Sumstad, D. M. Kadidlo, D. H. McKenna, J. S. Bromberg, B. L. Levine, J. L. Riley, C. H. June, P. Scheinberg, D. C. Douek, J. S. Miller, J. E. Wagner, B. R. Blazar, Massive ex Vivo Expansion of Human Natural Regulatory T Cells (Tregs) with Minimal Loss of in Vivo Functional Activity. Sci. Transl. Med. 3, 83ra41 (2011).

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