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Direct Expansion of Human Allospecific FoxP3⁺CD4⁺ Regulatory T Cells with Allogeneic B Cells for Therapeutic Application

Leo C. Chen^*, Julio C. Delgado, Peter E. Jensen and Xinjian Chen^1,

^* Georgia Institute of Technology, Atlanta, GA 30332; and Department of Pathology, University of Utah, Salt Lake City, UT 84112

Compelling evidence from animal studies has demonstrated that allospecific FoxP3⁺CD4⁺ regulatory T (Treg) cells expanded ex vivo can be used as effective therapeutic tools in the treatment of allograft rejection and graft-vs-host disease. Despite the promising results from animal studies, there remain major barriers to developing Treg cell-based immunotherapy in humans. Currently, no effective approach has been established for selective expansion of human allospecific Treg cells ex vivo. Additionally, the very low frequency of Treg cells present in human peripheral blood could pose a formidable challenge to obtaining a sufficient number of Treg cells from a single donor for ex vivo expansion for therapeutic utilization. Extending our recent finding that mouse B cells preferentially induce expansion of alloreactive Treg cells, we report herein that human Treg cells can be expanded ex vivo with allogeneic B cells. The expanded Treg cells express very high levels of FoxP3, maintain anergic phenotype, and are potent suppressors capable of inhibiting the alloproliferation of third-party responder T cells at very low Treg-to-T effector cell ratio in an alloantigen-specific manner. The alloantigen specificity demonstrated by B cell-expanded Treg cells is not determined by the HLA haplotypes of the Treg cells, but it is induced and determined by the haplotype of the B cells used to expand them. Our findings represent a significant advance in the development of Treg cell-based immunotherapy in humans and raise the possibility of using third-party Treg cells for therapeutic applications.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Xinjian Chen, Department of Pathology, University of Utah, 1520 Emma Eccles Jones Building, 30 North 1900 East, Salt Lake City, UT 84112. E-mail address: xinjian.chen{at}path.utah.edu

² Abbreviations used in this paper: Treg cells, naturally arising FoxP3⁺CD4⁺ T cells; GVHD, graft-vs-host disease; DC, dendritic cells; MFI, mean fluorescence intensity; BMT, bone marrow transplantation.