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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0800561v1 183/1/696    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Bohana-Kashtan, O. Articles by Civin, C. I. Search for Related Content PubMed PubMed Citation Articles by Bohana-Kashtan, O. Articles by Civin, C. I.

Selective Reduction of Graft-versus-Host Disease-Mediating Human T Cells by Ex Vivo Treatment with Soluble Fas Ligand¹

Osnat Bohana-Kashtan^*, Sebastien Morisot^*, Richard Hildreth^*, Cory Brayton, Hyam I. Levitsky^* and Curt I. Civin^2,*,

^* Divisions of Immunology and Hematopoiesis and Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, and Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21231

Previous work done in our laboratory, using mouse models, showed that soluble Fas ligand (sFasL) can efficiently delete donor anti-host T cells during their activation against irradiated host cells in MLCs. In the mouse models, this ex vivo sFasL treatment abrogated graft-vs-host disease (GVHD) while sparing donor T cells with antitumor reactivity. The present work was performed with human cells, to extend our work toward reduction of clinical GVHD. PBMC responders from a given individual (first party) were stimulated in vitro with irradiated PBMC stimulators from a second person (second party), in the presence of sFasL. In control MLCs without sFasL, alloreacting T cells began to up-regulate Fas (CD95) detectably and became sensitive to Fas-mediated apoptosis by as early as day 1–2. In MLCs containing sFasL, there were greatly reduced numbers of alloreacting CD3⁺CFSE^lo cells, activation Ag-expressing CD4^hi and CD8^hi cells, IFN--producing CD4⁺ and CD8⁺ cells, and CD8⁺CD107a⁺ CTLs. Furthermore, mice transplanted with the ex vivo sFasL/MLR-treated cells had prolonged time to fatal GVHD in an in vivo xenogeneic GVHD model. Responder cells harvested from primary MLCs containing sFasL had reduced proliferation in response to second party cells, but proliferated in response to CMV Ags, PHA, and third party cells. In addition, sFasL/MLR-treated cell populations contained influenza-specific T cells, CD4⁺FOXP3⁺ T cells, and CD4⁺CD25⁺ T cells. These data indicate that this ex vivo sFasL/MLR depletion of alloreacting human donor anti-host T cells was efficient and selective.

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 This work was supported in part by National Institutes of Health Grant CA70970 and a Fellow Award from the National Foundation for Cancer Research.

² Address correspondence and reprint requests to Dr. Curt I. Civin, BRB Room 14-023, 655 West Baltimore Street, Baltimore, MD 21201. E-mail address: ccivin{at}som.umaryland.edu

³ Abbreviations used in this paper: Allo, allogeneic; FasL, Fas ligand; Flu, influenza; GVHD, graft-vs-host disease; GVL, graft vs leukemia; LCL, lymphoblastoid cell line; MST, median survival time; sFasL, soluble FasL; Treg, T regulatory cell; xeno, xenogeneic; hi, high; lo, low.

⁴ The online version of this article contains supplemental material.