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TNF- Is Critical to Facilitate Hemopoietic Stem Cell Engraftment and Function¹

Francine Rezzoug^*, Yiming Huang^*, Michael K. Tanner^*, Marcin Wysoczynski, Carrie L. Schanie^*, Paula M. Chilton^*, Mariusz Z. Ratajczak, Isabelle J. Fugier-Vivier^* and Suzanne T. Ildstad^2,*

^* Institute for Cellular Therapeutics, University of Louisville, Louisville, KY 40202; and Stem Cell Biology Program, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202

The use of tolerogenic cells as an approach to induce tolerance to solid organ allografts is being aggressively pursued. A major limitation to the clinical application of cell-based therapies has been the ability to obtain sufficient numbers and also preserve their tolerogenic state. We previously reported that small numbers of bone marrow-derived CD8⁺/TCR^– graft facilitating cells (FC) significantly enhance hemopoietic stem cell (HSC) engraftment in allogeneic and syngeneic recipients. Although the majority of FC resemble precursor plasmacytoid dendritic cells (p-preDC), p-preDC do not replace FC in facilitating function. In the present studies, we investigated the mechanism of FC function. We show for the first time that FC significantly enhance HSC clonogenicity, increase the proportion of multipotent progenitors, and prevent apoptosis of HSC. These effects require direct cell:cell contact between FC and HSC. Separation of FC from HSC by transwell membranes completely abrogates the FC effect on HSC. p-preDC FC do not replace FC total in these effects on HSC function. FC produce TNF-, and FC from TNF--deficient mice exhibit impaired facilitation in vivo and loss of the in vitro effects on HSC. Neutralizing TNF- in FC similarly blocks the FC effect. The antiapoptotic effect of FC is associated with up-regulation of Bcl-3 transcripts in HSC and blocking of TNF- is associated with abrogation of up-regulation of Bcl-3 transcripts. These data demonstrate a critical role for TNF- in mediating FC function. FC may have a significant impact upon the safe use of chimerism to establish tolerance to transplanted organs and tissue.

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 (NIH) R01 DK069766 and NIH 5RO1 HL063442; Juvenile Diabetes Research Foundation (JDRF) 1-2005-1037 and JDRF 1-2006-1466; the Department of the Navy, Office of Naval Research N000140610084; the Commonwealth of Kentucky Research Challenge Trust Fund; the W. M. Keck Foundation; The Jewish Hospital Foundation; and the University of Louisville Hospital.

² Address correspondence and reprint requests to Dr. Suzanne T. Ildstad, Institute for Cellular Therapeutics, University of Louisville, 570 South Preston Street, Suite 404, Louisville, KY 40202-1760. E-mail address: stilds01{at}louisville.edu

³ Abbreviations used in this paper: BM, bone marrow; BMT, BM transplantation; FC, facilitating cell; HSC, hemopoietic stem cell; p-preDC, precursor plasmacytoid dendritic cell; ODN, oligodeoxynucleotide; LTCM, long-term culture medium; SN, supernatant; CFC, colony-forming cell; CAFC, cobblestone area-forming cell; LTC-IC, long-term culture-initiating cell; 7-AAD, 7-aminoactinomycin D; wt, wild type.