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Tissue-Specific Homing and Expansion of Donor NK Cells in Allogeneic Bone Marrow Transplantation¹

Janelle A. Olson^*, Robert Zeiser, Andreas Beilhack, Joshua J. Goldman^* and Robert S. Negrin^2,*

^* Department of Medicine, Division of Blood and Marrow Transplantation, Stanford University, Stanford, CA 94305; Department of Hematology and Oncology, Albert Ludwigs University Freiburg, Freiburg, Germany; and Department of Medicine II, Würzburg University, Würzburg, Germany

NK cells have potential therapeutic impact in suppressing graft-versus-host disease (GVHD) and enhancing antitumor effects as a cellular therapy for hematologic malignancies. However, few studies have addressed the trafficking and in vivo behavior of NK cells in murine models of bone marrow transplantation (BMT). We investigated NK cell trafficking and survival following allogeneic and syngeneic BMT using a novel bioluminescence-based imaging strategy. Transplantation of luciferase-expressing NK cells revealed CD62L-mediated trafficking to lymphoid organs and trafficking to GVHD target tissues, as evidenced by in vivo and ex vivo bioluminescence imaging. The NK cells persisted for 4 wk after transplantation in allogeneic recipients, but were not detectable in syngeneic recipients. CFSE-labeling studies showed extensive NK cell proliferation in vivo. Transplanted NK cells up-regulated molecules necessary for homing to the lymph nodes, gastrointestinal tract, and skin, yet did not cause clinical GVHD. This expansion and tissue-specific homing was not solely due to the conditioning regimen, as NK cells proliferated and reached lymphoid and GVHD target tissue in unconditioned allogeneic RAG2^–/– -chain^–/– recipients. IL-2 enhanced expansion and antitumor activity of NK cells. These results provide significant insight into the behavior and potential therapeutic impact of NK cells in BMT.

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 by National Institutes of Health Grants 2 P01 CA049605 and 1 R01 CA125276.

² Address correspondence and reprint requests to Dr. Robert S. Negrin, Center for Clinical Science Research Building Room 2205, 269 West Campus Drive, Stanford University, Stanford, CA 94305. E-mail address: negrs{at}stanford.edu

³ Abbreviations used in this paper: BMT, bone marrow transplantation; GVHD, graft-versus-host disease; GVT, graft-versus-tumor; BLI, bioluminescence imaging; luc⁺, luciferase expressing; LPL, lamina propria lymphocyte; IEL, intraepithelial lymphocyte; TCD-BM, T-cell depleted bone marrow; cLN, cervical lymph node; iLN, inguinal lymph node; aLN, axillary lymph node; mLN, mesenteric lymph node; pLN, peripheral lymph node; C, -chain.