Hydrodynamic Delivery of Human IL-15 cDNA Increases Murine Natural Killer Cell Recovery after Syngeneic Bone Marrow Transplantation Isabel Barao, Maite.

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Hydrodynamic Delivery of Human IL-15 cDNA Increases Murine Natural Killer Cell Recovery after Syngeneic Bone Marrow Transplantation Isabel Barao, Maite Alvarez, Doug Redelman, Jonathan M. Weiss, John R. Ortaldo, Robert H. Wiltrout, William J. Murphy Biology of Blood and Marrow Transplantation Volume 17, Issue 12, Pages 1754-1764 (December 2011) DOI: 10.1016/j.bbmt.2011.08.023 Copyright © 2011 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 High serum levels of hIL-15 with marked expansion of donor-derived NK cells in CD45-congenic BMT after pIL-15 administration. Lethally irradiated B6 (H-2b, CD45.2) mice received transplants of Ly5.1 congenic (H-2b, CD45.1) NK- and T cell–depleted BM (5 × 106 BMCs), and 10 μg of control plasmid or pIL-15 by hydrodynamic injection at day 11 postcongeneic BMT. Serum, spleens, BM, and liver were collected at days 14 and 18 post-BMT. Markedly higher serum levels of hIL-15 were detected by ELISA at day 14 post-BMT and gradually decreased over time (A). The percentages and absolute numbers of donor derived NK cells (CD45.1+NK1.1+CD3ˉ) were significantly increased in the spleen (B, D), BM (B, E), and liver (B, F) at day 14 and decreased at day 18 post-BMT (C, D, E, F). Values represent the mean ± SEM. ∗P < .01, ∗∗P < .001. Data are representative of 5 experiments. Biology of Blood and Marrow Transplantation 2011 17, 1754-1764DOI: (10.1016/j.bbmt.2011.08.023) Copyright © 2011 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 Phenotypic characterization of developing NK cells in CD45-congenic BMT. Splenocytes of B6 (H-2b) recipients treated with pGFP or pIL-15 at day 11 post-BMT were stained for CD45.1, NK1.1, CD3, Ly49C/I, Ly49G2, Ly49A, Ly49D, Thy1.2, CD11b, and CD43 at day 14 post-BMT and compared with control mice. Gated CD45.1+NK1.1+CD3ˉ cells are shown. Frequencies of NK cells positive for CD11b, CD43, and Ly49s (A); proportions of NK cells expressing Thy1.2 (B). The numbers represent the percentages of cells positive for the mentioned markers. Controls are adult untreated nontransplanted mice. Data are representative of 3 to 5 experiments. Biology of Blood and Marrow Transplantation 2011 17, 1754-1764DOI: (10.1016/j.bbmt.2011.08.023) Copyright © 2011 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 Increased frequency of Ly49G2+ NK cells in CD45-congenic BMT. Splenocytes of B6 (H-2b) recipients treated with pGFP or pIL-15 at day 11 post-BMT were stained for CD45.1, NK1.1, CD3, Ly49C/I, and Ly49G2 at day 14 and day 18 post-BMT and compared with control mice. Gated CD45.1+NK1.1+CD3ˉ are shown. Frequencies (A) and numbers (B) of NK cell subsets positive for Ly49G2 and Ly49CI. The numbers are derived from the percentages of donor NK1.1+ cells. Values represent the mean ± SEM. ∗P < .01, ∗∗P < .001. Controls are adult untreated nontransplanted mice. Data are representative of 5 experiments. Biology of Blood and Marrow Transplantation 2011 17, 1754-1764DOI: (10.1016/j.bbmt.2011.08.023) Copyright © 2011 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 pIL-15 hydrodynamic delivery does not enhance NK cell cytotoxicity. Splenocytes of B6 (H-2b) recipients treated with pGFP or pIL-15 at day 11 post-BMT were stained for CD45.1, CD122, and CD3 at day 14 (A) and day 18 (B) post-BMT. NK cells (CD45.1+CD122+CD3−) were sorted and NK cell cytotoxicity against YAC-1 targets was evaluated using a 6-hour 51Cr release assay. The recovered NK cells were functionally mature at day 14 (A) and day 18 (B) post-BMT. Splenocytes from pIL-15-treated recipients were stimulated in vitro with rhIL-2 for 3 hours, and NK cell cytotoxicity against YAC-1 targets was evaluated using a 6-hour 51Cr release assay. rhIL-2 treatment significantly increased cytolytic activity of donor NK cells from pIL-15-treated group (C). Values represent the mean ± SEM. ∗P < .01, ∗∗P < .001. Data are representative of 3 experiments. Biology of Blood and Marrow Transplantation 2011 17, 1754-1764DOI: (10.1016/j.bbmt.2011.08.023) Copyright © 2011 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 5 Multiple hydrodynamic injections of pIL-15 to recipients of congenic BMT do not result in prolonged NK cell expansion. Splenocytes of B6 (H-2b) recipients treated with pGFP or pIL-15 at day 4 and/or day 11 post-BMT were stained for CD45.1, NK1.1, and CD3 at day 14 and day 21 post-BMT. The percentages (A, C) and absolute numbers (B, D) of donor-derived NK cells (CD45.1+NK1.1+CD3ˉ) are shown in the spleen and liver at day 14 (A, B) and day 21 (C, D) post-BMT. Two injections of pIL-15 at day 4 and day 11 post-BMT do not prolong expansion of NK cell expansion. Values represent the mean ± SEM. ∗P < .05. Data are representative of 2 experiments. Biology of Blood and Marrow Transplantation 2011 17, 1754-1764DOI: (10.1016/j.bbmt.2011.08.023) Copyright © 2011 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 6 pIL-15 hydrodynamic delivery can increase graft-versus-tumor activity in recipients of a syngeneic BMT. BALB/c (H2d) recipient mice received 1 × 105 of Renca tumor cells intravenously. At day 3, lethally irradiated (750 cGy) BALB/c mice were transplanted with syngeneic donor cells (5 × 106 of BMCs depleted of T and NK cells). At day 11 post-BMT, 10 μg of control pGFP or pIL-15 were administrated by hydrodynamic injection. P = .001 on survival between pGFP and pIL-15-treated groups. Results are from 2 experiments. Biology of Blood and Marrow Transplantation 2011 17, 1754-1764DOI: (10.1016/j.bbmt.2011.08.023) Copyright © 2011 American Society for Blood and Marrow Transplantation Terms and Conditions