SEARCH:   Advanced

Prepublished online as a Blood First Edition Paper on July 5, 2002; DOI 10.1182/blood-2002-04-1252. This Article Abstract Full Text (PDF) All Versions of this Article: 2002-04-1252v1 100/9/3429    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Reddy, P. Articles by Ferrara, J. L. M. Search for Related Content PubMed PubMed Citation Articles by Reddy, P. Articles by Ferrara, J. L. M. Related Collections Immunobiology Transplantation Brief Reports Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 November 2002, Vol. 100, No. 9, pp. 3429-3431 BRIEF REPORT Interleukin 18 preserves a perforin-dependent graft-versus-leukemia effect after allogeneic bone marrow transplantation Pavan Reddy, Takanori Teshima, Gerhard Hildebrandt, Ulrich Duffner, Yoshinobu Maeda, Kenneth R. Cooke, and James L. M. Ferrara From the Blood and Marrow Transplantation Program, Division of Hematology-Oncology, Departments of Internal Medicine and Pediatrics, University of Michigan Comprehensive Cancer Center, Ann Arbor.     Abstract Top Abstract Introduction Study design Results and discussion References We have recently shown that early administration of interleukin 18 (IL-18) after bone marrow transplantation (BMT) attenuates acute graft-versus-host disease (GVHD) in a lethally irradiated parent into F1 (B6B6D2F1) BMT model. In this study, we investigated whether IL-18 can maintain graft-versus-leukemia (GVL) effect in this context. B6D2F1 mice received transplants of T-cell-depleted (TCD) bone marrow (BM) and splenic T cells from either syngeneic (H2b/d) or allogeneic B6 (H2b) donors. Recipient mice were treated with recombinant murine IL-18 or the control diluent. Initial studies demonstrated that IL-18 treatment did not affect the proliferative responses or the cytolytic effector functions of T cells after BMT. In subsequent experiments, animals also received host-type P815 mastocytoma cells at the time of BMT. All syngeneic BM transplant recipients died from leukemia by day 18. The allogeneic BM transplant recipients effectively rejected their leukemia regardless of treatment and IL-18 significantly reduced GVHD-related mortality. Examination of the cytotoxic mechanisms with perforin-deficient donor T cells demonstrated that perforin is critical for the GVL effect. Taken together these data demonstrate that IL-18 can attenuate acute GVHD without impairing the in vitro cytolytic function or the in vivo GVL activity after allogeneic BMT. (Blood. 2002;100:3429-3431) © 2002 by The American Society of Hematology.     Introduction Top Abstract Introduction Study design Results and discussion References Allogeneic bone marrow transplantation (BMT) is a widely performed therapy for many hematologic malignancies. Effective use of this powerful therapeutic modality has been hindered by its significant toxicity, acute graft-versus-host disease (GVHD). However, the graft-versus-leukemia (GVL) effect provided by allogeneic BMT represents a very potent form of immune therapy against malignancy.1 Unfortunately, GVHD and GVL are tightly linked as demonstrated by the inverse correlation between leukemia relapse rates and the severity of GVHD.2-4 Prevention of GVHD by T-cell depletion or nonspecific immune suppression is associated with increased risk for leukemia relapse after allogeneic BMT.5-7 Thus, approaches that can reduce the toxicity of GVHD while preserving the beneficial GVL effects are necessary to better harness this very effective therapeutic modality against hematologic malignancies. Interleukin 18 (IL-18) is a recently discovered cytokine that is structurally related to IL-1 but functionally similar to IL-12.8 It is produced by a wide variety of cells such as macrophages, dendritic cells, keratinocytes, T cells, osteoblasts, and Kupffer cells and is a potent inducer of Th1 response in concert with IL-12.8,9 We have recently demonstrated that when administered early after allogeneic BMT it can significantly attenuate acute GVHD.10 Because IL-18 enhances the cytolytic activity of T cells and has been shown to provide antitumor immunity,8,11,12 we examined whether IL-18 could preserve the GVL effect conferred by donor T cells after allogeneic BMT.     Study design Top Abstract Introduction Study design Results and discussion References Mice Female C57BL/6 (B6 Ly5.2, H-2b, CD45.1+), B6D2F1 (H-2b/d , CD45.2+) and perforin-deficient C57BL/6 (H-2b, pfp/) mice were purchased from the Jackson Laboratory (Bar Harbor, ME). Mice were housed and fed as previously described.10 All the methods were done as described previously.10,13-16 Bone marrow transplantation Mice underwent transplantation according to a standard protocol described previously.13 Briefly, on day 0 mice received 13 Gy total body irradiation (TBI; 137Cs source) split into 2 doses. After TBI, 5 × 106 T-cell-depleted (TCD) bone marrow (BM) and 2 × 106 nylon wool purified (NWP) splenic donor T cells were injected intravenously into recipients. Survival was monitored daily; recipient body weight and GVHD clinical score were measured weekly.10,13 IL-18 treatment Recombinant murine IL-18 (RD, Flanders, NJ) was reconstituted per the manufacturer's recommendations in sterile distilled H2O and injected intraperitoneally (10 µg/mouse/d) from day 2 to +2. Mice from the control groups received phosphate-buffered saline (PBS). Leukemia induction Briefly, 2000 P815 (H-2d) cells (a mastocytoma derived from a DBA/2 mouse) were injected intravenously into B6D2F1 recipients on day 0 along with the BM transplant inoculum. Survival was monitored daily. P815-induced leukemic death was defined by the occurrence of either macroscopic tumor nodules in liver or spleen or hindleg paralysis.15 GVHD death was defined by the absence of leukemia and the presence of clinical signs of GVHD.13,14 Animals surviving beyond day 50 after BMT were killed and the liver and spleen were harvested for flow cytometric evaluation (has sensitivity of 0.5%15). Fluorescence-activated cell sorting analysis Fluorescein isothiocyanate-conjugated monoclonal antibodies to mouse CD45.1+, CD45.2+, and H-2d+, phycoerythrin-conjugated CD4+, CD8+, and H-2b+ were purchased from Pharmingen (San Diego, CA). Cells were analyzed by 2-color flow cytometry on a FACScan cytometer (Becton Dickinson Immunocytometry Systems, San Jose, CA).13,15 Cell cultures Briefly, splenocytes were harvested from animals 14 days after transplantation and 3 spleens combined from each group. Donor (CD45.1+CD3+) T cells in the spleens were determined and normalized between groups. Donor T-cell engraftment was 94% ± 4% in the controls and 86% ± 8% in IL-18 recipients (P = NS) on day +14 after BMT. These cells were then plated in 96-well flat-bottomed plates (Falcon, Lincoln Park, NJ) at a concentration of 2 × 105 T cells (CD45.1+CD3+)/well with 2 × 105 irradiated (2000 rad) splenocytes harvested from naive B6D2F1 (allogeneic) or B6 (syngeneic) animals. At 48 hours, supernatants were collected for cytokine analysis and the cultures were pulsed with 3[H]-thymidine (1 µCi/well; 0.037 MBq) and proliferation was determined 24 hours later on a 1205 Betaplate reader (Packard, Downers Grove, IL). Cytokine ELISAs Antibodies used in the interferon  (IFN-) and IL-2 assays were purchased from Pharmingen. All assays were performed according to the manufacturer's protocol in a 1:5 dilution. Plates were read at 450 nm using a microplate reader (Bio-Rad Labs, Hercules, CA). Recombinant murine IFN- and IL-2 (Pharmingen) were used as standards for enzyme-linked immunosorbent assays (ELISAs). Samples and standards were run in duplicate and the sensitivity of the assays was 0.063 U/mL for IFN, and less than 0.13 U/mL for IL-2. 51Cr release assays Briefly, splenocytes were removed from B6D2F1 recipients 14 days after BMT, and 3 spleens were combined from each group. Donor CD8+ cells in each group were determined and the counts were normalized. They were added at varying effector to target ratios and incubated for 4 hours with either allogeneic P815 (H-2d) or syngeneic EL-4 (H-2b) targets (2 × 106 cells), labeled with 100 µCi (3.7 MBq) 51Cr. 51Cr activity in supernatants was determined in an autogamma counter (Packard Instrument, Meriden, CT). The percentage of specific lysis was calculated as follows: 100 × (sample count  background count)/(maximal count  background count).15 Statistical analysis Survival curves were plotted using Kaplan-Meier estimates. The Mantel-Cox log-rank test was used to analyze survival data. Statistical significance was set at P < .05.     Results and discussion Top Abstract Introduction Study design Results and discussion References We have previously demonstrated that administration of IL-18 early in the time course of allogeneic BMT attenuated early in vivo donor T-cell proliferation by enhancing activation induced Fas-mediated apoptosis and resulted in reduced GVHD.10 We now determined whether the effects of IL-18 on acute GVHD severity were also associated with a decrease in donor responses to host antigens after BMT. B6D2F1 mice received 13 Gy of TBI followed by infusion of BM and T cells from either allogeneic B6 Ly5.2 or syngeneic donors as described in "Study design." Donor splenic T cells were harvested from allogeneic BM transplant recipients on day +14 and then restimulated in vitro with B6D2F1 stimulators in standard mixed lymphocyte reaction (MLR) cultures. As shown in Figure 1A, splenic T cells from both IL-18-treated or control allogeneic recipients displayed similar proliferative responses to host antigens. There was also no difference in secretion of either IFN- or IL-2 between T cells from IL-18-treated or control mice (Figure 1B,C). We next tested the cytotoxic capability of donor CD8+ T cells harvested from recipient spleens on day +14 against host type P815 (H2d) tumor targets, which was also equivalent between the 2 groups (Figure 1D). Taken together with our previous study,10 these data demonstrate that administration of IL-18 to BM transplant recipients attenuates donor T-cell proliferation by enhancing Fas-mediated increasing activation induced cell death early after BMT but does not alter donor T-cell responses to host antigens measured 2 weeks after BMT. View larger version (19K): [in this window] [in a new window]   Figure 1. Donor T-cell cytokine and cytolytic functions after BMT. B6D2F1 animals were injected with control diluent (solid bar) or IL-18 (dotted bar) from day 2 to +2, received 13 Gy TBI, and received transplants of 5 × 106 TCD BM and 2 × 106 splenic T cells from B6 Ly5.2 (CD45.1+) donor mice. Splenocytes from the recipients (n = 3/group) were harvested on day 14 after BMT, combined and normalized for donor T cells (CD45.1+ and CD3+); and restimulated in quadruplicate with irradiated naive host (B6D2F1) splenocytes in MLR cultures. Supernatants were collected after 48 hours of culture and proliferation was determined by pulsing with [3H]-thymidine (1 µCi/well; 0.037 MBq) for an additional 20 hours. T-cell proliferation (A), IFN- secretion (B), and IL-2 production (C) were all similar (solid bar versus dotted bar, P = NS). Results from 1 of 3 similar experiments are shown. (D) Splenocytes harvested from allogeneic animals on day 14 after BMT were pooled (n = 3/group), and normalized for donor CD8+ cells and used in a 51Cr release assay. CTL activity against allogeneic P815 in control () and IL-18 () groups was similar; there was no significant lysis of syngeneic targets by either group (IL-18, ; control, ). The preservation host-specific responses in donor cells suggested that GVL effects might be preserved. We next determined the ability of IL-18 treatment to promote leukemia-free survival after allogeneic BMT in a well-established mouse GVL model described in "Study design."15,16 As expected all recipients of syngeneic BM transplants receiving P815 tumor cells died with evidence of massive hepatosplenomegaly. Although IL-18 by itself has been shown to possess antitumor effects,8,17 all IL-18-treated syngeneic mice that received P815 cells also died from leukemia by day 18, thus ruling out any direct antitumor effect of IL-18 in this system (Figure 2A). All allogeneic BM transplant recipients treated with control died by day 40. By contrast, 50% of IL-18-treated allogeneic animals survived the entire observation period (P < .03). Clinical GVHD scores were also more severe in controls than in IL-18-treated animals (5.6 ± 0.7 versus 3.5 ± 0.4, P < .05) consistent with our previous observation.10 In each case, allogeneic recipients effectively rejected their leukemia with no evidence of tumor at autopsy. In additional experiments with a lower dose (1 × 106) of allogeneic T cells, 25% of the control compared to 70% of IL-18-treated recipients survived (P < .04) and had less clinical GVHD. No animals showed morphologic evidence of leukemia at the end of the observation period, demonstrating that IL-18 preserved GVL effect at both higher and lower T-cell doses. We tested for minimal residual leukemia by killing all the surviving animals on day 50 and analyzing peripheral blood and splenocytes by FACS. No cells with the P815 phenotype (CD45.2+, H2d+/H2b) were detected. Residual leukemia was evaluated by injecting 10 × 106 TCD splenocytes from these mice into lethally irradiated secondary F1 hosts. No secondary hosts (0 of 6) died from leukemia, confirming the eradication of P815 cells by adoptive transfer (ie, < 2000 tumor cells in 10 × 106 cells, sensitivity of 0.02%). These results indicate that IL-18 enhances leukemia-free survival after allogeneic BMT by attenuating acute GVHD and maintaining GVL activity. View larger version (14K): [in this window] [in a new window]   Figure 2. IL-18 retains a perforin-dependent GVL effect. (A) B6D2F1 mice were injected with IL-18 or diluent, given 13 Gy TBI, and received transplants of allogeneic or syngeneic BM and T cells as in Figure 1. All animals were also injected intravenously with 2000 P815 tumor cells on day 0. (Allogeneic: control treated, , n = 8 and IL-18 treated, O, n = 8 or syngeneic: control treated, , n = 8 and IL-18 treated, , n = 8 donors). P < .03 for O, allo IL-18 versus , allo control. Data from 1 of 2 similar experiments are shown. (B) Lethally irradiated (13 Gy) B6D2F1 mice received transplants of 5 × 106 TCD BM from wild-type B6 (H2b) and 2 × 106 splenic T cells from allogeneic pfp/ B6 (H2b) donors. Survival in control (, n = 8) and IL-18-treated (, n = 8) recipients of T cells from pfp/ donors was significantly different. P < .01,  versus . (C) B6D2F1 mice underwent transplantations as above and injected intravenously with 2000 P815 cells on day 0. All syngeneic (, n = 10), allogeneic control (, n = 10), allogeneic IL-18-treated pfp/ T cells (, n = 10) and allogeneic IL-18-treated wild-type T cells (, n = 10) survived. P = NS,  versus ; and P < .04,  versus . Earlier studies have demonstrated that CD8+ T cells are more potent effectors of GVL than are CD4+ cells in several models.15,18,19 CD8+ cells mediate cytotoxicity, which is critical for GVL effect, either by the perforin-granzyme granule exocytosis pathway or the Fas pathway.20 Several recent studies have demonstrated that perforin rather than Fas ligand (FasL) is important for GVL activity.19-21 We therefore evaluated the cytotoxic mechanisms responsible for GVL by using perforin (pfp)-deficient B6 (H2b) mice as donors and undergoing transplantation as above. Consistent with previous studies, most of the recipients of allogeneic perforin-deficient splenic T cells treated with control diluent died from GVHD (Figure 2B).22,23 In contrast, IL-18 treatment conferred a significant survival advantage to allogeneic BM transplant recipients (88% versus 12%; Figure 2B). When F1 recipients were injected with P815 at the time of BMT all the recipients died from leukemia regardless of treatment if they received perforin-deficient donor T cells (Figure 2C). These data indicate that the perforin-dependent cytotoxicity of donors is critical for preservation of GVL activity in this model. Interleukin 18 did not impede engraftment of donor marrow in this parent into F1 model.10 It should be noted, however, that the effects of IL-18 in other models where rejection might be mediated by T cells as well as natural killer cells have not yet been evaluated. Immune reconstitution after IL-18 treatment was also better than controls in this model (data not shown) and IL-18 has been shown to be critical for defense against cytomegalovirus24,25 and Aspergillus.26,27 Thus IL-18 treatment may reduce the risk of opportunistic infections after allogeneic BMT, but detailed evaluation of this effect of IL-18 on posttransplantation immune responses against infections remains to be determined. In conclusion, when taken together with our previous study,10 these data demonstrate that brief administration of IL-18 to recipients early after allogeneic BMT may represent a novel strategy to attenuate acute GVHD without compromising GVL activity.     Footnotes Submitted April 26, 2002; accepted June 17, 2002. Prepublished online as Blood First Edition Paper, July 5, 2002; DOI 10.1182/blood-2002-04-1252. Supported by National Institutes of Health grants CA 49542 to J.L.M.F. and 2KIZHD28820 to K.R.C. P.R. is the recipient of an ASCO Young Investigator Award. K.R.C is a scholar of NMDP Amy Strelzer-Manasevit Scholarship Program, a Fellow of the Robert Wood Johnson Minority Medical Faculty Development Program. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734. Reprints: James L. M. Ferrara, University of Michigan Cancer Center, 1500 E Medical Center Dr, Ann Arbor, MI 48109; e-mail: ferrara{at}umich.edu.     References Top Abstract Introduction Study design Results and discussion References 1. Appelbaum FR. Haematopoietic cell transplantation as immunotherapy. Nature . 2001;411:385-389[CrossRef][Medline] [Order article via Infotrieve]. 2. Horowitz MM, Gale RP, Sondel PM, et al. Graft-verus-leukemia reactions after bone marrow transplantation. Blood. 1990;75:555-562[Abstract/Free Full Text]. 3. Barrett AJ, Malkovska V. Graft-versus-leukemia: understanding and using the alloimmune response to treat haematological malignancies. Br J Haematol. 1996;93:754-761[CrossRef][Medline] [Order article via Infotrieve]. 4. Truitt RL, Johnson BD, McCabe C, Weiler MB. Graft versus leukemia. In: Ferrara JLM,Deeg HJ,Burakoff SJ, eds. Graft-vs-Host Disease. 2nd ed. New York, NY: Marcel Dekker; 1997:385-423. 5. Butturini A, Gale RP. T cell depletion in bone marrow transplantation for leukemia: current results and future directions. Bone Marrow Transplant. 1988;3:185-192[Medline] [Order article via Infotrieve]. 6. Butturini A, Gale RP. Graft versus leukemia. Immunol Res. 1992;11:24-33[Medline] [Order article via Infotrieve]. 7. Barrett AJ. Mechanisms of the graft-versus-leukemia reaction. Stem Cells. 1997;15:248-258[Medline] [Order article via Infotrieve]. 8. Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H. Interleukin-18 regulates both th1 and th2 responses. Annu Rev Immunol. 2001;19:423-474[CrossRef][Medline] [Order article via Infotrieve]. 9. Swain SL. Interleukin 18: tipping the balance towards a T helper cell 1 response. J Exp Med. 2001;194:F11-F14[CrossRef][Medline] [Order article via Infotrieve]. 10. Reddy P, Teshima T, Kukuruga M, et al. Interleukin-18 regulates acute graft-versus-host disease by enhancing Fas-mediated donor T cell apoptosis. J Exp Med. 2001;194:1433-1440[Abstract/Free Full Text]. 11. Osaki T, Peron JM, Cai Q, et al. IFN-gamma-inducing factor/IL-18 administration mediates IFN-gamma- and IL-12-independent antitumor effects. J Immunol. 1998;160:1742-1749[Abstract/Free Full Text]. 12. Heuer JG, Tucker-McClung C, Hock RA. Neuroblastoma cells expressing mature IL-18, but not proIL-18, induce a strong and immediate antitumor immune response. J Immunother. 1999;22:324-335[Medline] [Order article via Infotrieve]. 13. Hill GR, Crawford JM, Cooke KJ, Brinson YS, Pan L, Ferrara JLM. Total body irradiation and acute graft versus host disease. The role of gastrointestinal damage and inflammatory cytokines. Blood. 1997;90:3204-3213[Abstract/Free Full Text]. 14. Cooke KR, Kobzik L, Martin TR, et al. An experimental model of idiopathic pneumonia syndrome after bone marrow transplantation, I: the roles of minor H antigens and endotoxin. Blood. 1996;88:3230-3239[Abstract/Free Full Text]. 15. Teshima T, Hill GR, Pan L, et al. IL-11 separates graft-versus-leukemia effects from graft-versus-host disease after bone marrow transplantation. J Clin Invest. 1999;104:317-325[Medline] [Order article via Infotrieve]. 16. Pan L, Teshima T, Hill GR, et al. Granulocyte colony-stimulating factor-mobilized allogeneic stem cell transplantation maintains graft-versus-leukemia effects through a perforin-dependent pathway while preventing graft-versus-host disease. Blood. 1999;93:4071-4078[Abstract/Free Full Text]. 17. Belardelli F, Ferrantini M. Cytokines as a link between innate and adaptive antitumor immunity. Trends Immunol. 2002;23:201-208[CrossRef][Medline] [Order article via Infotrieve]. 18. Yang Y, Sergio JJ, Pearson D, Szot G, Shimizu A, Sykes M. Interleukin-12 preserves the graft-versus-leukemia effect of allogeneic CD8 T cells while inhibiting CD4-dependent graft-versus-host disease in mice. Blood. 1997;90:4651-4660[Abstract/Free Full Text]. 19. Schmaltz C, Alpdogan O, Horndasch KJ, et al. Differential use of Fas ligand and perforin cytotoxic pathways by donor T cells in graft-versus-host disease and graft-versus-leukemia effect. Blood. 2001;97:2886-2895[Abstract/Free Full Text]. 20. Russell JH, Ley TJ. Lymphocyte-mediated cytotoxicity. Annu Rev Immunol. 2002;20:323-370[CrossRef][Medline] [Order article via Infotrieve]. 21. Tsukada N, Kobata T, Aizawa Y, Yagita H, Okumura K. Graft-versus-leukemia effect and graft-versus-host disease can be differentiated by cytotoxic mechanisms in a murine model of allogeneic bone marrow transplantation. Blood. 1999;93:2738-2747[Abstract/Free Full Text]. 22. Blazar BR, Taylor PA, Vallera DA. CD4+ and CD8+ T cells each can utilize a perforin-dependent pathway to mediate lethal graft-versus-host disease in major histocompatibility complex-disparate recipients. Transplantation. 1997;64:571-576[CrossRef][Medline] [Order article via Infotrieve]. 23. Baker MB, Altman NH, Podack ER, Levy RB. The role of cell-mediated cytotoxicity in acute GVHD after MHC-matched allogeneic bone marrow transplantation in mice. J Exp Med. 1996;183:2645-2656[Abstract/Free Full Text]. 24. Pien GC, Satoskar AR, Takeda K, Akira S, Biron CA. Cutting edge: selective IL-18 requirements for induction of compartmental IFN-gamma responses during viral infection. J Immunol. 2000;165:4787-4791[Abstract/Free Full Text]. 25. Kanakaraj P, Ngo K, Wu Y, et al. Defective interleukin (IL)-18-mediated natural killer and T helper cell type 1 responses in IL-1 receptor-associated kinase (IRAK)-deficient mice. J Exp Med. 1999;189:1129-1138[Abstract/Free Full Text]. 26. Brieland JK, Jackson C, Menzel F, et al. Cytokine networking in lungs of immunocompetent mice in response to inhaled Aspergillus fumigatus. Infect Immun. 2001;69:1554-1560[Abstract/Free Full Text]. 27. Blease K, Kunkel SL, Hogaboam CM. IL-18 modulates chronic fungal asthma in a murine model; putative involvement of Toll-like receptor-2. Inflamm Res. 2001;50:552-560[CrossRef][Medline] [Order article via Infotrieve]. © 2002 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: G. Socie and B. R. Blazar Acute graft-versus-host disease: from the bench to the bedside Blood, November 12, 2009; 114(20): 4327 - 4336. [Abstract] [Full Text] [PDF] Y. Yoshida, T. Hirano, G. Son, Y. Iimuro, T. Imado, T. Iwasaki, and J. Fujimoto Allogeneic bone marrow transplantation for hepatocellular carcinoma: hepatocyte growth factor suppresses graft-vs.-host disease Am J Physiol Gastrointest Liver Physiol, December 1, 2007; 293(6): G1114 - G1123. [Abstract] [Full Text] [PDF] J. N. MacGregor, Q. Li, A. E. Chang, T. M. Braun, D. P.M. Hughes, and K. T. McDonagh Ex vivo Culture with Interleukin (IL)-12 Improves CD8+ T-Cell Adoptive Immunotherapy for Murine Leukemia Independent of IL-18 or IFN-{gamma} but Requires Perforin. Cancer Res., May 1, 2006; 66(9): 4913 - 4921. [Abstract] [Full Text] [PDF] D. S. Krause and R. A. Van Etten Adoptive immunotherapy of BCR-ABL-induced chronic myeloid leukemia-like myeloproliferative disease in a murine model Blood, December 15, 2004; 104(13): 4236 - 4244. [Abstract] [Full Text] [PDF] C.-K. Min, Y. Maeda, K. Lowler, C. Liu, S. Clouthier, D. Lofthus, E. Weisiger, J. L. M. Ferrara, and P. Reddy Paradoxical effects of interleukin-18 on the severity of acute graft-versus-host disease mediated by CD4+ and CD8+ T-cell subsets after experimental allogeneic bone marrow transplantation Blood, November 15, 2004; 104(10): 3393 - 3399. [Abstract] [Full Text] [PDF] T. Imado, T. Iwasaki, Y. Kataoka, T. Kuroiwa, H. Hara, J. Fujimoto, and H. Sano Hepatocyte growth factor preserves graft-versus-leukemia effect and T-cell reconstitution after marrow transplantation Blood, September 1, 2004; 104(5): 1542 - 1549. [Abstract] [Full Text] [PDF] C. C. Matte, J. Cormier, B. E. Anderson, I. Athanasiadis, J. Liu, S. G. Emerson, W. Pear, and W. D. Shlomchik Graft-versus-leukemia in a retrovirally induced murine CML model: mechanisms of T-cell killing Blood, June 1, 2004; 103(11): 4353 - 4361. [Abstract] [Full Text] [PDF] This Article Abstract Full Text (PDF) All Versions of this Article: 2002-04-1252v1 100/9/3429    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Reddy, P. Articles by Ferrara, J. L. M. Search for Related Content PubMed PubMed Citation Articles by Reddy, P. Articles by Ferrara, J. L. M. Related Collections Immunobiology Transplantation Brief Reports Social Bookmarking                   What's this?

	Copyright © 2002 by American Society of Hematology         Online ISSN: 1528-0020