Induction of Graft-versus-Leukemia (GVL) Effect without Graft-versus-Host Disease (GVHD) by Pretransplant Donor Treatment with Immunomodulators Shoshana.

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Induction of Graft-versus-Leukemia (GVL) Effect without Graft-versus-Host Disease (GVHD) by Pretransplant Donor Treatment with Immunomodulators Shoshana Morecki, Elena Yacovlev, Yael Gelfand, Yehudit Shabat, Shimon Slavin Biology of Blood and Marrow Transplantation Volume 15, Issue 4, Pages 406-415 (April 2009) DOI: 10.1016/j.bbmt.2008.12.504 Copyright © 2009 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 Cyotoxic activity and phenotypic analysis of LAK cells derived from CpG + IFA-treated donors. Splenocytes were harvested from C57 naïve mice or mice treated with non-CpG + IFA or CpG + IFA 10 days previously and incubated with rIL-2 for 4 days. Cytotoxicity (A) was tested by 51Cr release assay. Results are presented as mean of % specific lysis ± SE measured at a 25:1 cell ratio of effector: target. P = .001 for the comparison of cytotoxicity directed to 3B3 cells by LAK cells derived from naïve versus CpG + IFA-treated donors. Results represent 1 of 2 experiments. Phenotypic analysis (B) was carried out by using flow cytometry. Data were pooled from 3 experiments, and results are presented as mean of % positive cells ± SE. P = .014 for the comparison of %NK1.1+ LAK cells following CpG + IFA donor treatment versus %NK1.1 + in LAK cells derived from naïve mice. P < .001 for the comparison of %NK1.1+ , %CD11b+GR-1+, %CD8+, and %CD3+ in splenocytes versus LAK cells derived from mice treated with CpG+IFA (C). Biology of Blood and Marrow Transplantation 2009 15, 406-415DOI: (10.1016/j.bbmt.2008.12.504) Copyright © 2009 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 Effect of LAK cells derived from CpG-treated donor mice on GVHD induction, as measured by body weight. Sublethally (5.5 Gy) irradiated (BALB × C57) F1 mice were inoculated with 20 × 106 LAK cells derived from either naïve or CpG- or non-CpG-treated C57 donor mice 6 days before spleen harvest, and CpG + IFA- or non-CpG + IFA-treated C57 donor mice 10 days before spleen harvest. Results represent 1 of 2 experiments. P < .012 for the comparison of body weight on day 10 following donor treatment with CpG + IFA versus donor treatment with CpG, non-CpG, non-CpG + IFA, IFA, or no treatment of naïve donor splenocytes. Biology of Blood and Marrow Transplantation 2009 15, 406-415DOI: (10.1016/j.bbmt.2008.12.504) Copyright © 2009 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 Effect of splenocytes from CFA-treated donors on GVL. Sublethally (5.5 Gy) irradiated (BALB × C57) F1 mice were inoculated with 104 BCL1 cells 24 hours following irradiation. One day later, naïve or CFA pretreated C57 splenocytes were injected i.v. CFA was inoculated s.c. into C57 donor mice (200 μL) 10 days before spleen harvesting. Data was pooled from 3 experiments. P < .001 for the comparison of treatment with CFA-C57 cells versus BCL1 only and naïve C57 cell treatment. Biology of Blood and Marrow Transplantation 2009 15, 406-415DOI: (10.1016/j.bbmt.2008.12.504) Copyright © 2009 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 Effect of Splenocytes from CpG-Treated Donors on GVL. Sublethally (5.5 Gy) irradiated (BALB × C57) F1 mice were inoculated with 104 BCL1 cells 24 hours following irradiation. On the day after, mice were injected i.v. with 30 × 106 C57 splenocytes derived from naïve mice, or from mice pretreated 6 days previously with CpG, or non-CpG (A); or from mice pretreated 10 days previously with CpG + IFA or non-CpG + IFA (B). All pretreatments were carried out by s.c. inoculation (100 μg). Data were pooled from 2 experiments. P < .001 for the comparison of treatment with CpG versus non-CpG, for the comparison of CpG + IFA versus non-CpG+IFA and for the comparison of CpG + IFA versus CpG. Biology of Blood and Marrow Transplantation 2009 15, 406-415DOI: (10.1016/j.bbmt.2008.12.504) Copyright © 2009 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 5 Effect of T cell-depleted splenocytes (TCD) from CpG-treated donors on GVL. Sublethally (5.5 Gy) irradiated (BALB × C57) F1 mice were inoculated with 104 BCL1 cells 24 hours following irradiation. One day later, mice were injected i.v. with 30 × 106 C57 splenocytes derived from either naïve mice or from mice pretreated 10 days previously with CpG + IFA or non-CpG + IFA. Eight days later, the last 2 groups received either C57 naïve T cells (3 × 106) together with TCD splenocytes (35 × 106) from CpG + IFA-treated donors or C57 naïve T cells together with TCD splenocytes from non-CpG + IFA-treated donors. All pretreatments were carried out by s.c. inoculation (100 μg). Data represent 1 experiment. P < .002 for the comparison of CpG + IFA treatment versus naïve control of BCL1 only and P < .001 for the comparison of CpG + IFA versus non-CpG + IFA treatment. Biology of Blood and Marrow Transplantation 2009 15, 406-415DOI: (10.1016/j.bbmt.2008.12.504) Copyright © 2009 American Society for Blood and Marrow Transplantation Terms and Conditions