Blocking LFA-1 Activation with Lovastatin Prevents Graft-versus-Host Disease in Mouse Bone Marrow Transplantation Yang Wang, Dan Li, Dan Jones, Roland.

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Blocking LFA-1 Activation with Lovastatin Prevents Graft-versus-Host Disease in Mouse Bone Marrow Transplantation Yang Wang, Dan Li, Dan Jones, Roland Bassett, George E. Sale, Jahan Khalili, Krishna V. Komanduri, Daniel R. Couriel, Richard E. Champlin, Jeffrey J. Molldrem, Qing Ma Biology of Blood and Marrow Transplantation Volume 15, Issue 12, Pages 1513-1522 (December 2009) DOI: 10.1016/j.bbmt.2009.08.013 Copyright © 2009 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 Lovastatin inhibits the adhesion, proliferation, and cytokine production of mouse T cells in vitro. (A) Blocking of mouse T cell binding to ICAM-1 with lovastatin. Primary mouse T cells (WT or LFA-1-/-) were activated with Mn++, and WT were preincubated with lovastatin or pravastatin at a concentration of 10 μM. Binding to ICAM-1 was measured by counting cells adherent to the wells after washes. (B and C) Inhibition of mouse T cell proliferation (B) and cytokine production (C) with lovastatin. Column-purified C57BL/6 responder cells were plated at 1×106 cells/mL in a volume of 200 μL/well and co-cultured at a ratio of 2:1 with 3400-cGy irradiated stimulator cells from the Balb/C mice. Proliferation was assayed on day 3 by adding [3H]-thymidine to the culture for the final 8 hours. Production of IL-2, TNF-α, and IFN-γ in culture supernatant was measured by ELISA after 24 hours in the presence of DMSO (black bar), lovasatin (gray bar), and pravastatin (white bar). Results are the mean and standard deviation of 3 independent experiments normalized to that of WT controls. An asterisk indicates data with P value < .05 in t-tests. Biology of Blood and Marrow Transplantation 2009 15, 1513-1522DOI: (10.1016/j.bbmt.2009.08.013) Copyright © 2009 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 Lovastatin treatment reduces the mortality associated with GVHD. Mice were treated with statins at the dose of 50 μg/mouse every other day, starting on the day of BMT. The control group received vehicle (10% DMSO in saline). Survival was monitored daily and followed up to 28 days. The data are compiled from all of the mice examined. Distributions of time to death were estimated using the Kaplan-Meier method and compared between treatments using the log-rank test. No adjustment was made for the comparisons. The results are from at least 3 independent experiments, with 3 mice per group in each experiment. Biology of Blood and Marrow Transplantation 2009 15, 1513-1522DOI: (10.1016/j.bbmt.2009.08.013) Copyright © 2009 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 Lovastatin treatment reduces GVHD in the skin and liver. Mice were sacrificed on day 7 posttransplantation (4 mice per group). Tissues were placed in 10% formalin, embedded in paraffin, sectioned, stained with hematoxylin and eosin, and scored for GVHD histopathology. (A) The top panels are representative sections from the skin of mice treated with DMSO, lovastatin, and pravastatin. The skin shows moderate to severe changes consistent with GVHD, with lymphoid infiltrates (arrow) and epidermal and adnexal cell apoptosis in the WT and pravastatin-treated mice. Only mild changes in the skin of the lovastatin-treated mice were noted. The lower panels are representative sections from the liver. Perivascular lymphoid infilrates (arrows) within portal triads associated with bile duct damage were noted in the livers of the WT and pravastatin-treated mice, but not of the lovastatin-treated mice. (B) The average score of skin and liver GVHD of each group. Results are mean and standard deviation of 4 mice. An asterisk indicates data with P value < .05 in t-tests. Biology of Blood and Marrow Transplantation 2009 15, 1513-1522DOI: (10.1016/j.bbmt.2009.08.013) Copyright © 2009 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 Donor-derived T cell homing to the secondary lymphoid organs. Donor-derived splenocytes were labeled with CFSE and transferred into mice on the day of BMT immediately after statin treatment. At 2 hours after transfer, the recipient mice were sacrificed. Cells were collected from spleen, peripheral lymph nodes, and Peyer's patches and then stained with CD4-PerCP, CD8-APC, and H-2Db-PE antibodies. The number of injected T cell subsets recovered from each tissue, CD4+/H-2Db+/CFSEhi (A) and CD8+/H-2Db+/CFSEhi (B), was determined by FACS. Results were calculated as the mean and SD of at least 3 independent experiments normalized to that of WT controls. An asterisk indicates data with P value < .05 in t-tests. Biology of Blood and Marrow Transplantation 2009 15, 1513-1522DOI: (10.1016/j.bbmt.2009.08.013) Copyright © 2009 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 5 Donor-derived T cell proliferation in the spleen. The in vivo proliferation of donor-derived T cells in the spleen was measured by a CFSE tracking assay. Donor splenocytes were labeled with CFSE and then infused into the recipients with the bone marrow cells. On day 3 posttransplantation, the mice were sacrificed, and cells from the spleens were stained with CD4-PerCP, CD8-APC, and H-2Db-PE. The CD4+ T cells (A) and CD8+ T cells (B) are displayed on dot plots for the donor marker H-2Db. The percentage of donor-derived cells (CD4+/H-2Db+ or CD8+/H-2Db+) is noted on the top of the boxed region, and the lower-left insert of each plot shows a CFSE histogram of this designated population. The data given here are representative of at least 3 independent experiments. Biology of Blood and Marrow Transplantation 2009 15, 1513-1522DOI: (10.1016/j.bbmt.2009.08.013) Copyright © 2009 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 6 Donor-derived T cell proliferation in the peripheral lymph nodes. The in vivo proliferation of donor-derived T cells in the lymph nodes was measured on day 4 posttransplantation using a CFSE tracking assay. Cells from lymph nodes were stained with CD4-PerCP, CD8-APC, and H-2Db-PE. The donor-derived T lymphocyte subsets (CD4+/H-2Db+ and CD8+/H-2Db+) were identified by FACS. (A) The proliferation kinetics of donor-derived CD4+ (left) and CD8+ (right) cells were analyzed using FlowJo. The cell proliferation models were generated based on the CFSE histogram data. The cell division numbers are displayed on the top of each panel. The percentages of undivided cells and dividing cells are labeled. (B) Cell division indexes were calculated using FlowJo based on the proliferation kinetics. The data shown here are representative of 3 independent experiments. An asterisk indicates data with P value < .05 in t-tests. Biology of Blood and Marrow Transplantation 2009 15, 1513-1522DOI: (10.1016/j.bbmt.2009.08.013) Copyright © 2009 American Society for Blood and Marrow Transplantation Terms and Conditions