Interleukin 17 Is Not Required for Autoimmune-Mediated Pathologic Damage during Chronic Graft-versus-Host Disease Xiao Chen, Rupali Das, Richard Komorowski,

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Interleukin 17 Is Not Required for Autoimmune-Mediated Pathologic Damage during Chronic Graft-versus-Host Disease Xiao Chen, Rupali Das, Richard Komorowski, Jacques van Snick, Catherine Uyttenhove, William R. Drobyski Biology of Blood and Marrow Transplantation Volume 16, Issue 1, Pages 123-128 (January 2010) DOI: 10.1016/j.bbmt.2009.09.008 Copyright © 2010 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 Blockade of IL-17 signaling has no protective effect on the development of autoimmunity during cGVHD. Lethally irradiated (900cGy) Balb/c mice were transplanted with B6 bone marrow (BM) (10×106) plus 0.4-0.5×106 B6 spleen cells. On days 19 to 21 posttransplantation, mice were sacrificed and spleen cells from fully donor-engrafted animals (0.45-0.5×106) were transferred into nonirradiated B6 Rag mice. Cohorts of B6 Rag animals were then treated with either IgG1 isotype control or anti-IL-17 antibody (200μg/dose) twice weekly. Mice were sacrificed 48 to 75 days posttransfer. (A) Pathologic damage in the colon, liver, and lung of mice treated with isotype control (▪, n=12) or anti-IL-17 antibody (□, n=12) using a semiquantitative scoring system as detailed in the Methods section. (B) Histology of colon, liver, and lung from representative recipients treated with either isotype or anti-IL-17 antibody. In isotype control animals, colon shows inflammation in the lamina propria, and goblet cell depletion, liver reveals portal triad inflammation with mononuclear cells and endothelialitis, and lung demonstrates perivascular cuffing with mononuclear cells. In anti-IL-17 antibody-treated mice, colon also shows extensive inflammation in the lamina propria, goblet cell depletion, and crypt cell destruction, liver has portal triad inflammation and lung demonstrates perivascular cuffing. (C) Total cellularity and absolute number of Gr-1+ Mac-1+ cells in the spleen are depicted. (D) Serum proinflammatory cytokine levels from B6 Rag mice treated with either isotype (n=9) or anti-IL-17 antibody (n=9) immediately prior to sacrifice of animals. (E) Absolute number of CD4+ and CD8+T cells in the spleens of mice administered isotype (n=9) or anti-IL-17 antibody (n=9) 48 to 69 days posttransfer. (F) Spleens and colon tissue from animals that received either control or anti-IL-17 antibody (n=3/group) were pooled and the percentage of CD4+T cells secreting IL-17, IFN-γ, or both, in each organ is shown. Data are presented as the mean±SEM and are the cumulative results from 3 to 4 independent experiments for all studies depicted. Statistics: ∗P ≤ .05. ∗∗P ≤ .01; Biology of Blood and Marrow Transplantation 2010 16, 123-128DOI: (10.1016/j.bbmt.2009.09.008) Copyright © 2010 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 Absence of donor-derived IL-17 has no protective effect on the development of autoimmunity. Lethally irradiated Balb/c mice were transplanted with BM (10×106) and spleen cells (0.4×106) from wild-type B6 or IL-17−/− animals to induce GVHD. Mice from each group were sacrificed 19 to 21 days after transplantation and pooled spleen cells (0.5×106) were transferred into nonirradiated B6 Rag mice. (A) Representative dot plot depicting the percentage of IL-17 and/or IFN-γ-secreting cells within the gated CD4+T cell population obtained from the spleen, liver, or colons of mice 60 to 65 days after transfer of spleen cells from B6→Balb/c or IL-17−/−→Balb/c chimeras. (B,C) Individual spleens, liver, and colon tissue from B6 Rag mice that received adoptive transfer of spleen cells from B6→Balb/c (▪) or IL-17−/−→Balb/c (□) chimeras (n=2-4/group) were pooled and the percentage (B) and absolute number (C) of CD4+T cells secreting IFN-γ in each organ is depicted. Data are the cumulative results from 3 independent experiments. Each experiment had the same number of mice per group. (D) Individual spleens, livers, and colon tissue from B6 Rag mice that received adoptive transfer of spleen cells from B6→Balb/c or IL-17−/−→Balb/c chimeras (n=2-4/group) were pooled and the percentage of CD4+T cells secreting IL-17 in each organ is depicted. (E) Pathologic damage in the colon, liver and lung of mice 60-65 days after adoptive transfer of spleen cells from B6→Balb/c (n=9) or IL-17−/−→Balb/c (n=9) chimeras. Data are the cumulative results from 3 independent experiments. Data are presented as the mean±SEM. Statistics: ∗P ≤ .05. Biology of Blood and Marrow Transplantation 2010 16, 123-128DOI: (10.1016/j.bbmt.2009.09.008) Copyright © 2010 American Society for Blood and Marrow Transplantation Terms and Conditions