Mammalian Target of Rapamycin Inhibitors Permit Regulatory T Cell Reconstitution and Inhibit Experimental Chronic Graft-versus-Host Disease Haruko Sugiyama,

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Mammalian Target of Rapamycin Inhibitors Permit Regulatory T Cell Reconstitution and Inhibit Experimental Chronic Graft-versus-Host Disease Haruko Sugiyama, Yoshinobu Maeda, Hisakazu Nishimori, Yoshiko Yamasuji, Ken-ichi Matsuoka, Nobuharu Fujii, Eisei Kondo, Katsuji Shinagawa, Takehiro Tanaka, Kengo Takeuchi, Takanori Teshima, Mitsune Tanimoto Biology of Blood and Marrow Transplantation Volume 20, Issue 2, Pages 183-191 (February 2014) DOI: 10.1016/j.bbmt.2013.11.018 Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 Regulatory T cell reconstitution after allogeneic BMT. Lethally irradiated C3H (H-2k) recipient mice received 10 × 106 T cell–depleted bone marrow (TCD-BM) cells from B6.Ly-5a (H-2b,CD45.1) mice with/without 1 to 2 × 106 spleen cells from B6 (H-2b,CD45.2) mice. The syngeneic group received transplantation from C3H mice. (A) Survival: the recipients of allogeneic BM plus 1 × 106 spleen cells (BM plus Sp cells) showed a survival rate of 60% by day 120. Open circle, syngeneic; closed circle, TCD-BM cells only; triangle, -with 1 × 106 spleen cells; square, -with 2 × 106 spleen cells. (B) Origin of CD4+Foxp3+ Treg in the spleen on day 21 post transplantation: CD45.2+ splenic T cell–derived (white bars) and CD45.2– BM–derived (black bars) are shown. (C) The absolute numbers of Treg in the recipients of BM plus Sp cells (triangles) and TCD-BM (closed circles) are shown. Each group consisted of 7 to 25 mice. The means (±SE) of each group are shown. Data are from a representative of at least 3 independent experiments. *P < .05; **P < .01. Biology of Blood and Marrow Transplantation 2014 20, 183-191DOI: (10.1016/j.bbmt.2013.11.018) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 Donor BM–derived progenitors comprise the long-term peripheral Treg pool. Lethally irradiated C3H recipients underwent transplantation as in Figure 1: (B6 → C3H). The rates of CD45.2+ spleen cell–derived (broken lines) and CD45.2– BM–derived (solid lines) Treg in CD4+Foxp3+ Treg are shown. Spleen (A) and mesenteric lymph nodes (MLN) (B) were isolated from (B6 → C3H) mice at various time points after BMT and cells were analyzed by fluorescent activated cell sorter. (C) Lethally irradiated C3.SW (H-2b) recipients underwent transplantation from B6 (H-2b) donors. The rates of CD45.2+ splenic T cell–derived (broken lines) and CD45.2– BM–derived (solid lines) Treg in CD4+Foxp3+ Treg in the spleen are shown. Each group consisted of 20 to 23 mice. The means (±SE) of each group are shown. Data are from a representative of at least 2 independent experiments. (D) CD25+CD4+ Treg were purified from the spleens of (B6 → C3H) mice (on day 120) or naïve B6 (WT). B6 CD4+CD25– T cells (Tcon) together with various numbers of Treg were cultured with irradiated C3H CD11c+ DC as stimulators for 72 hours. Proliferative activities were determined by monitoring 3H-thymidine uptake. Biology of Blood and Marrow Transplantation 2014 20, 183-191DOI: (10.1016/j.bbmt.2013.11.018) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 Effects of CSA and mTOR inhibitors on the Treg compartment. Lethally irradiated C3H recipients underwent transplantation from B6 donor mice as shown in Figure 1 and received i.p. injections of CSA (closed squares), mTOR inhibitor (rapamycin, RAPA; open triangles), or vehicle control (open squares) daily from day 0 to 110. The rates of CD45.2+ splenic T cell–derived (broken lines) and CD45.2– BM–derived (solid lines) Treg in CD4+Foxp3+ Treg are shown. Spleen (A) and mesenteric lymph nodes (MLN) (B) were isolated from (B6 → C3H) mice at various time points after BMT and cells were analyzed by fluorescent activated cell sorter. Each group consisted of 16 to 23 mice. The means (±SE) of each group are shown. Data are from a representative of at least 2 independent experiments. Biology of Blood and Marrow Transplantation 2014 20, 183-191DOI: (10.1016/j.bbmt.2013.11.018) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 CSA, but not mTOR, inhibitors hampered reconstitution of BM-derived Treg. (B6 → C3H) mice received i.p. injections of CSA (black bars), mTOR inhibitor (rapamycin, RAPA; gray bars), or vehicle control (white bars) daily from day 0 to 110. The absolute numbers of Treg in the spleen (A), MLN (B), and thymus (C) are shown. Each group consisted of 19 to 26 mice. The means (±SE) of each group are shown. Data are from a representative of at least 2 independent experiments. *P < .05; **P < .01. Biology of Blood and Marrow Transplantation 2014 20, 183-191DOI: (10.1016/j.bbmt.2013.11.018) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 5 CSA, but not mTOR, inhibitors increased the likelihood of chronic GVHD. (A) Histological findings of the skin (a to d), liver (e to h), and salivary glands (i to l) (on day 120) from (B6 → C3H) mice given CSA, mTOR inhibitor (RAPA, RAD), or vehicle control. Sclerodermatous skin changes, such as epidermal atrophy, fat loss, follicular dropout, and dermal thickness (b); fibrosis in the portal area and peripheral mononuclear cells infiltrates in the liver (f); and fibrosis and atrophy of acinar tissue in the salivary glands (j) were observed (original magnification: × 100) Pathological scores of skin (B), salivary gland (C) and liver (D). The data are expressed as means ± SE. Data are from a representative of at least 2 independent experiments. *P < .05; **P < .01. Biology of Blood and Marrow Transplantation 2014 20, 183-191DOI: (10.1016/j.bbmt.2013.11.018) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 6 CSA, but not mTOR, reduces Treg infiltration in skin tissue. (A) Lethally irradiated C3H recipients underwent transplantation from B6 donor mice as shown in Figure 1 and received vehicle control (a, d), CSA (b, e), or mTOR inhibitor (RAD; c, f), daily from day 0 to 120. Immunohistochemical staining was performed using anti-Foxp3 (a to c) and anti-CD3 (d to f) antibodies on day 120. Arrows indicate Foxp3 positive cells. (B) The ratio of Foxp3 Tregs per 100 CD3+ lymphocytes. The number of CD3 and Foxp3 cells was counted in all the high-power ﬁelds. Results are expressed as mean ± SD. Pictures and data are from a representative of 2 independent experiments. (n = 3 to 4 per group). *P < .05. Biology of Blood and Marrow Transplantation 2014 20, 183-191DOI: (10.1016/j.bbmt.2013.11.018) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 7 Adoptive transfer of pathogenic CD4+ T cells caused severe chronic GVHD. (A) Lethally irradiated C3H recipients were reconstituted with TCD BM from MHC class II-deficient (H2-Ab1−/−) B6 mice. These mice developed chronic GVHD and CD4+ T cells isolated from chronic GVHD mice ([H2-Ab1−/−→C3H] CD4+ T cells) were primarily donor reactive. These pathogenic CD4+ T cells cause chronic GVHD when B6 antigens are provided by hematopoietic cells in the absence of B6 antigen expression on target epithelium ([B6→C3H] chimeras). (B) C3H recipient mice underwent transplantation from B6 donors as shown in Figure 1 and received CSA, RAPA, or vehicle solution until 60 days post BMT. These C3H recipient mice received adoptive transfer of [H2-Ab1−/−→C3H] CD4+ T cells. Body weight change is shown in (C) and overall survival is shown in (D). Data from 3 similar experiments are combined (n = 8 to 12 per group). The data are expressed as means ± SE. *P < .05; **P < .01. Biology of Blood and Marrow Transplantation 2014 20, 183-191DOI: (10.1016/j.bbmt.2013.11.018) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions