A Role for TNF Receptor Type II in Leukocyte Infiltration into the Lung during Experimental Idiopathic Pneumonia Syndrome Gerhard C. Hildebrandt, Krystyna.

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A Role for TNF Receptor Type II in Leukocyte Infiltration into the Lung during Experimental Idiopathic Pneumonia Syndrome Gerhard C. Hildebrandt, Krystyna M. Olkiewicz, Leigh Corrion, Shawn G. Clouthier, Elizabeth M. Pierce, Chen Liu, Kenneth R. Cooke Biology of Blood and Marrow Transplantation Volume 14, Issue 4, Pages 385-396 (April 2008) DOI: 10.1016/j.bbmt.2008.01.004 Copyright © 2008 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 The absence of TNFRI in allo-SCT recipients results in an early reduction of clinical GVHD and improved survival. BM and T cells from allogeneic, MHC matched LP/J donor mice were transplanted into wt (♦, —), TNFRI−/− (▴,…..), or TNFRII−/− (•,---) B6 recipients as described in Materials and Methods. In all experiments, some B6 wt mice also received BM and T cells from syngeneic B6 donors (▪, -•-•-•-). Clinical GVHD scores were determined weekly and survival was monitored daily. (A) TNFRI−/− (▴), but not TNFRII−/− (•), mice develop significantly reduced clinical GVHD scores 7 to 28 days after allo-SCT when compared to wt controls (♦). Data presented are combined from 3 comparable experiments; n = 12 to 20 per group; ∗P < .05. (B) The reduction in clinical GVHD correlates with decreased early mortality of TNFRI−/− recipients (…..) after allo-SCT, but no difference in survival is seen between allogeneic wt (—) and TNFRII deficient (---) animals. Data presented are combined from 4 comparable experiments; n = 21 to 38 per group; ∗P < .05. (C) T cell chimerism was assessed 5 weeks after transplant by FACS analysis for surface expression of the donor marker Ly9.1. Donor T cell engraftment after SCT was independent of the p55 or the p75 TNF receptor expression in the recipient, and comparable in all allogeneic groups. Data presented are from 1 of similar 2 experiments; n = 3-4 animals per group. Biology of Blood and Marrow Transplantation 2008 14, 385-396DOI: (10.1016/j.bbmt.2008.01.004) Copyright © 2008 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 Leukocyte infiltration into the lung is significantly reduced in TNFRII−/− but not TNFRI−/− allo-SCT recipients. Animals were transplanted as described in Figure 1 and lung injury was assessed 5 weeks after SCT. (A, B) TNFRII−/− (), but not TNFRI−/− (), recipients developed significantly less lung histopathology in comparison to allogeneic wt controls (▪). Syngeneic controls maintained normal lung histology (□). (C-E) Decreased lung histopathology scores were associated with a reduction in BALF cellularity and BALF T cells. Data presented are combined from 2 comparable experiments; n = 10 to 15 per group; ∗∗P < .01; ∗P < .05; +P = .06 () versus (). Biology of Blood and Marrow Transplantation 2008 14, 385-396DOI: (10.1016/j.bbmt.2008.01.004) Copyright © 2008 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 Reduction of leukocyte infiltration into the lungs of TNFRII−/− allo-SCT recipients is associated with significantly decreased BALF levels of RANTES. Animals received syngeneic or allo-SCT as described in Figure 1, and BALF levels of Mip-1α, RANTES, and MCP-1 and were determined 5 weeks later. (A-C) BALF levels of each chemokine were increased following allo-SCT compared to syngeneic controls (□). Although no differences in BALF levels of Mip-1α were observed among allogeneic groups, BALF RANTES, and MCP-1 levels were reduced in TNFRII−/− () but not TNFRI−/− () recipients compared to allogeneic controls (▪). Data shown are from 1 experiment; n = 3 to 5 per group; ∗P < .05; +P = .07 () versus (). Biology of Blood and Marrow Transplantation 2008 14, 385-396DOI: (10.1016/j.bbmt.2008.01.004) Copyright © 2008 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 Absence of TNFRII is associated with decreased pulmonary ICAM-1 expression following allo-SCT. Animals received syngeneic or allogeneic SCT as described in Figure 1 and the pulmonary expression of ICAM-1 was analyzed by immunohistochemistry as described in Materials and Methods. Sections shown are representative of staining observed in lungs from each group. Allogeneic wt and TNFRI−/− recipients (C, D) demonstrate increased signal intensity for ICAM-1 both in the interstitium and the bronchial epithelium when compared to syngeneic SCT controls (B). By contrast, the intensity of ICAM-1 expression in lungs of TNFRII−/− recipients is reduced (E). (900× and 400× magnification; ICAM-1 brown; counterstain: hematoxylin). Biology of Blood and Marrow Transplantation 2008 14, 385-396DOI: (10.1016/j.bbmt.2008.01.004) Copyright © 2008 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 5 Reduction in whole-lung ICAM-1 mRNA expression confirms immunohistochemical staining in TNFRII−/− recipients. Animals received syngeneic or allogeneic SCT as described in Figure 1 and the pulmonary expression of ICAM-1 was analyzed by RT-PCR as described in Materials and Methods. Data are expressed as fold difference in expression compared to that observed, in syngeneic controls. n = 4 to 6 animals per group. ∗P < .05. Biology of Blood and Marrow Transplantation 2008 14, 385-396DOI: (10.1016/j.bbmt.2008.01.004) Copyright © 2008 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 6 Absence of TNFRII is associated with reduced lung injury following allo-SCT in an isolated MHC class I mismatched system. Lethally irradiated B6 wt and B6 TNFRII−/− received SCT from allogeneic bm1 donors. Syngeneic B6 → B6 controls were included (□) and lung injury was assessed 5 weeks after SCT as described in Materials and Methods. (A) Allogeneic TNFRII−/− recipients () demonstrate a significant reduction in lung histopathology scores compared to allo-SCT controls (▪). (B-D) Reduction in lung histopathology in TNFRII−/− recipients () was associated with decreased BALF cellularity, BALF CD8+ T cell counts, as well as a reduction of RANTES levels in the BALF fluid. n = 4 to 7 per group; ∗∗P < .01; ∗P < .05; #P < .09. Biology of Blood and Marrow Transplantation 2008 14, 385-396DOI: (10.1016/j.bbmt.2008.01.004) Copyright © 2008 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 7 TNFRII-mediated effects of donor-derived TNF-α are important to the development of acute lung injury after allo-SCT. Lethally irradiated bm 1 recipients were transplanted with BM and T cells from either syngeneic (bm1; □), allogeneic TNF-α+/+ B6 (▪), or allogeneic TNF-α−/− B6 donor mice (). Lung injury was assessed 5 weeks after transplant. (A-C) Allogeneic transplantation with TNF-α-deficient donor cells resulted in a nearly complete abrogation of lung histopathology associated with decreases in BALF cellularity and CD8+ T cells. (D) Although TNF-α levels in the BALF of allogeneic recipients of TNF-α+/+ donor cells were significantly elevated, no differences were found between syngeneic controls and recipients after allo TNF-α−/− SCT. All data are from 1 of 2 comparable experiments; n = 4 to 7 per group; ∗P < .05. Biology of Blood and Marrow Transplantation 2008 14, 385-396DOI: (10.1016/j.bbmt.2008.01.004) Copyright © 2008 American Society for Blood and Marrow Transplantation Terms and Conditions