Histological Assessment of the Sclerotic Graft-versus-Host Response in the Humanized RAG2−/−γc−/− Mouse Model Marieke C.H. Hogenes, Suzanne van Dorp,

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Histological Assessment of the Sclerotic Graft-versus-Host Response in the Humanized RAG2−/−γc−/− Mouse Model Marieke C.H. Hogenes, Suzanne van Dorp, Joyce van Kuik, Filipa R.P. Monteiro, Natalie ter Hoeve, Marijke R. van Dijk, Anton C. Martens, Roel A. de Weger Biology of Blood and Marrow Transplantation Volume 18, Issue 7, Pages 1023-1035 (July 2012) DOI: 10.1016/j.bbmt.2012.05.002 Copyright © 2012 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 Human infiltrating cells in spleen of RAG2−/−γc−/− mice injected with huPBMCs. Infiltrate analysis of spleen comparing both histological and immunohistochemical stainings of a control mouse and a mouse surviving 45 days after huPBMC injection is shown. The morphology is representative of the observed reaction in a total of 15 examined mice (6 mice in experiment 1 and 9 mice in experiment 2). (A) Normal murine spleen, without human cell infiltrate or fibrosis (H & E staining; original magnification, 20×). (B) Normal murine spleen without human cell infiltrate or fibrosis (AZAN staining; original magnification, 20×; fibrosis score 0). (C) Normal murine spleen, showing no immunohistochemical positivity and no cross-reactivity when staining for human CD2+ T cells (huCD2 staining; original magnification, 20×; T cell score 0). (D) Perivascular fibrosis in spleen in a mouse 45 days after huPBMC injection (H & E staining; original magnification, 20×; fibrosis score 2). (E) Perivascular fibrosis spleen (identical area to that shown in D) showing blue staining of the formed collagenous fibrosis (AZAN staining; original magnification, 20×; fibrosis score 2). (F) HuCD68 cells showing the absence of human macrophages in a mouse injected with huPBMCs (huCD68 staining; original magnification, 20×; macrophage score 0). (G) Follicular/perivascular concentration of human B cells in the spleen after injection with human PBMCs (huCD20 staining; original magnification, 20×; B cell score 2). (H) Diffuse spreading of human T cells in the spleen after injection of human PBMCs (huCD2 staining; original magnification, 20×; T cell score 4). (I) Focal localization of human Tregs with nuclear positive staining for huFoxP3 after injection with human PBMCs (huFoxP3 staining; original magnification, 20×; Treg score 1). A circle indicates localization of capillary blood vessels; asterisk, fibrosis area; arrow, FoxP3+ Tregs. Biology of Blood and Marrow Transplantation 2012 18, 1023-1035DOI: (10.1016/j.bbmt.2012.05.002) Copyright © 2012 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 Histological and immunohistochemical analysis of infiltrating human cells in RAG2−/−γc−/− lungs. Infiltrate analysis of the lungs comparing a control mouse and a mouse from experiment 1, surviving 45 days after huPBMC injection, is shown. The morphology is representative of the observed pattern in a total of 15 examined mice (6 mice in experiment 1 and 9 mice in experiment 2). (A) Normal murine lung showing thin alveolar septae around bronchi and blood vessels (H & E staining; original magnification, 10×; fibrosis score 0). (B) Lung after injection with human PBMCs, showing perivascular and peribronchial fibrosis and cell infiltration with hypercellular alveolar septae 45 days after huPBMC injection (H & E staining; original magnification 10×; fibrosis score 1). (C) Detail from (B) (inset) showing plasma cells in the area of fibrosis (H & E staining; original magnification 40×; plasma cell score 1). (D) Normal lung showing thin alveolar septae without extensive fibrosis around bronchi or vessels (AZAN staining; original magnification, 10×; fibrosis score 0). (E) and (F) Same areas as in (B) and (C) respectively, in AZAN staining, with blue staining of the collagenous fibrosis (E, original magnification 10×; (F) detail from (E) inset; original magnification, 40×; fibrosis score 1). (G) Foamy alveolar macrophages after injection with huPBMCs (H & E staining; original magnification, 40×). (H) The macrophages do not show human CD68 positivity (huCD68; original magnification, 40×; identical area to that shown in H). (I) Positive staining of macrophages for mouse CD68 confirms murine origin (mouse CD68; original magnification, 40×; identical area to that shown in H). Br, bronchus. An asterisk denotes the peribronchial artery; an arrow, foamy alveolar bronchophages. The square is a detail of the area shown in (C) (corresponding to the square in B) and (F) (corresponding to the square in D). Biology of Blood and Marrow Transplantation 2012 18, 1023-1035DOI: (10.1016/j.bbmt.2012.05.002) Copyright © 2012 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 Histological and immunohistochemical analysis of infiltrating human cells in RAG2−/−γc−/− liver and skin. Infiltrate analysis comparing a control mouse with a representative mouse surviving 29 days (liver) and 45 days (skin) after huPBMC injection in experiment 1. The morphology is representative of the observed fibrosis and cell infiltration patterns in a total of 15 examined mice (6 mice in experiment 1 and 9 mice in experiment 2). (A) Normal murine liver, showing no infiltrate or fibrosis in the portal tract (H & E staining; original magnification 20×; control mouse, fibrosis score 0). (B) Liver after injection with human PBMCs, showing infiltration of human cells in the portal tract with extensive fibrosis and an intact bile duct 29 days after huPBMC injection (H & E staining; original magnification 20×; fibrosis score 2). (C) Area corresponding to that shown in (A) demonstrating green staining of collagenous fibers in the hepatic portal area of normal mice (Trichrome staining; original magnification 20×; fibrosis score 0). (D) Area corresponding to that shown in (B) showing extensive collagenous fibrosis (in green) in a mouse injected with huPBMCs (Trichrome staining; original magnification 10×; fibrosis score 2). (E) Normal murine skin, with many hair follicles in the dermis and normal presence of subcutaneous fat (H & E staining; original magnification 20×; control mouse, fibrosis score 0). (F) Skin 45 days after injection with huPBMCs, showing extensive fibrosis of the dermal collagen at the cost of subcutaneous fat and infiltration of human cells subepidermally, perifollicularly, and interstitially (H & E staining; original magnification 20×; fibrosis score 4). (G) Area corresponding to that shown in (E) showing a normal ratio between dermal collagen (green) and subcutaneous fat (Trichrome staining; original magnification, 20×; fibrosis score 0). (H) Area corresponding to that shown in (F) showing extensive collagenous fibrosis (green) in the dermis with a loss of subcutaneous fat (Trichrome staining; original magnification 20×; fibrosis score 4). a, portal artery; v, portal vein; asterisk, bile duct; s, subcutaneous fat; d, dermal tissue; e, epidermal layer; m, muscle. Biology of Blood and Marrow Transplantation 2012 18, 1023-1035DOI: (10.1016/j.bbmt.2012.05.002) Copyright © 2012 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 Expression of mRNA for fibrogenic proteins and macrophage markers. Shown is the RQ of RNA for human and murine TGF-β, CD68, BMP4, and CTGF in spleen, lungs, liver, and skin of RAG2−/−γc−/− mice injected with huPBMCs. Biology of Blood and Marrow Transplantation 2012 18, 1023-1035DOI: (10.1016/j.bbmt.2012.05.002) Copyright © 2012 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 5 Expression of T cell marker mRNA. Shown is the RQ of RNA for different human cell types, including FoxP3 (Tregs), GATA3 (Th2 cells), Tbet (Th1 cells), RORC (Th17 cells), CD4 (T helper cells), and CD8 (CTLs), including CXCR4 (chemotactin for lymphocytes), in the spleen, lungs, liver, and skin of RAG2−/−γc−/− mice injected with huPBMCs. Biology of Blood and Marrow Transplantation 2012 18, 1023-1035DOI: (10.1016/j.bbmt.2012.05.002) Copyright © 2012 American Society for Blood and Marrow Transplantation Terms and Conditions