Early changes in gene expression profiles of hepatic GVHD uncovered by oligonucleotide microarrays

Abstract

The liver, skin, and gastrointestinal tract are major target organs of acute graftversus-host disease (GVHD), the major complication of allogeneic bone marrow transplantation (BMT). In order to gain a better understanding of acute GVHD in the liver, we compared the gene expression profiles of livers after experimental allogeneic and syngeneic BMT using oligonucleotide microarray. At 35 days after allogeneic BMT when hepatic GVHD was histologically evident, genes related to cellular effectors and acute-phase proteins were up-regulated, whereas genes largely related to metabolism and endocrine function were down-regulated. At day 7 after BMT before the development of histologic changes in the liver, interferon ␥ ( IntroductionAllogeneic bone marrow transplantation (BMT) is the treatment of choice for a number of malignant conditions as well as hematologic and metabolic disorders. Acute graft-versus-host disease (GVHD), a major complication of allogeneic BMT, is a rapidly progressing systemic illness characterized by tissue injury in various organs, including the liver, skin, gut, and lymphoid tissues. 1,2 Acute GVHD is initiated by donor T cells in response to host antigen-presenting cells (APCs). 3 Damage to the intestinal mucosa by the conditioning regimen of BMT, such as irradiation or chemotherapy, allows the translocation of lipopolysaccharide (LPS) into the systemic circulation, which activates host APCs and stimulates monocytes and macrophages to secrete inflammatory cytokines. 4 This cytokine cascade synergies with cellular effectors such as cytotoxic T-lymphocytes (CTLs) and natural killer (NK) cells, and results in the amplification of tissue injury. 5 In the liver, the histologic signature of acute GVHD is inflammatory cell infiltration into portal areas, bile duct epithelial damage, cholestasis, and endothelialitis. 6 We hypothesized that the global quantitative analysis of gene expression would help to illuminate the mechanisms of the complex and multifactorial process of acute GVHD in the liver, particularly early during the disease process when histology is rarely evaluable because of the morbidity of hepatic biopsies early after transplantation. We therefore analyzed hepatic tissue at 2 different time points after BMT in a well-characterized murine model to evaluate the kinetics of changes in gene expression. Materials and methods MiceFemale C57BL/6 (B6, H-2 b ) and B6D2F1 (H-2 b/d ) mice were purchased from the Jackson Laboratories (Bar Harbor, ME). The age of mice used as BM transplant recipients ranged between 9 and 15 weeks, while the age of donors was 9 to 11 weeks. BMT and isolation of the liverMice underwent transplantation according to a standard protocol described previously. 7 On day 0, B6D2F1 mice received 13 Gy total body irradiation (TBI; 137 Cs source), split into 2 doses separated by 3 hours to minimize gastrointestinal toxicity. After TBI, 5 ϫ 10 6 bone marrow cells (BMCs) and 2 ϫ 10 6 nylon wool-purified splenic donor T cells from allogeneic B6 donors or syngeneic B6D2F1 donors we...

Therapeutic effect of CXCR3-expressing regulatory T cells on liver, lung and intestinal damages in a murine acute GVHD model

“…[4][5][6][7][8][9][10][11][12][13][14][15][16][17] Several chemokines such as CCL2, CCL3, CCL4, CCL5, CCL11, CXCL9, CXCL10 and CXCL11, are expressed in the liver, intestine and lung during experimental GVHD. Studies using conditioned murine GVHD models have demonstrated a consistent pattern in the kinetics of expression of these chemokines.…”

“…3 Expression of several chemokines in target organs during GVHD has been demonstrated in a number of experimental models. [4][5][6][7][8][9][10][11][12][13][14][15] Published data on the role of chemokines in GVHD are somewhat conflicting, since upregulation of chemokines in target organs during GVHD is influenced by transplant conditioning and recipient strain. 16,17 In conditioned murine GVHD models, the expression of chemokines such as CCL2, CXCL9, CXCL10 and CXCL11 is upregulated in the liver early after GVHD induction.…”

“…16,17 In conditioned murine GVHD models, the expression of chemokines such as CCL2, CXCL9, CXCL10 and CXCL11 is upregulated in the liver early after GVHD induction. 6,8,15 On the other hand, significant expression of chemokines including CCL2, CCL3, CCL4, CCL5, CCL11, CXCL9, CXCL10 and CXCL11 has been demonstrated in the intestine and lung early after GVHD induction. 5,7,16,17 In addition, expression of CXCR3 and CCR5, the receptors for Th1-associated chemokines (CXCL9, CXCL10 and CXCL11) and CCL3, CCL4 and CCL5, respectively, also increases significantly in the liver, lung and intestine during acute GVHD.…”

Differential chemokine expression in chronic GVHD of the conjunctiva

“…28,29,40 In addition, the influence of chemokines on the recruitment of activated CD4 þ T cells into the skin of GVHD patients has been elucidated. 41 Supporting these data, another study found an elevated expression of CXCL10 in the epidermis and also higher levels of its receptor CXCR3 in dermal inflammatory infiltrates of patients suffering from GVHD.…”

“…[25][26][27] The upregulation of several chemokines is associated with acute GVHD. 28,29 However, the pathogenic role of chemokines in chronic conjunctival GVHD remains elusive to a large extent.…”