Division of Hematology, Department of Internal Medicine, Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Suppressor of cytokine signaling genes (
Expression levels of
Overall, the expression levels of
This is the first study to show that
Graft-versus-host disease (GVHD) is one of the main causes of death in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) in hematologic malignancies, including acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and myelodysplastic syndromes (MDS) [1, 2]. GVHD can be divided into acute GVHD (aGVHD) and chronic GVHD (cGVHD). aGVHD is caused by donor T cell-mediated recognition in response to recipient nonhematopoietic antigen presenting cells, especially dendritic cells. In consequence, in the immune reaction, alloantigens are presented to alloreactive T cells with huge amounts of cytokines [3, 4]. Unlike aGVHD, cGVHD is generated by thymic damage, production of aberrant B cells, defective function of T cells, along with cytokine dysregulation . Numerous approaches have been applied as part of transplantation protocols in order to inhibit the occurrence of GVHD, such as T cell depleted donor grafts, pharmacological agents, infusion of regulatory T cells, and gene expression profiling of T cell subsets from donors [6-10]. However, the incidence of aGVHD remains high, at over 60%, while 50-70% of recipients develop cGVHD [2, 11].
Recently, Nishimori et al.  demonstrated that immune cell-related cytokines, which aid differentiation into effector T cells (e.g. Th1, Th2, and Th17), may also function as key modulators in GVHD [8, 12, 13], and their activities can be attenuated by suppressor of cytokine signaling (SOCS) proteins . SOCS proteins are inhibitors of cytokine signaling pathways and are key physiological regulators of both innate and adaptive immunity. The cytokine inducible SH2-containing (CIS) SOCS family contains 8 members (CIS and SOCS1-SOCS7), each of which has a central SH2 domain, an N-terminal domain of variable length and sequence, and a 40-amino-acid C-terminal module called the SOCS box . In particular, the role of SOCS1 and SOCS3 in Toll-like receptor immune responses has been extensively investigated [16, 17]. Furthermore, previous studies have shown the potential for enhancing T-cells in tumors by high-level transcription of
Despite increasing evidence for the importance of
All experiments were performed with authorization from the Institutional Review Board for Human Research at the Catholic University of Korea. All blood samples were collected from post-HSCT recipients, who were initially diagnosed with one of the hematologic diseases designated by the World Health Organization. In addition, peripheral blood was donated from a set of healthy transplant donors (N=55). Heparinized blood samples were obtained from all transplant recipients within 1 week of GVHD development, and on the day of transplantation from all donors. Mononuclear cells were isolated by overlaying the blood samples on a Ficoll-Hypaque gradient (density, 1.077; Lymphoprep; Gibco-BRL, Carlsbad, CA, USA), followed by centrifugation at 400 ×
Clinical characteristics of the recipients and donors enrolled in this study are detailed in Table 1. A total of 71 recipients with AML (N=40), ALL (N=12), MDS (N=10), chronic myelogenous leukemia (CML; N=2), severe aplastic anemia (SAA; N=5), or others (N=2), who received allogeneic HSCT from human leukocyte antigen-identical siblings or unrelated donors between 2009 and 2011, were included in the present study.
Diagnoses of aGVHD and cGVHDs were determined as described previously, based on consensus criteria [25, 26]. The classification of aGVHD was determined by its severity as no (none GVHD and grade I), grade II, and grade III-IV. Based on clinical impressions of its overall severity, cGVHD was classified from mild-moderate to severe. Recipients without GVHD after HSCT were classified into the none-GVHD group. Methylprednisolone was administered at 2.4 mg/kg/day for 4.7 days with a gradual taper to treat aGVHD graded II or more. Skin, rectal, stomach, or duodenal biopsies were performed in order to confirm the GVHD diagnoses . The treatment of cGVHD was also variable; in accordance with National Institute of Health recommendations, the mild type was treated with topical immunosuppressants, whereas both moderate and severe types were treated with a calcineurin inhibitor and systemic steroids .
Since no data regarding the levels of
All results are presented as mean±standard error of the mean (SEM) values. Statistical analyses of more than 2 groups were performed using one-way analysis of variance (ANOVA). The difference in the frequency of each gene between donors and recipients was analyzed using a two-tailed Wilcoxon matched-pairs signed rank
Of the 71 HSCT recipients with successful engraftment evaluated, 18 (25.4%) developed grade II to IV aGVHD: 14 (77.8%) with grade II and 4 (22.2%) with grade III-IV. cGVHD developed in 17 (23.9%) of the recipients evaluated. Our data showed that
We further analyzed the expression levels of
We further investigated the expression of
Prevention of GVHD after allogeneic HSCT has been extensively investigated in the past decade [6-9]. A successful engraftment of normal hematopoietic stem cells without rejection and/or severe GVHD should be a goal for all procedures involving allogeneic HSCT. To achieve this, various cytokines that can regulate donor-derived T cell immune activation need to be balanced prior to GVHD occurrence after HSCT . In particular, immune suppressor cytokines, which are regulated by SOCS family genes, may play an important role in the various pathophysiological events that occur following allogeneic HSCT, as indicated by animal studies [21, 24]. Results of previous animal studies on the role of
We found that
However, the present study is somewhat limited, as clinical relevance of these results could not be established due to the small number of patients, although drug treatments commonly start from grade II of aGVHD. More defined clinical outcomes will likely emerge with the accumulation of further studies correlating
Among members of the SOCS family, SOCS1 and SOCS3 have been shown to contain a kinase inhibitory receptor (KIR), based on a knockout system applied to KIR-containing SOCS members, implying the importance of KIR domains in immune systems [18, 19]. Therefore, we focused on the
In conclusion, we present the first report that