Jae Hee Suh

4-1BB-mediated immunotherapy of rheumatoid arthritis

Collagen type II–induced arthritis is a CD4+ T-cell–dependent chronic inflammation in susceptible DBA/1 mice and represents an animal model of human rheumatoid arthritis. We found that development of this condition, and even established disease, are inhibited by an agonistic anti-4-1BB monoclonal antibody. Anti-4-1BB suppressed serum antibodies to collagen type II and CD4+ T-cell recall responses to collagen type II. Crosslinking of 4-1BB evoked an antigen-specific, active suppression mechanism that differed from the results of blocking the interaction between 4-1BB and its ligand, 4-1BBL. Anti-4-1BB monoclonal antibodies induced massive, antigen-dependent clonal expansion of CD11c+CD8+ T cells and accumulation of indoleamine 2,3-dioxygenase in CD11b+ monocytes and CD11c+ dendritic cells. Both anti-interferon-γ and 1-methyltryptophan, a pharmacological inhibitor of indoleamine 2,3-dioxygenase, reversed the anti-4-1BB effect. We conclude that the suppression of collagen-induced arthritis was caused by an expansion of new CD11c+CD8+ T cells, and that interferon-γ produced by these cells suppresses antigen-specific CD4+ T cells through an indoleamine 2,3-dioxygenase–dependent mechanism.

Comparison of clinicopathologic characteristics and genetic alterations between microsatellite instability-positive and microsatellite instability-negative sporadic colorectal carcinomas in patients younger than 40 years old.

AbstractPURPOSE: Many studies have demonstrated that sporadic microsatellite instability–positive colorectal cancers share several clinicopathologic features with hereditary nonpolyposis colorectal cancers, including right-sided location, young age of onset, characteristic histomorphologic features, and a good prognosis. The aim of this study was to define distinct clinicopathologic features of sporadic microsatellite instability–positive colorectal cancers and to compare genotypic characteristics between microsatellite instability–positive and microsatellite instability–negative colorectal cancers in a young group. METHODS: We analyzed 61 cases of young patients (<40 years old) with colorectal cancers for microsatellite instability at five mononucleotide and three dinucleotide repeats, loss of heterozygosity at APC and DCC, and K-ras and p53 mutations. Microsatellite instability status was correlated with molecular genetic factors and clinicopathologic parameters. RESULTS: Microsatellite instability positivity was detected in 19 (31.1 percent) of 61 cases. Allelic alterations in TGFβRII, BAX, and IGFIIR were observed exclusively in microsatellite instability–positive tumors (63.1, 26.3, and 26.3 percent, respectively). Microsatellite instability–positive tumors exhibited a lower frequency of the p53 mutation (10.5 percent) than microsatellite instability–negative tumors (47.6 percent; P < 0.05). However, microsatellite instability status was not associated with APC or DCC allelic deletion or with the K-ras mutation. Microsatellite instability–positive colorectal cancers exhibited a proclivity toward proximal location, expansive growth pattern, and large tumor size (P < 0.05). Microsatellite instability–positive colorectal cancers had lower preoperative serum carcinoembryonic antigen levels (P < 0.05), a less advanced stage at presentation (P < 0.05), and a tendency toward better prognosis (P = 0.051) than microsatellite instability–negative colorectal cancers. However, there was no difference between microsatellite instability–positive and microsatellite instability–negative colorectal cancers regarding gross features, tumor grade, and extracellular mucin production. CONCLUSION: These results suggest that sporadic microsatellite instability–positive colorectal cancers in young patients have different histomorphologic features from microsatellite instability–negative colorectal cancers and hereditary nonpolyposis colorectal cancers, some overlap of genetic alterations on multistep carcinogenesis with microsatellite instability–negative colorectal cancers, and a tendency for better prognosis.

Glucocorticoid-induced tumour necrosis factor receptor family-related receptor signalling exacerbates hapten-induced colitis by CD4+ T cells.

The glucocorticoid‐induced tumour necrosis factor receptor family related gene (GITR) has been reported to be expressed on the activated T and CD4+CD25+ regulatory T cells (Treg). Signalling triggered by GITR not only neutralizes the suppressive effect of Treg cells, but also augments activation, proliferation and cytokine production of effector T cells. To test the role of GITR in 2,4,6‐trinitrobenzene sulphonic acid (TNBS)‐induced colitis − a murine model of mucosal inflammation − TNBS‐injected Balb/c mice were treated with agonistic anti‐GITR monoclonal antibody (mAb). Anti‐GITR treatment increased the death rate compared to rat IgG‐treated mice. Typically, death occurred within 4 days after the TNBS injection when the mice were treated with anti‐GITR. The mice that survived anti‐GITR treatment suffered from severe inflammation in their entire intestines. CD4+ T‐depletion protected the mice from colitis; even an anti‐GITR effect was not apparent. In contrast, CD8+ T depletion showed less protective than did CD4+ T depletion. Stimulation of GITR enhanced the production of proinflammatory cytokines including interferon (IFN)‐γ, tumour necrosis factor (TNF)‐α, interleukin (IL)‐6 and IL‐12. It also enhanced the humoral response such as serum levels of IgG2b and IgA, which was completely dependent on CD4+ T cells. Taken together, this study demonstrated that GITR signalling on CD4+ T cells is involved in the development and progress of colitis by enhancing both T helper type 1 (Th1) and Th2 type responses.

Soluble glucocorticoid-induced TNF receptor (sGITR) induces inflammation in mice

Glucocorticoid-induced TNF receptor (GITR) was a new member of the TNF/nerve growth factor receptor (TNFR/ NGFR) family and induced in murine T cells by dexamathasone. Recombinant soluble GITR (sGITR) induced an inflammation in peritoneal membrane and changes in spleen after i.p. injection of 3 mg/kg in C57BL/6 mice. Spleen was enlarged and percentage of neutrophils and monocytes were increased. The area of red pulp in spleen was increased, while that of white pulp was decreased after GITR injection. The thickening of membrane and neutrophil infiltration was observed in peritoneal membrane with increased myeloperoxidase activity. At later time, neutrophil infiltration moved to inside the tissue with tissue damage. GITR ligand and GITR were expressed constitutively on the surface of spleen cells and cells from peritoneal fluid. In contrast, no significant change in the spleen and in peritoneal membrane was observed in mice treated with LPS. GITR may play a role in bodys inflammatory processes.

Thoracic Splenosis: A Case Report and the Importance of Clinical History

We present a case of thoracic splenosis in a 42-yr-old man with a medical history of abdominal surgery for a penetration injury with an iron bar of the left abdomen and back. He had been in good condition, but a chest radiograph taken during a regular checkup showed a multinodular left pleura-based mass. Computed tomography (CT) showed that the mass was well-enhanced and homogeneous, indicating a sclerosing hemangioma. Following its removal by video-assisted thoracoscopic surgery, the mass appeared similar to a hemangioma, with marked adhesion to the left side diaphragmatic pleura and lung parenchyma. Frozen section showed that the lesion was a solid mass consisted with abundant lymphoid cells, suggesting a low grade lymphoma. On permanent section, however, the mass was found to be composed of white pulp, red pulp, a thick capsule and trabeculae and was diagnosed as ectopic splenic tissue, or thoracic splenosis. Review of the patients history and chest CT at admission revealed that the patient had undergone a splenectomy for the penetration injury 20 yr previously.

4-1BB Signaling Breaks the Tolerance of Maternal CD8+ T Cells That Are Reactive with Alloantigens

4-1BB (CD137, TNFRSF9), a member of the activation-induced tumor necrosis factor receptor family, is a powerful T-cell costimulatory molecule. It generally enhances CD8+ T responses and even breaks the tolerance of CD8+ T cells in an antigen-specific manner. In the present study we found that it was expressed in the placentas of pregnant mice and that its expression coincided with that of the immunesuppressive enzyme indoleamine 2,3-dioxygenase (IDO). Therefore, we investigated whether 4-1BB signaling is involved in fetal rejection using agonistic anti-4-1BB mAb and 4-1BB-deficient mice. Treatment with agonistic anti-4-1BB mAb markedly increased the rate of rejection of allogeneic but not syngeneic fetuses, and this was primarily dependent on CD8+ T cells. Complement component 3 (C3) seemed to be the effector molecule because 4-1BB triggering resulting in accumulation of C3 in the placenta, and this accumulation was also reversed by anti-CD8 mAb treatment. These findings demonstrate that 4-1BB triggering breaks the tolerance of CD8+ T cells to alloantigens in the placenta. Moreover, triggering 4-1BB protected the pregnant mice from Listeria monocytogenes (LM) infection, but led to rejection of semi-allogeneic fetuses. Therefore, given the cross-recognition of alloantigen by pathogen-reactive CD8+ T cells, the true function of 4-1BB may be to reverse the hypo-responsiveness of pathogen-reactive CD8+ T cells in the placenta in cases of infection, even if that risks losing the fetus.

Developmentally regulated GTP-binding protein 2 ameliorates EAE by suppressing the development of TH17 cells.

Developmentally regulated GTP-binding protein 2 (DRG2) represents a novel subclass of GTP-binding proteins. We here report that transgenic overexpression of DRG2 in mice ameliorates experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS). The protective effect of DRG2 in EAE was mediated by the inhibition of the development of T(H)17 cells. DRG2 enhanced the activity of PPARγ, which led to an inhibition of the nuclear factor kappa B (NF-κB) activity and IL-6 production in antigen presenting cells and an inhibition of the development of T(H)17 cells. Our results demonstrate that DRG2 is an essential modulator of EAE.

Simultaneous occurrence of malignant fibrous histiocytoma and hepatocellular carcinoma in cirrhotic liver: A case report

Primary hepatic malignant fibrous histiocytoma (MFH) is rarely encountered. There have been no reports to date of hepatic MFH associated with liver cirrhosis. The presence of liver cirrhosis is considered an adjunctive feature favoring sarcomatoid hepatocellular carcinoma (HCC) in the diagnosis of spindle cell tumors in liver. We describe here a 59-year-old man with liver cirrhosis due to hepatitis B virus infection 20 years ago. On abdominal computed tomography scanning, two distinct hepatic masses were identified in the background of cirrhosis, which had different radiological features from conventional HCC. He underwent segmentectomy for removal of the tumors. The pathological examination of surgically resected specimen revealed the large malignant spindle cell tumor and small conventional HCC. Additional tissue sampling and immunohistochemical stainings demonstrated that the spindle cell tumor was consistent with MFH. On the post-operative follow-up for 21 mo, a round mass showing similar radiological findings for the previous MFH was appeared on the surface of resection margin, suggesting the recurrence. Despite its rarity, hepatic MFH should be considered during differential diagnosis, even in cirrhotic patients, and extensive tissue sampling and immunohistochemical analyses are necessary in the diagnosis of hepatic spindle cell tumors.

Improved Surgical Technique for Heterotopic Aortic Transplantation in Mice

Transplant arteriosclerosis is the main limitation for long-term survival of solid organ transplant recipients. Animal models would provide invaluable tools to investigate the cellular and molecular mechanisms underlying the pathogenesis of transplant arteriosclerosis, as well as for studies with novel drugs and other reagents for the prevention of the disease. We have therefore developed a modified technique for aortic transplantation in mice. The central suture ligation of the recipient abdominal aorta allowed a simpler end-to-side anastomosis of a segment of the donor thoracic aorta into the infrarenal portion of the recipient abdominal aorta. Using this technique, the overall survival rate was 94%. We also observed typical aspects of chronic rejection of the aortic allografts not observed with isografts. Our new technique is relatively easy to perform and has a low incidence of thrombosis, thus being useful for studying various aspects of transplant arteriosclerosis.

MRI features of calcifying aponeurotic fibroma in the upper arm: a case report and review of the literature

Calcifying aponeurotic fibroma is a rare soft tissue tumor that occurs in the distal extremities of children and adolescents. We report a case of pathologically proven calcifying aponeurotic fibroma in the left upper arm of a 23-year-old female. Radiographs revealed increased soft tissue density with multiple stippled calcifications in the mid-portion of the patient’s left upper arm. Magnetic resonance imaging (MRI) showed a well-defined soft tissue mass with low to intermediate signal intensity on T1-weighted images, heterogeneously low signal intensity on T2-weighted images, and heterogeneous enhancement on fat-suppressed, contrast-enhanced T1-weighted images. Histologically, spindle cell proliferation with scattered calcifications and hyalinization was present. Seven years after surgery, there was no evidence of local recurrence. This is the first report of MRI findings of calcifying aponeurotic fibroma in the upper arm. We also summarize the MRI findings of 16 previously reported cases of calcifying aponeurotic fibroma originating in the upper or lower extremities.