Katsuhiko Hasegawa

A Similar Expression Pattern of Adhesion Molecules between Intermediate TCR Cells in the Liver and Intraepithelial Lymphocytes in the Intestine

Two major populations of extrathymically differentiated T cells exist in the liver and intestine. Such T cells in the liver have TCR of intermediate intensity (i.e., intermediate TCR cells) and constitutively express IL‐2 receptor β‐chain (IL‐2Rβ), whereas those in the intestine, especially intraepithelial lymphocytes, have TCR of bright intensity, consisting of a mixture of IL‐2Rβ+ and IL‐2Rβ–. All mature thymocytes and thymus‐derived T cells seen in the peripheral immune organs are TCR‐bright+IL‐2Rβ– under resting conditions. When the expression pattern of adhesion molecules, including CD44, L‐selectin, LFA‐1 and ICAM‐1, was compared among these T‐cell populations, they displayed quite unique patterns of expression. All extrathymic T cells in the liver, intestine, and even other organs were CD44+L‐selectin– LFA‐1++ICAM‐1+, whereas thymocytes and thymus‐derived T cells were CD44– L‐selectin+LFA‐1+ICAM‐1–. This inverted expression of adhesion molecules between extrathymic T cells and thymus‐derived T cells might be associated with their unique tissue‐localization.

Intraepithelial lymphocytes in colon have similar properties to intraepithelial lymphocytes in small intestine and hepatic intermediate TCR cells.

Recently, properties of intraepithelial lymphocytes (IEL) in the colon (C-IEL) have been analyzed in comparison with those of IEL in the small intestine (SI-IEL). We compared the properties of C-IEL with those of SI-IEL and hepatic intermediate TCR cells, two other types of extrathymic T cells. C-IEL and intermediate TCR cells contain many NK1+T cells, although SI-IEL contain few. Vγ and Vδ usage of C-IEL was the same as that of SI-IEL, and that of intermediate TCR cells was different. C-IEL responded to Con A while SI-IEL did not. As to adhesion molecules, C-IEL include both extrathymic and thymus-originated type T cells. With age, TCR-αβ+CD4+CD8+ cells do not increase among C-IEL but do increase among SI-IEL. IL-2Rβ+ or CD4−CD8− C-IEL increase as observed in the liver. These results indicate that these organ-specific T cells have different roles at their respective sites and that they may be of different lineages.

Synchronous development of HCC and CCC in the same subsegment of the liver in a patient with type C liver cirrhosis

As a result of having undergone computed tomography (CT), a 75-year-old woman with type-C liver cirrhosiswas shown to have two tumors on the ventral and dorsal sides of subsegment 3 (S3). The tumor on the ventral side was diagnosed as a classic hepatocellular carcinoma (HCC), while that on the dorsal side was considered atypical for a HCC. Although the indocyanine green (ICG) findings indicated poor hepatic reserve, the prothrombin time (PT) was relatively good. An operation was performed in February 2007; however, this resulted in exploratory laparotomy. Dynamic CT performed 12 mo after the operation revealed that the tumor on the dorsal side of S3 had apparently increased. The marginal portion of the tumor was shown to be in the early and parenchymal phases, while the internal portion was found to have grown only slightly in the delayed phase. We diagnosed this tumor as a cholangiocellular carcinoma (CCC). S3 subsegmentectomy was performed in April 2008. The tumor on the ventral side was pathologically diagnosed as a moderately differentiated HCC, and that on the dorsal side was diagnosed as a CCC. We can therefore report a rare case of synchronous development of HCC and CCC in the same subsegment of the liver in a patient with type-C liver cirrhosis. We also add a literature review for all the reported cases published in Japan and around the world, and summarize the features of double cancer exhibiting both HCC and CCC.

Correlation between serum phospholipase A2 IIA levels and histological activity in patients with ulcerative colitis

HeadingAbstract Background and aims. Phospholipase A2 (PLA2) participates in the regulation of phospholipid metabolism and biosynthesis of eicosanoids, serum levels of PLA2 are suggested to reflect the disease activity in patients with ulcerative colitis (UC). We examined the relationship between histological disease activity and serum levels of PLA2 IIA and also clarified mucosal production sites of PLA2 IIA by immunohistochemistry. Patients and methods. Serum samples from 44 patients with UC, 125 with Crohns diseases (CD), and 68 controls were studied. Biopsy specimens of colonic mucosa obtained from 23 patients with UC were used for assessment of histological activity. The histological score was determined active (1) or inactive (0), and the sum of each histological score from ten segments of the large intestine was assessed as disease activity. The levels of PLA2 IIA in sera were measured by a radioimmunoassay kit using a specific monoclonal antibody; immunohistochemical study was performed using the same monoclonal antibody. Results. The serum PLA2 IIA levels in patients with UC and CD were significantly higher than those of controls. Serum PLA2 IIA levels in UC were closely correlated with histological disease activity. Immunohistochemical study showed the production of PLA2 IIA by the polymorphonuclear cells, macrophages, and colonic epithelial cells. Conclusion. Serum PLA2 IIA is a good candidate for assessing disease activity in UC as one of clinical laboratory tests.

Gut-associated lymphoid tissues in ulcerative colitis.

BACKGROUND The main feature of ulcerative colitis (UC) is numerous infiltration of not only lymphocytes and plasma cells but also neutrophils and macrophages, indicating acute on chronic inflammation. Recent studies show that apoptosis may play an important role in the regulation of gut-associated lymphoid tissues (GALT). Therefore, this study was performed to clarify apoptosis of lymphocytes in the peripheral blood and colonic mucosa of UC. METHODS Three-color flow cytometry was used to clarify apoptosis of lymphocytes in the peripheral blood and colonic mucosa of patients with active and inactive UC compared with controls using fluorescence-labeled monoclonal and polyclonal antibodies such as Fas (CD95), Fas ligand, CD4, CD8, CD45RO, etc. RESULTS The ratio of Fas and CD45RO double-positive cells in the peripheral blood of UC patients was significantly increased in CD8 but not CD4 T cells when compared with controls. The ratio of Fas-positive and CD45RO-negative cells was significantly increased in CD4 and CD8 T cells of UC when compared with controls. There was unbalanced immunoregulation between CD4 and CD8 T cells in the colonic mucosa of UC probably due to apoptosis through Fas-Fas ligand system. CONCLUSIONS Abnormal GALT system was found in UC probably due to dysregulation of T cells through Fas-Fas ligand system.

Natural regression of fibrosis in chronic hepatitis B

The fibrosis of liver cirrhosis was considered to be irreversible before the anti-viral drugs showed that it is reversible when they lead to continuous suppression of viral replication and inflammation. However, several reports previously showed that fibrosis of type B liver cirrhosis was almost completely absorbed after the natural remission of chronic inflammation. This phenomenon might not be limited to exceptional patients, but rather occur commonly, considering the dynamic clinical features of chronic hepatitis B (CHB), where inactive carrier stage normally follows aggravation of hepatitis and progression of fibrosis at the time of HBeAg seroconversion. Thus, fibrosis levels of CHB as a hepatocellular carcinoma (HCC)-surveillance marker, particularly those of the inactive stage, could be underestimated, because some of them might have been (pre)cirrhotic in the past and recovered with the natural regression of fibrosis. We argue that cirrhosis-induced HCC mechanisms, rather than direct action of viral genome, may be more common than generally considered in CHB patients. This may have some impact on reconsidering the surveillance rationale for HCC in CHB, from where advanced HCCs tended to be missed. In addition, a molecular marker to assess the cancer-prone characteristics of the liver will definitely be needed to resolve the issue.

Regenerative medicine using dental pulp stem cells for liver diseases

Acute liver failure is a refractory disease and its prognosis, if not treated using liver transplantation, is extremely poor. It is a good candidate for regenerative medicine, where stem cell-based therapies play a central role. Mesenchymal stem cells (MSCs) are known to differentiate into multiple cell lineages including hepatocytes. Autologous cell transplant without any foreign gene induction is feasible using MSCs, thereby avoiding possible risks of tumorigenesis and immune rejection. Dental pulp also contains an MSC population that differentiates into hepatocytes. A point worthy of special mention is that dental pulp can be obtained from deciduous teeth during childhood and can be subsequently harvested when necessary after deposition in a tooth bank. MSCs have not only a regenerative capacity but also act in an anti-inflammatory manner via paracrine mechanisms. Promising efficacies and difficulties with the use of MSC derived from teeth are summarized in this review.

Increase in the proportion of CD56+T cells in patients with chronic type C hepatitis after treatment with α-interferon

Abstract Recently CD56 + T cells, which are unique T cells that have one of the NK markers and are few in peripheral blood mononuclear cells (PB MNC), have been found to be predominant in the liver. We investigated the phenotypical changes of PB MNC in 18 patients with chronic type C hepatitis before and during α-interferon (IFN-α) treatment. In the treatment response group ( n = 11 ), CD56 + T cells increased significantly ( P ). Conversely, no increase of CD56 + T cells was observed in the non-response group ( n = 7 ). Phenotypically studied, CD56 + T cells were mostly CD8 + , about half comprised γδ-TCR and all expressed high levels of LFA-1. These results suggest that CD56 + T cells might play an important role in the pathogenesis of chronic type C hepatitis.

A Case of Right-Sided Ulcerative Colitis with Mesalamine-Induced Hypersensitivity Reactions

Patient: Female, 56 Final Diagnosis: Right-sided ulcerative colitis • mesalamine-induced hypersensitivity Symptoms: High fever • vague discomfort of the upper abdomen Medication: Mesalamine Clinical Procedure: — Specialty: Gastroenterology and Hepatology Objective: Unusual clinical course Background: Ulcerative colitis (UC) is a chronic inflammatory bowel disease, affecting the colon continuously from the rectum proximally. However, a clinical type with right-sided colitis sparing the anal side of the colon is also known. Mesalamine, which is generally used to treat UC, can rarely aggravate the disease. Case Report: A 56-year-old woman with no history of colonic diseases visited our hospital because of a positive fecal occult blood test. The first colonoscopy showed inflamed and edematous mucosa extending from the ascending colon to the right-half of the transverse colon. Colonic biopsy specimens demonstrated infiltrations of chronic inflammatory cells in the mucosa and crypt abscesses, but no epithelioid granulomas, compatible with UC. She was highly positive for PR3-ANCA, confirming the diagnosis of UC. After starting mesalamine, she had hypersensitivity reactions and aggravations of UC, which were confirmed endoscopically. Conclusions: Right-sided colitis may be a subgroup of UC, and this is the first report of this type of disease complicated by aggravation due to mesalamine hypersensitivity.

7070 Endoscopic follow-up study of ulcerative colitis with skipped appendiceal involvement.

Background and aims : Recently it has been reported that appendiceal involvement can occur as a skip lesion in ulcerative colitis (UC), although the clinical significance of this finding is still debatable. In such cases, we evaluated the changes in disease extent endoscopically and histologically, and also assessed the presence of appendiceal orifice (AO) inflammation. Materials and methods : From January 1993 to August 1999, a total of 17 patients with skipped AO involvement were entered into this study with their informed consent. All of them received medical therapy, and colonoscopy was performed twice or more at intervals of more than 3 months. Results : The patients with endoscopically skipped AO involvement were divided into two groups with respect to disease extent; 6 (3M, 3F; median age at disease onset 36 yr; range 20-65 yr) showed fixed areas that were spared endoscopically and histologically (S-type), and 11 (8M, 3F; 23 yr; range 13-46 yr) showed endoscopically active lesions in some areas at some time, histological examination revealing continuous pancolitis (C- type). The median follow-up periods were 23.7 (range 12-39) months for the Stype and 29 (3-47) months for the C-type. The median times of colonoscopic examinations were 4 (2-6) and 4 (2-8) months,respectively. The transverse colon was affected significantly less frequently in the S-type than in the C-type (p=0.03). There was a close correlation (p=0.005) between the activity of AO and that of the main lesion in the S-type, but not in the Ctype. Conclusion :Cases of UC with endoscopically skipped AO lesions were divided into two types; those showing histological skipping and those showing histological continuity. In the S-type, AO inflammation was correlated with the activity of the main lesions, and active lesions were rarely found in the transeverse colon. In the C-type, although histological continuity was evident, relapse as pancolitis seldom or never occurred.