Induction of autoimmune colitis by Yersinia enterocolitica 60-kilodalton heat-shock protein.

BACKGROUND: Many investigations of the relationship between ulcerative colitis (UC) and heat-shock protein (Hsp) 60 have been reported. We have already established an animal model exhibiting UC-like lesions caused by administration of Escherichia coli expressing Yersinia enterocolitica Hsp60. In this study, we therefore attempted to induce mouse colitis by purified Y. enterocolitica Hsp60. METHODS: Purified Y. enterocolitica Hsp60 was injected intraperitoneally into B10A/SgSn mice at a dose of 3 microg/0.2 ml once a week for 2 months, and morphological changes in the intestine were examined by light and electron microscopical analysis. Autoimmune responses were also examined. RESULTS: The mice treated with Y. enterocolitica Hsp60 exhibited immune reaction between large intestine and autologous serum. Light and electron microscopically, degradation of glandular ducts, erosions, ulceration, crypt abscess-like formation, infiltration of inflammatory cells and absence of perivascular reticular fibers in lamina propria mucosae and subepithelial reticular layer were observed. CONCLUSIONS: These findings indicate that administration of Y. enterocolitica Hsp60 induces UC-like lesions with autoimmune responses.

Mouse colitis induced by Escherichia coli producing Yersinia enterocolitica 60-kilodalton heat-shock protein: light and electron microscope study.

In patients with inflammatory bowel disease (IBD), including ulcerative colitis (UC), heat-shock protein (Hsp) 60 has been detected in serum and the intestinal tract. Our mouse colitis model was established using Escherichia coli transformed with Yersinia enterocolitica Hsp60 gene as an immunizing antigen, and examined light and electron microscopically as compared with lesions of UC. The large intestine of mice injected with Hsp60 antigen showed swollen goblet cells, glandular dilation, erosion, ulceration, and infiltration of inflammatory cells. The change like crypt abscesses was also found, and various phases of inflammation were observed simultaneously in individual mice. In addition, the reticulum fibers were absent ultrastructurally in the subepithelial reticular layer. Hyperplasia of the thymus was found in antigen-treated mice. These lesions were similar to those of UC. These results suggest that UC-like enteritis in mice was induced by using Hsp60, considered as one of the pathogens for UC.

[Recovery process from myocardial stunning after transient ischemia: assessment with pulsed wave Doppler transmitral flow pattern].

Sustained left ventricular systolic dysfunction after transient myocardial ischemia is well known as "myocardial stunning", but little is known about the recovery in left ventricular diastolic function. Changes in left ventricular systolic and diastolic performance following dobutamine-induced ischemia were investigated in 13 patients with chest pain syndrome and normal coronary arteries (control) and 34 patients with coronary artery disease. Two-dimensional echocardiography and pulsed wave Doppler transmitral flow velocity curves were recorded at baseline, after infusion of a peak dose of dobutamine and at 20 min and 2 hours after dobutamine infusion. In control subjects, left ventricular ejection fraction and the peak early diastolic filling velocity increased at the peak dose of dobutamine. At 20 min after the cessation of dobutamine infusion, these values were restored to the baseline levels. In patients with coronary artery disease, ejection fraction and peak velocity increased at the peak dose of dobutamine but decreased at 20 min after infusion compared with baseline values despite the restoration of heart rate and blood pressure. Although ejection fraction increased at 2 hours compared with 20 min after infusion, peak velocity did not increase. Left ventricular diastolic dysfunction may be sustained longer than systolic dysfunction after transient myocardial ischemia.

Tumor necrosis factor production and colon cancer.

Tumor necrosis factor (TNF) production in B10 mice exhibiting H-2 gene heterogeneity and in C3H/He mice differing in lipopolysaccharide (LPS) responsiveness was investigated following stimulation with OK-432. TNF-producing capacity in these mice was H-2-restricted, while their LPS responsiveness was independent of the gene. TNF production in humans was found to be HLA-B antigen-restricted. An investigation was then made of the effect of endogenous TNF induction with OK-432 on the survival rate of colorectal cancer patients. Patients in the TNF-producing group showed a trend toward having a better prognosis as compared to those in the TNF-nonproducing group. Cancer therapy formulated with consideration of host responsiveness to OK-432 may afford greater therapeutic benefit and may prolong survival.

Nodular cutaneous lupus mucinosis: report of a case and review of previously reported cases.

A wide variety of cutaneous manifestations of lupus erythematosus have been reported. Among them, papulonodular eruptions produced by dermal mucin deposition have been recognized as nodular cutaneous lupus mucinosis (NCLM), and many cases have been reported in Japan. A 21-year-old woman with systemic lupus erythematosus (SLE) showed papulonodular eruptions on her back. A skin specimen from the nodule revealed mucin deposition (hyaluronic acid) in the dermis. NCLM should be recognized as a clinical form associated with SLE. The pathogenesis of the mucin deposition in NCLM is still uncertain.

[Development of quality of life questionnaire for patients with colorectal cancer in surgical area--a study of reliability and validity of Tokyo Yamabuki Forum Version].

We developed a new questionnaire in the surgical area based on a core quality of life (QOL) questionnaire for patients with gastrointestinal cancer. In this study, we investigated the validity and reliability of a QOL questionnaire (Tokyo Yamabuki Forum Version) for patients with colorectal cancer. The questionnaire was composed of 17 items including 5 scales (basic sensory scale, psychological scale, physiological scale, defection-related scale and active scale) and a face scale as an global scale. The time needed to answer questionnaires was expected to be around 7 minutes and the questionnaires should basically be answered by the patients themselves everyday in the hospital. The study was performed in 10 hospitals in the Tokyo area, and 394 samples collected from 21 patients with rectal and colonic cancers were analyzed. A number of respondents failed to answer the question "Do you feel your foods tasty?", so we judged this item inappropriate and deleted it from the analysis. Fifteen items, including 5 scales showed satisfactory internal consistency and construct validity in correlation and factor analyses. Performance status showed a low correlation between each item, each scale and the global scale, while SDS and STAI showed an inordinately negative correlation with the fundamental and physical scales. Especially, SDS revealed an extremely close correlation with the active scale, and STAI showed an excessive correlation with the psychological scale. In the time course of QOL under chemotherapy, reductions (aggravations) were observed in both the total score of 15 items and global scale within one week postoperatively, but after that recovered to preoperative levels at 2 weeks postoperatively. A tendency to QOL improvement was observed 2 weeks after starting chemotherapy or chemoimmunotherapy. QOL of 13 patients was measured over 3 months, and the longest term was 8 months. The results suggested that this QOL questionnaire has sufficient reliability and validity to be usable for patients with colorectal cancer in the surgical area and that this model is applicable for long-term QOL surveys and frequent measurement.

Evaluation of antitumor activities of hyaluronate binding antitumor drugs: synthesis, characterization and antitumor activity.

To enhance the selective delivery of antitumor drugs into regional lymph nodes and cancerous tissues via a hyaluronate (HA) receptor (CD44), we synthesized HA-mitomycin C complex and HA-epirubicin complex. To investigate the specific distribution of HA into regional lymph nodes and to evaluate the HA receptor on lewis lung carcinoma cells, we also synthesized 14C-labelled HA and fluorescent HA (FR-HA). The metabolic studies of 14C-HA and HA-epirubicin complex were performed in rats. The specific distribution of both compounds to the lymph nodes were observed after sc treatment. Internalization mechanisms of HA into carcinoma cells (lewis lung carcinoma) via HA receptor was investigated using fluorescent HA (FR-HA) in vitro. Internalization of FR-HA following binding to the cell surfaces was observed. HA-Mitomycin C (MMC) exhibited potent anti-metastatic effects against lewis lung carcinoma implanted in mice at an extremely low dose (0.01 mg/kg) whereas free MMC had no effects.

Erythema nodosum, lichen planus and lichen nitidus in Crohn's disease: report of a case and analysis of T cell receptor V gene expression in the cutaneous and intestinal lesions.

A wide variety of cutaneous manifestations have been described in association with Crohn's disease (CD). We describe a patient with a 2-year history of CD who developed both lichen planus (LP) and lichen nitidus (LN) in addition to erythema nodosum (EN) lesions. The clinical course of EN reflected the activity of the bowel disease, whereas LP and LN appeared to persist independently of the ongoing disease activity. Immunohistochemical studies of the infiltrates in these cutaneous and intestinal lesions showed that the majority of the infiltrates were T cells expressing T cell receptor (TCR)-alpha beta. Analyses of TCR V gene expression in these infiltrating T cells demonstrated a different pattern of V beta expression that provides an explanation for the difference in the clinical courses of these lesions. LP and LN lesions are likely to be mediated by T cells with antigen specificity distinct from those that cause EN and intestinal lesions.

Analysis of genes within the HLA region affecting susceptibility to ulcerative colitis.

To clarify the molecular relationship between HLA loci and ulcerative colitis (UC) in Japanese patients, we performed HLA-DP genotyping by the PCR-RFLP method and studied tumor necrosis factor beta-chain genetic polymorphism by Southern hybridization, in addition to conventional serologic typing. Significant increase was observed in Bw52, DPw9 (DPB1*0901), and DR2 (DRB1*1502) in Japanese patients with UC. Linkage analysis indicated that A24-Bw52-DR2-DPw9 alleles constitute a common haplotype in Japanese UC patients. Among the patients not carrying Bw52, B13 was significantly increased and B44 was relatively increased. These Bw52, B13, and B44 alleles share the unique amino acids, serine and aspartic acid at positions 67 and 77, respectively. These positions are in the second hypervariable region of the alpha 1-domain of the HLA-B13, B44, Bw52, and B49 antigens (B49 is quite rare in the Japanese population). The inflammatory region in UC patients was found to vary depending on their HLA-B alleles. These results suggest that the HLA-B locus itself plays an important role in the susceptibility to Japanese UC.

Linear IgA bullous dermatosis associated with rheumatoid arthritis.

A case of linear IgA bullous dermatosis associated with rheumatoid arthritis is described. The eruption consisted of multiple irregular erythematous plaques and small numbers of tense vesicles mainly on the trunk. An immunofluorescence study showed linear IgA and IgG deposition along the basement membrane zone, whereas C3 deposition was not found. IgA or IgG anti-basement membrane zone antibody was not detected in the serum. Treatment with dapsone resulted in good control of the eruption. Coexistence of linear IgA bullous dermatosis and rheumatoid arthritis has not been reported previously.

HLA-DR, DQ and T cell antigen receptor constant beta genes in Japanese patients with ulcerative colitis.

We studied the T cell antigen receptor (TcR) constant beta chain genes on HLA typed Japanese patients with ulcerative colitis (UC). A TcR constant beta EcoRI 6.0-kb fragment was present in all Japanese UC patients (n = 17) but completely absent in the controls (n = 35) (chi2 = 47.6, P less than 0.001). The frequency of HLA-DR2 antigen was significantly higher in UC patients (85% versus 28% in controls, P less than 0.001). Furthermore, HLA-DQw1 antigen was also increased in UC patients (96% versus 60% in controls, P less than 0.001). However, HLA-DR4 antigen was significantly decreased in UC patients (12% versus 37%, P = 0.02). HLA-DR1 antigen was not found in UC patients and was present in only 15% of the controls. These results suggest that TcR beta chain and HLA-DQw1 antigen may be important in the pathogenesis of Japanese UC.

Crohn's disease in the Japanese is associated with the HLA-DRw53.

The association of Crohn's disease (CD) with the HLA system was investigated in Japanese patients by serological and genomic methods. HLA antigens were typed in 30 unrelated Japanese patients with CD and 54 healthy controls. The frequencies of HLA-DR4, DRw53 and DQw3 antigens were increased in CD (76.7, 86.7 and 80.0%) compared with controls [37.0%, p corrected (pc) = 0.007; 52.9%, pc = 0.001; 52.0%, pc = 0.009]. DQw7 and DQw8 antigens, the new split antigens of DQw3 produced by the TA10 antibody and linked to the DR4 and DRw53 antigens, were not significantly different in the DQw3-positive CD and controls. Class I antigens were not significantly different in the CD and controls. HLA-DR-B and DQ-B probes were used to study PstI-generated restriction fragment length polymorphism (RFLP) in CD and controls. The DRw53-specific PstI DR-B 2.6-kb fragment was increased in CD (88.0%) compared with controls (37.5%, pc = 5.6 X 10(-4)). The PstI DR-B 3.2-kb fragment was also increased in CD (80.0%) compared with controls (35.0%, pc = 5.6 X 10(-3)). It is reasonable to infer that the DRw53 is the most important susceptibility antigen in Japanese CD. The subtypes of the DR4 were determined by the hybridization of the DQ-B probe. The DQ-B PstI fragment patterns were not different in CD and controls.

[A case report of patient with advanced stomach carcinoma of linitis plastica type responding to multi-immunotherapy and chemotherapy].

Multiple-drug (OK-432, PSK and SPG) immunotherapy and chemotherapy provided remission of symptoms for 36 months in a patient aged 21 years suffering scirrhous gastric carcinoma associated with carcinomatous peritonitis in which direct infiltration to the pancreas, retroperitoneum and the left colon was observed. A remarkable improvement with time was observed by endoscopic and roentgenographic observation, and a substantial improvement was also observed in the NK-cell ratios of lymphocyte subsets of the OKT series in relation to immunologic parameters. A tumor necrosis factor [TNF]-like substance was thought to have been induced by multiimmunotherapy in this case.

[A long-term survivor of primary hepatoma--a case suggesting the superiority of a multi-drug (OK-432, SPG, PSK) over mono-drug immunotherapy].

The studied patient (70 years old, male) had primary hepatoma with rupture of the liver. We resected his left lobe partially and were able to save him. Since a residual tumor was found after surgery, we injected a total of 30 mg of MMC into the SCA 3 times. Under continuous administration of OK-432, the patient survived for 3 years and 6 months in remission. Because the tumor grew gradually, we started a multi-drug immunotherapy (OK-432 5 KE/2 W/intradermal, PSK/3.0 g/day/P.O., SPG/20 mg/2 W/I. M.) which we have advocated. In 6 months the tumor regressed to 1/3 of its original size. The patient is currently in good condition 4 years and 7 months after the operation. This case demonstrated the superiority of multi-drug immunotherapy over single-drug immunotherapy.