CD4+ T cells transfer resistance against Citrobacter rodentium-induced infectious colitis by induction of Th 1 immunity.

Citrobacter rodentium induces an acute, self-limited colitis in mice which is histologically associated with crypt hyperplasia. The infection serves as a model for human infectious colitis induced by enteropathogenic Escherichia coli. We investigated if Balb/c mice, which had spontaneously cleared C. rodentium infection, were protected against re-infection and if resistance against intestinal infection can be systemically transferred using spleen cells. The course of infection was monitored by faecal excretion. Spleen cells, splenic CD3+ and CD4+ cells were transferred from resistant mice to non-infected recipients prior to infection. Cytokine secretion, serum and faecal antibody titres and histological disease severity were assessed. Balb/c mice were resistant against re-infection. The course of infection was shorter in mice receiving primed spleen cells, CD3+ and CD4+ cells. Transfer of CD4+ T cells from resistant mice induced gamma-interferon, interleukin (IL)-2 and IL-17 secretion and suppressed IL-10 secretion. Anti-Citrobacter serum IgG1 and IgG2a enzyme-linked immunosorbent assay OD levels were increased. Faecal IgA secretion was increased while serum IgA was suppressed in recipients of CD4+ cells. Large bowel histology showed protection from colitis in recipients of primed cells as indicated by normal colonic epithelium. In Balb/c mice, C. rodentium infection is followed by resistance, which can be transferred by CD4+ cells. Transfer of protection is associated with IL-17 secretion, enhanced serum IgG and faecal IgA secretion. This is the first study to demonstrate the mechanisms by which systemic resistance from previously C. rodentium-infected mice can be transferred to non-infected animals.

Amelanotic malignant melanoma of the esophagus: case report.

We present the case of a primary malignant esophageal melanoma arising in a 75-year-old male, initially diagnosed as anaplastic squamous cell carcinoma. After resection of the tumor, histological work-up was indicative of a marked morphological heterogeneity, resembling a focally amelanotic primary malignant melanoma. Primary malignant melanomas of the esophagus are exceptionally rare. An exact preoperative diagnosis is critical with respect to the appropriate therapeutic strategy. Clinicopathological features of this entity with a brief review of the literature are presented.

Modulating the intestinal immune system: the role of lymphotoxin and GALT organs.

The gut associated immune system fences off potentially harmful intestinal antigens from the systemic circulation and induces systemic tolerance against luminal antigens. Intestinal immune responses against luminal antigens include IgA secretion and induction of regulatory cells. Unlike few other cytokines, lymphotoxin alpha/beta regulates the development of intestinal lymphoid organs. The embryonic development of Peyer's patches, postnatal lamina propria B cell development, and isolated lymphoid follicle development all depend on lymphotoxin beta receptor interactions. Lymphotoxin alpha/beta signalling also contributes to the development of mesenteric lymph nodes. In addition, intestinal inflammation is suppressed by inhibition of lymphotoxin beta signalling, an observation which has initiated clinical studies using this treatment principal. Intestinal follicular lymphoid organs are sites of antigen presentation. Antigen presenting cells tune the delicate balance between intestinal immune tolerance and inflammation. Therefore, gut associated lymphatic organs and factors regulating their development are critical for the prevention of adverse immune reactions to intestinal antigens. This review provides an overview on the role of lymphotoxin and the gut associated lymphatic organs in the regulation of oral tolerance and intestinal inflammation.

[Fulminant liver failure after administration of the herbal antidepressant Kava-Kava]. / Fulminantes Leberversagen nach Einnahme des pflanzlichen Antidepressivums Kava-Kava.

HISTORY AND CLINICAL FINDINGS: A 60 year-old woman was admitted to hospital because of jaundice, fatigue, weight loss over several months and icteric skin. Because of progressive liver failure, concomitant renal failure and progressive encephalopathy she was transferred to an intensive care unit. INVESTIGATIONS: Biochemical tests revealed acute liver failure with high levels of total and conjugated bilirubin (30 mg/dl) as well as aspartate aminotransferase (921 IU/l) and alanine aminotransferase (1350 IU/l) concentrations. Prothrombin time was less than 10 %. Serological tests could rule out viral hepatitis, metabolic or autoimmune causes of liver failure. On abdominal computed tomography and ultrasonography no pathological changes were detected. Above all portal vein thrombosis, ascites, focal lesions of the liver and extrahepatic cholestasis could be excluded. Liver histology showed extensive hepatocellular necrosis with intrahepatic cholestasis. TREATMENT AND CLINICAL COURSE: The patient's physical condition deteriorated. She had to be intubated because of respiratory insufficiency and encephalopathy stage IV. Because of progressive liver failure under conservative treatment the patient received an orthotopic liver transplant 11 days after admission. CONCLUSIONS: The exclusion of other causes and the histological diagnosis made Kava-Kava as the cause of acute liver failure most likely. This is the 18th case of Kava-Kava induced liver failure reported to the European regulatory authorities.

Induction of oral tolerance to cellular immune responses in the absence of Peyer's patches.

Systemic hyporesponsiveness occurs following oral administration of antigen (oral tolerance) and involves the uptake and processing of antigen by the gut-associated lymphoid tissue (GALT), which includes Peyer's patches (PP) lamina propria lymphocytes and mesenteric lymph nodes (MLN). Animals with targeted mutations of genes in the tumor necrosis factor (TNF) family have differential defects in the development of peripheral lymphoid organs including PP and MLN, and provide a unique opportunity to investigate the role of GALT structures in the induction of oral tolerance. Oral tolerance could not be induced in TNF/lymphotoxin (LT) alpha-/- mice, which are devoid of both PP and MLN, although these animals could be tolerized by intraperitoneal administration of antigen, demonstrating the requirement for GALT for oral tolerance induction. LTbeta-/- mice and LTalpha/LTbeta+/- animals do not have PP but could be orally tolerized, as measured by IFN-gamma production and delayed-type hypersensitivity responses by administration of both low or high doses of ovalbumin. To further investigate the requirement for PP, we tested the progeny of LTbeta-receptor-IgG-fusion-protein (LTbetaRigG)-treated mice, which do not form PP but have an otherwise intact immune system. Although these animals had decreased fecal IgA production, they could be orally tolerized. Our results demonstrate that PP are not an absolute requirement for the induction of either high- or low-dose oral tolerance, although oral tolerance could not be induced in animals devoid of both PP and MLN.

Decreased severity of myelin oligodendrocyte glycoprotein peptide 33 - 35-induced experimental autoimmune encephalomyelitis in mice with a disrupted TCR delta chain gene.

Immunization of C57BL / 6 mice with myelin oligodendrocyte glycoprotein (MOG) peptide (p) 35 - 55 induces chronic experimental autoimmune encephalomyelitis (EAE). The role of gamma delta T cells in the regulation of EAE is unclear. We investigated gamma delta T cells in C57BL / 6 wild-type mice and C57BL / mice with a disrupted TCRdelta chain gene (delta(- / -) mice) using MOG p35 - 55. We found significantly less disease in delta(- / -) mice immunized with MOG / complete Freund's adjuvant (mean maximal EAE score 4.3 +/- 0.8 in wild-type vs. 2.3 +/- 0.5 in delta(- / -) mice). Transfer of wild-type spleen cells restored the ability of delta(- / -) mice to develop equally severe EAE as wild-type mice. In addition to IFN-gamma, IL-2, IL-5 and IL-10 was decreased in delta(- / -) mice. Decreased immune responses were also seen in delta(- / -) animals immunized with OVA peptide or protein and in concanavalin A-stimulated splenocytes from delta(- / -) mice. Enriched dendritic cells from delta(- / -) mice secreted significantly less TNF-alpha in response to lipopolysaccharide stimulation. Furthermore, when EAE was induced by adoptive transfer of an anti-MOG p35 - 55 alpha beta T cell line, there was a striking reduction of disease incidence (0 %) and severity in delta(- / -) as compared to wild-type mice (83 % incidence). delta(- / -) mice showed no cellular infiltration in the spinal cord whereas wild-type animals had infiltration of macrophages, B cells, alpha beta- and gamma delta T cells. In adoptive transfer EAE, there was reduced IL-2 and IFN-gamma secretion in delta(- / -) mice. These results demonstrate an impaired immune response in the delta(- / -) mouse that is associated with a defect in developing both actively induced and adoptively transferred EAE.

Zenker's diverticulum: analysis of surgical complications from diverticulectomy and cricopharyngeal myotomy.

OBJECTIVE: To identify risk factors for postoperative complications in patients undergoing diverticulectomy and cricopharyngeal (CP) myotomy for Zenker's diverticulum. STUDY DESIGN: Retrospective. MATERIALS AND METHODS: A chart review was conducted of all patients with a Zenker's diverticulum who were treated with diverticulectomy and cricopharyngeal myotomy at three tertiary care centers in central Indiana between 1988 and 1998. RESULTS: Of the 24 patients identified, 9 developed postoperative complications (2 medical and 7 surgical). Statistical analysis of multiple potential risk factors revealed that only diverticulum size greater than 10 cm2 at surgery placed the patient at increased risk for postoperative surgical complications. To our knowledge, this is the first report that has specifically addressed diverticulum size as an independent risk factor for postoperative surgical complications following diverticulectomy and CP myotomy. CONCLUSIONS: Given our findings, we recommend considering diverticulopexy rather than diverticulectomy in a patient with a Zenker's diverticulum greater than 10 cm2 in size if a cervical approach is the selected treatment.

Cellular and humoral immunity to the 60-kD heat shock protein in inflammatory bowel disease.

BACKGROUND: Mycobacteria have been considered a possible etiological agent in Crohn's disease. Since cross-reactivity between epitopes of mycobacterial and self-heat shock protein might represent a potential disease mechanism, we determined the cellular and humoral immune responses to the mycobacterial and the human 60-kD heat shock protein, as well as various control antigens. METHODS: We studied samples from 19 patients with Crohn's disease, 12 patients with ulcerative colitis, and from 19 healthy individuals. T cell responses were studied using a standard proliferation assays to purified recombinant mycobacterial and human 60-kD heat shock protein. Antibody levels were measured by establishing an enzyme-linked immunosorbent assays to recombinant purified 60-kD heat shock protein. RESULTS: The proliferative responses to the mycobacterial and the human 60-kD heat shock protein were closely correlated, but the cellular immune response to both antigens was not significantly different between the two patient groups and healthy controls. In addition, antibody levels to heat shock protein were also not significantly different between the three groups. CONCLUSIONS: These results argue strongly against a role for mycobacterial heat shock protein in the pathogenesis of Crohn's disease. However, in view of previous data demonstrating overexpression of 60-kD heat shock protein in inflammatory Crohn's disease tissue, this considerable cellular and humoral autoreactivity suggests an important immunoregulatory role for the 60-kD heat shock protein.

Nodular nonsuppurative panniculitis in association with primary biliary cirrhosis and Hashimoto's thyroiditis.

Recurrent episodes of livid, painful, subcutaneous nodules on both lower extremities with consecutive soft tissue atrophy developed in a 57-year-old woman with previously undiagnosed primary biliary cirrhosis (PBC) and Hashimoto's thyroiditis. Histological examination of a biopsy taken from an active area of the skin showed nodular nonsuppurative panniculitis. Immunosuppressive therapy with prednisone was necessary to control disease activity. The etiology and pathogenesis of nodular nonsuppurative panniculitis is still unknown. Frequently, the disease occurs in patients with autoimmune disorders. The association with PBC and Hashimoto's disease as described herein reinforces the view that nodular nonsuppurative panniculitis may be the response of the subcutaneous adipose tissue to an unknown autoimmune stimulus.

Remission of severe alcoholic polyneuropathy after liver transplantation.

Alcoholic polyneuropathy presents with variable severity. Only few very severely disabled patients showed good clinical and electrophysiological improvement after cessation of alcohol abuse. We report a 55 year old patient with polyneuropathy who underwent orthotopic liver transplantation for decompensated alcoholic cirrhosis. After an initial postoperative exacerbation of her neurological disorder the patient developed an impressive remission of her clinical condition during the 4 year post transplantation follow up period. Nine months after surgery the initially wheel chair bound patient regained the ability to walk on her own. The previously severely impaired sensory modalities returned to nearly normal function. Electrophysiological findings also improved. The right tibial nerve conduction velocity increased from 16.8 to 26.7 m/s between the 27th and 37th post transplantation month. We postulate that liver transplantation facilitated the remission of this patient's alcohol-induced polyneuropathy. This observation suggests that alcoholic polyneuropathy, even when severe, should not be considered a contraindication for liver transplantation.

Lack of requirement for CD8+ cells in recovery from and resistance to experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is a model of T-cell mediated autoimmune disease. Active disease is mediated by myelin basic protein specific CD4+ T-cells, whose adoptive transfer can also induce passive disease. In the Lewis rat EAE is a transient disease inducing lasting resistance to rechallenge. The mechanisms of recovery and resistance are poorly understood. CD8+ suppressor T-cells have mostly been thought to be central, especially in resistance to reinduction of the disease. In this study we showed by complete depletion of CD8+ cells that this subset does not influence either recovery or resistance to EAE in the Lewis rat. This was further confirmed by depleting CD8+ cells only after recovery from acute EAE. Such depletion did not diminish the effective resistance to rechallenge. Recovery from and resistance to EAE appear not to require the presence of CD8+ cells.

Induction of the anti-ergotypic response.

The injection of syngeneic activated T cells into rodents can induce a T cell response against activation markers of the T cells, ergotopes. The responding anti-ergotypic T cells have been shown to suppress experimental autoimmune encephalomyelitis (EAE). This paper reports the characteristics of the anti-ergotypic response. It was found that irradiated activated T cells were as good as untreated living activated T cells in inducing anti-ergotypic cells in vivo. Glutardialdehyde-fixed (0.3%) cells were poor stimulators in vivo and non-stimulatory in vitro. Dilution of glutardialdehyde to 0.003% before fixation preserved the stimulatory capacity in vitro. Fixation or irradiation of T cells at different times after activation showed that the stimulatory ergotope appears only after more than 12 h of activation. This ergotope is not secreted by activated T cells, but is a structural component of the activated T cell. Injection of solubilized proteins from activated T cells, but not of supernatants from activated T cells, was able to induce an anti-ergotypic response in vivo. In vitro supernatants from activated T cells also were not stimulatory to anti-ergotypic T cells. The anti-ergotypic response could be measured in draining lymph nodes 3 days after injection, reached a maximum after 7-10 days and subsided thereafter. It was earlier and stronger than the anti-idiotypic response. Induction of the response was dose dependent. As few as 100 cells were able to induce a marked anti-ergotypic response. The ease of the induction and the strength of the anti-ergotypic response suggest a physiological role in immunoregulation.