Emerging Role of HMGB1 in the Pathogenesis of Schistosomiasis Liver Fibrosis.

In chronic schistosomiasis, liver fibrosis is linked to portal hypertension, which is a condition associated with high mortality and morbidity. High mobility group box 1 (HMGB1) was originally described as a nuclear protein that functions as a structural co-factor in transcriptional regulation. However, HMGB1 can also be secreted into the extracellular milieu under appropriate signal stimulation. Extracellular HMGB1 acts as a multifunctional cytokine that contributes to infection, injury, inflammation, and immune responses by binding to specific cell-surface receptors. HMGB1 is involved in fibrotic diseases. From a clinical perspective, HMGB1 inhibition may represent a promising therapeutic approach for treating tissue fibrosis. In this study, we demonstrate elevated levels of HMGB1 in the sera in experimental mice or in patients with schistosomiasis. Using immunohistochemistry, we demonstrated that HMGB1 trafficking in the hepatocytes of mice suffering from acute schistosomiasis was inhibited by Glycyrrhizin, a well-known HMGB1 direct inhibitor, as well as by DIC, a novel and potential anti-HMGB1 compound. HMGB1 inhibition led to significant downregulation of IL-6, IL4, IL-5, IL-13, IL-17A, which are involved in the exacerbation of the immune response and liver fibrogenesis. Importantly, infected mice that were treated with DIC or GZR to inhibit HMGB1 pro-inflammatory activity showed a significant increase in survival and a reduction of over 50% in the area of liver fibrosis. Taken together, our findings indicate that HMGB1 is a key mediator of schistosomotic granuloma formation and liver fibrosis and may represent an outstanding target for the treatment of schistosomiasis.

Catheter-related complications in 52 patients treated with continuous infusion of low dose recombinant interleukin-2 via an implanted central venous catheter.

In this study we evaluated the catheter-related complications in 52 patients with advanced melanoma, renal cell cancer or non-Hodgkin's lymphoma treated with continuous infusion of low-dose recombinant interleukin-2 by central venous access (CVA) of the port-a-cath type. We noted a high incidence (55.5%) of catheter infection, defined as positive blood cultures drawn from the CVA in symptomatic or asymptomatic patients. Six infections were noted before rIL-2 treatment was started. Twelve of the 30 documented infections were symptomatic (fever and/or chills), with only four documented bacteraemias. The most frequently cultured microorganism was Staphylococcus epidermidis (73%). Treatment initially consisted of systemic antibiotics via the CVA, but as experience increased, the mostly asymptomatic CVA infections were not treated. In 30% of the documented CVA infections a thrombus at the tip of the catheter was found by radiological contrast examination. Local thrombosis can be effectively treated with constant infusion of low dose streptokinase via the CVA.

Phase II study of intermittent continuous infusion of low-dose recombinant interleukin-2 in advanced melanoma and renal cell cancer.

BACKGROUND: Previously we described the immunological and clinical effects of prolonged continuous infusion of low dose rIL-2. In this phase II study we explored the therapeutic efficacy of intermittent continuous infusion of low dose rIL-2. PATIENTS AND METHODS: We selected 15 patients with advanced melanoma and 8 patients with renal cell cancer in good clinical condition, with low tumour burden and no previous systemic treatment. A treatment cycle consisted of infusion of 1.8 x 10(6) IU/m2/24 hrs rIL-2 for 3 weeks on an out-patient basis followed by a 3-week rest. A maximum of four cycles were given. RESULTS: A total of 35 cycles were given. Treatment was well tolerated. Transient hyperthyroidism occurred in 8 patients. No objective responses were noted. We noted a high incidence of central nervous system involvement occurring shortly after treatment. CONCLUSIONS: Intermittent continuous infusion of low dose rIL-2 in advanced melanoma and renal cell cancer is well tolerated but the initial therapeutic results are not promising.

A phase I study of prolonged continuous infusion of low dose recombinant interleukin-2 in melanoma and renal cell cancer. Part I: Clinical aspects.

The optimal schedule for recombinant interleukin-2 (rIL-2) administration is unclear. Because the clinical and immunological effects of prolonged continuous exposure to rIL-2 are unknown, we have conducted a phase I study to assess the toxicity and feasibility of continuous low dose infusion of rIL-2 (EuroCetus) using central venous access with a portable infusion device on an out-patient basis. Twenty-two patients entered the study, 13 with melanoma and nine with renal cell cancer, age range 26-66 years (median 51), performance status less than or equal to 1. They were treated with one of the following doses per m2 per 24 h: 0.18 x 10(6) IU, 0.6 x 10(6) IU, 1.8 x 10(6) IU, 3 x 10(6) IU, 6 x 10(6) IU and 9 x 10(6) IU. Toxicity was evaluable in 20 patients receiving greater than or equal to 3 weeks treatment duration or in whom treatment was discontinued prematurely because of toxicity. Constitutional symptoms consisting of fatigue, malaise and fever up to 40 degrees C without significant organ dysfunction occurred with doses greater than or equal to 1.8 x 10(6) IU m-2. The maximum tolerated dose was 6 x 10(6) IU m-2 24 h-1. In all patients toxicity reached a peak at 3 weeks and resolved thereafter despite continued rIL-2 treatment. Peripheral blood eosinophilia (up to 66% of white blood cell count) followed the same pattern. An infection of the central venous access occurred in 55% of the patients but this was mostly asymptomatic. Thirteen patients were treated greater than or equal to 6 weeks and were evaluable for tumour response. A partial remission occurred in a patient with melanoma with a dose of 1.8 x 10(6) IU rIL-2 m-2 24 h-1.

Fibreoptic bronchoscopy in the elderly.

To evaluate the efficacy and safety of fibreoptic bronchoscopy in the elderly, the bronchoscopy records of 1000 patients were retrospectively reviewed. Of these, 423 were in-patients aged 65 years or over. This population was further subdivided into 'young' elderly (65-74 years old) and 'old' elderly (75+ years old). The indications for bronchoscopy in each group were similar and included haemoptysis, chest radiographic changes suggestive of collapse or consolidation, and hilar or paratracheal shadowing. The results in each group were also comparable and bronchoscopy was not tolerated in only five. A visible tumour was present in 165 patients. We conclude that, like upper gastrointestinal endoscopy, fibreoptic bronchoscopy in the elderly is safe, well tolerated and has a significant diagnostic yield.

Pulmonary sarcoidosis presenting with large haemoptysis.

We describe a previously healthy young male Caucasian with pulmonary sarcoidosis whose presenting symptoms were two copious haemoptyses.

Cutaneous vasculitis and immune complexes in severe bronchiectasis.

Four patients with severe bronchiectasis (chronic bronchial suppuration) are described who developed cutaneous lesions associated with exacerbations of their respiratory disease. The skin abnormalities consisted of purpuric lesions in three patients and an erythematous vasculitis in one. Circulating immune complexes were present in all patients and in three skin biopsy specimens showed deposition of C3, IgG, and IgA in dermal blood vessels. Haemophilus influenzae had been isolated from the sputum of all four patients and in two patients was present at the time the cutaneous lesions appeared. It is suggested that local immune complex deposition was responsible for the skin lesions which occurred during acute exacerbations of bronchiectasis.

C1q binding activity in the sera of patients with chronic lung diseases.

Sera from patients with chronic lung diseases were tested for the presence of immune complexes (ICs) by the 125I-C1q-binding assay. Contrary to earlier reports, modification of the test system by addition of heparin decreased rather than increased the ability of the test to discriminate between control and pathological sera. Using the unmodified system, elevated C1q-binding activity (C1qBA) was found in patients with asthma (18%), chronic bronchitis (18%), sarcoidosis (18%), fibrosing alveolitis (50%), bronchogenic carcinoma (52%) and bronchiectasis (67%). Studies with the reducing agent 2-mercaptoethanol (2-ME) suggested a role for IgM rheumatoid factor (RF) and/or IgG-containing complexes in the C1q-reactive material of sera from patients with bronchiectasis and bronchogenic carcinoma. In the latter two groups, C1qBA was found to correlate with serum levels of IgG and IgA but not with C3 and C4. A weak condition between levels of C-reactive protein (CRP) and C1qBA was found in the bronchogenic carcinoma group. Carcinoembryonic antigen (CEA) levels were elevated in all groups studied but no correlation with C1qBA was demonstrated, suggesting that CEA and CEA-ICs, if present, do not have an influence on the C1qBA of such sera. The results indicate that elevated serum C1qBA is a concomitant of both chronic inflammatory and neoplastic diseases of the lung but the extent of any similarity in the non-immunoglobulin components of the immune complexes in the respective conditions remains unknown.

Inhibition of antibody-dependent cellular cytotoxicity by artificial immune complexes and pathological sera.

Detection of immune complexes by inhibition of antibody-dependent cellular cytotoxicity (ADCC) is based on the principle that soluble complexes can compete with target cell-bound antibody for receptors (FcR) on cytotoxic lymphocytes. The objective of this study was to define a cytotoxicity system for the determination of soluble immune complexes in the sera of patients with inflammatory bowel disease (IBD). For this purpose, the conditions under which soluble complexes of rat serum albumin (RSA) and rabbit anti-RSA inhibited human K-cell mediated lysis of sensitized Chang cells were examined, on the assumption that the behaviour in the system of circulating immune complexes putatively present in inflammatory bowel disease, is similar to that of artificial immune complexes. Inhibition of ADCC by a standard amount of artificial complex in different normal human sera was relatively uniform provided that the final concentration of the latter did not exceed 10% of the culture medium. In the absence of extraneous complexes, the effect of both normal and IBD sera on ADCC varied widely. Differential inhibition of ADCC by sera from patients with IBD and normal subjects was thus expressed as a function of ADCC in a standard batch of foetal bovine serum (FBS). Under these conditions differences between pathological (n = 51) and normal (n = 52) sera were highly significant (P less than 0.001), which could not be explained by the presence in the patients' sera of HL-A antibodies reactive with the effector cells, nor by a deficit in nutritional support of ADCC. The absence of a correlation between inhibition of ADCC and total serum IgG or IgM inferred that inhibition was attributable to immune complexes in the IBD sera. The limitations of this assay for assessment of the incidence of immune complexes in pathological sera are discussed.

Immunological abnormalities in bronchiectasis with chronic bronchial suppuration.

Fifty-three patients with bronchiectasis (chronic bronchial suppuration) of unknown cause, in whom the chronic production of purulent sputum was the prominent clinical feature, were investigated for possible immunological abnormalities. They were compared with two control groups comprising 50 patients with chronic bronchitis and emphysema and 33 patients with bronchial asthma. Forty-two patients with bronchiectasis(79%) had at least one abnormality of immunoglobulin, usually elevation of IgA, IgG or IgM. Eight patients had all three immunoglobulin levels raised and this was related to severity of disease. Similar increases in immunoglobulin levels were observed in the control groups, but the frequency and severity of these changes were significantly greater in the bronchiectasis patients. Two patients had IgA deficiency. There was a very high prevalence of rheumatoid factor (52%) and an increased prevalence of antinuclear factor (10%) in the bronchiectasis patients compared with the control groups. The presence of these autoantibodies did not correlate closely with severity of disease. Ten patients with bronchiectasis (19%) had one or more autoimmune disorders, and the association of severe bronchiectasis, Hashimoto's thyroiditis and pernicious anaemia in one patient is described in detail. The immunoglobulin changes, high incidence of autoantibodies and association with autoimmune disorders raises the possibility that in some patients with bronchiectasis (chronic bronchial suppuration) of apparent unknown cause abnormal immune mechanisms may be important in causing or perpetuating the condition.