Effects of tumour necrosis factor α on bone marrow aspirates of patients with acute myelogenous leukemia determined by flow-cytometric cell-cycle analysis

Summary Tumour necrosis factor (TNF) exerts cytotoxic and antiproliferative effects on neoplastic cells. It has been used as a therapeutic agent for solid tumours and haematological malignancies. We report on the ex vivo determination of the effect of recombinant human rhuTNF on bone marrow aspirates by a bromodeoxyuridine/propidium iodide method. Cell samples were drawn after 0.5, 2, 4, 6, 8, 10, 22, and 25 h from shortterm suspension bone marrow cultures from patients with acute myelogenous leukemia (AML). Flow-cytometric cell-cycle analysis was performed after double DNA staining with propidium iodide and anti-BrdU antibodies. By this method the effect of rhuTNF on cell proliferation can be evaluated after only 35 h. In about two-thirds of the bone marrow aspirates of AML an inhibiting effect on rhuTNF can be demonstrated, developing to its full extent after 10 h.Abbreviations TNF tumour necrosis factor - AML acute myelogenous leukemia     

Treatment of intestinal Behçet's syndrome with chimeric tumour necrosis factor alpha antibody

Few patients with Behçet''s syndrome have gastrointestinal ulceration. Such patients are difficult to treat and have a higher mortality. Faced with refractory symptoms in two patients with intestinal Behçet''s, we used the tumour necrosis factor α (TNF-α) monoclonal antibody infliximab to induce remission. Both women (one aged 27 years, the other 30 years) presented with orogenital ulceration, pustular rash, abdominal pain, bloody diarrhoea due to colonic ulceration, weight loss, and synovitis. One had thrombophlebitis, digital vasculitis, perianal fistula, and paracolic abscess; the other had conjunctivitis and an ulcer in the natal cleft. Treatment with prednisolone, methyl prednisolone, and thalidomide in one and prednisolone, colchicine, and cyclosporin in the other was ineffective. After full discussion, infliximab (3 mg/kg, dose reduced because of recent sepsis in one, and 5 mg/kg in the other) was administered. Within 10 days the ulcers healed, with resolution of bloody diarrhoea and all extraintestinal manifestations. A second infusion of infliximab was necessary eight weeks later in one case, followed by sustained (>15 months) remission on low dose thalidomide. Remission was initially sustained for 12 months in the other but thalidomide had to be stopped due to intolerance, and a good response to retreatment lasted only 12 weeks without immunosuppression, before a third infusion. The cause of Behçet''s syndrome is unknown but peripheral blood CD45 γδ T cells in Behçet''s produce >50-fold more TNF-α than controls when stimulated with phorbol myristate acetate and anti-CD3. Infliximab could have a role for inducing remission in Behçet''s syndrome.     

Tumor necrosis factor α antibody prevents brain damage of rats with acute necrotizing pancreatitis

AIM:To study the protective effects of tumor necrosis factor α(TNFα)antibody on pancreatic encephalopathy in rats.METHODS:One hundred and twenty SD rats were randomlydivided into normal control group,acute necrotizingpancreatitis group and TNFα antibody treated group.Acutehemorrhage necrotizing pancreatitis model in rats wasinduced by retrograde injection of 50g/L sodium taurocholateinto the pancreatobiliary duct.Serum TNFα was detectedand animals were killed 12 h after drug administration.Changes in content of brain water,MDA and SOD as wellas leucocyte adhesion of brain microvessels were measured.RESULTS:In TNFα antibody treated group,serum TNFαlevel was decreased.Content of brain water,MDA and SODas well as leucocyte adhesion were decreased significantlyin comparison with those of acute necrotizing pancreatitisgroup (P<0.05).CONCLUSION:TNFα antibody can alleviate the brain damageof rats with acute hemorrhage necrotizing pancreatitis.     

Tumor necrosis factor α antibody prevents brain damage of rats with acute necrotizing pancreatitis

AIM: To study the protective effects of tumor necrosis factor α (TNFα) antibody on pancreatic encephalopathy in rats.METHODS: One hundred and twenty SD rats were randomly divided into normal control group, acute necrotizing pancreatitis group and TNFα antibody treated group. Acute hemorrhage necrotizing pancreatitis model in rats was induced by retrograde injection of 50 g/L sodium taurocholate into the pancreatobiliary duct. Serum TNFα was detected and animals were killed 12 h after drug administration. Changes in content of brain water, MDA and SOD as well as leucocyte adhesion of brain microvessels were measured.RESULTS: In TNFα antibody treated group, serum TNFα level was decreased. Content of brain water, MDA and SOD as well as leucocyte adhesion were decreased significantly in comparison with those of acute necrotizing pancreatitis group (P&lt;0.05).CONCLUSION: TNFα antibody can alleviate the brain damage of rats with acute hemorrhage necrotizing pancreatitis.     

Establishment and expression of recombinant human glial cell line-derived neurotrophic factor and TNF α receptor in human neural stem cells

ObjectiveTo investigate the interference and expression of human glial cell line-derived neurotrophic factor (hGDNF) and soluble TNF alpha (sTNFR |) receptor genes in neural stem cells and to evaluate the roles of these proteins in the genetic treatment of spinal cord injury.MethodsFull-length of GDNF cDNA (558 bp) and sTNFR|cDNA (504 bp) were inserted into the early 1 region of adenovirus genomic DNA respectively and were immediated by the human cytomegalovirus (gene promoter/enhancer). These adenoviruses were propagated in HEK293 cells via homologous recombination for 7-10 days in vivo, then they were used to infect human neural stem cells. The infection and expression of gene were tested under immunofluorescence, ELISA and Western-blot after 48 hours.ResultsAlmost all the cultured cells showed the nestin immunofluorescence positive staining, which was the characteristics of neural stem cell. A great quantity of EGFP and RFP were observed in neural stem cells, which indicated the expression of GDNF and sTNFR |. After transfection of GDNF and sTNFR | genes, many neural stem cells show GFAP and tubulin immunofluorescence positive staining, which meant that most neural stem cells differentiated into neuron at that condition.ConclusionsThe infective efficiency of adenovirus is greatly acceptable to neural stem cell, thus adenovirus provide a useful vector for exogenous GDNF and sTNFR | genes expressing in neural stem cells, which is useful for differentiation of neural stem cell.     

Withdrawal of anti-tumour necrosis factor α therapy in inflammatory bowel disease

Anti-tumour necrosis factor α(anti-TNFα) therapy is an established treatment in inflammatory bowel disease.However, this treatment is associated with high costs and the possibility of severe adverse events representing a true challenge for patients, clinicians and health care systems.Consequently, a crucial question is raised namely if therapy can be stopped once remission is achieved and if so, how and in whom.Additionally, in a real-life clinical setting, discontinuation may also be considered for other reasons such as the patient's preference, pregnancy, social reasons as moving to countries or continents with less access, or different local policy or reimbursement.In contrast to initiation of anti-TNFα therapy guidelines regarding stopping of this treatment are missing.As a result, the decision of discontinuation is still a challenging aspect in the use of anti-TNFα therapy.Currently this is typically based on an estimated, case-by-case, benefit-risk ratio.This editorial is intended to provide an overview of recent data on this topic and shed light on the proposed drug withdrawal strategies.     

How early should ankylosing spondylitis be treated with tumour necrosis factor blockers?

Recognition and treatment of ankylosing spondylitis (AS) in the early stages of the disease has yet to be established. This paper considers the evidence available and the questions that need to be answered regarding the benefits of early diagnosis and treatment with tumour necrosis factor (TNF) blockers in AS. The authors conclude that AS can and has to be diagnosed earlier than is being done at present, before radiological changes are evident, and the potential of TNF blockers to induce long term remission if given early enough needs to be clarified.     

Real-life outcome of anti-tumor necrosis factor α in the ambulatory treatment of ulcerative colitis

AIM:To evaluate the outcome of anti-tumor necrosis factor alpha(anti-TNFα) therapy in outpatients with ulcerative colitis at a tertiary referral center.METHODS:All patients with a confirmed diagnosis of ulcerative colitis undergoing therapy with infliximab and/or adalimumab at the outpatient clinic for inflammatory bowel diseases at the University Hospital Heidelberg between January 2011 and February 2014 were retrospectively enrolled.Patients with a followup period of less than 6 mo from start of anti-TNFα therapy were excluded.Medical records of all eligible individuals were carefully reviewed.Steroid-free clinical remission of a duration of at least 3 mo,colectomy rate,duration of anti-TNFα therapy,need for anti-TNFα dose escalation,and the occurrence of adverse events were evaluated as the main outcome parameters.RESULTS:Seventy-two patients were included(35 treated with infliximab,17 with adalimumab,20 with both consecutively).Median follow-up was 27 mo(range:6-87 mo).Steroid-free clinical remission was achieved by 22.2% of the patients(median duration:21 mo until end of follow-up; range:3-66 mo).Patients attaining steroid-free clinical remission displayed lower hemoglobin and albumin blood levels at the start of treatment than those who did not achieve remission.The overall colectomy rate was 20.8%.Nearly 50% of the patients underwent anti-TNFα dose escalation during the follow-up period.For both the infliximab and the adalimumab treated patients,non-response to anti-TNFα therapy was the major reason for treatment discontinuation.18.2% of the infliximab-treated patients and 13.5% of the adalimumab-treated patients had to discontinue their therapy due to adverse events.CONCLUSION:Real-life remission rates of ulcerative colitis under anti-TNFα are overall low,but some patients have a clear long-term benefit.     

Reduction of tumor necrosis factor α and interleukin-1β levels in human synovial tissue by interleukin-4 and glucocorticoid

Summary The effects of recombinant human interleukin-4 (IL-4) and the glucocorticoid, dexamethasone, on tumor necrosis factor (TNF) and interleukin-1 (IL-1) levels in cultures of rheumatoid and osteoarthritic synovial tissue were studied. Low concentrations of IL-4 and dexamethasone suppressed the levels of both cytokines in the supernatants of both types of tissue after stimulation with lipopolysaccharide (LPS); the IL-1 and TNF levels were measured by ELISA. It is suggested that it is the monocyte/macrophage in the synovial tissues that is responsive to the inhibitors. It is proposed that glucocorticoids may act on synovial tissue in this manner in vivo and IL-4 may do so if administered intraarticularly.     

Diabetes mellitus risk in rheumatoid arthritis: reduced incidence with anti-tumor necrosis factor α therapy

Objective

To examine the association of tumor necrosis factor α (TNFα) inhibitor use and the risk of developing diabetes mellitus in a rheumatoid arthritis (RA) inception cohort.

Methods

Adults diagnosed with RA between January 1, 2001, and December 31, 2009, were identified (n = 1,881). Prevalent cases of diabetes mellitus (n = 294) were excluded. Information on sociodemographic data, medical history, body mass index (BMI), laboratory measures, and medications was collected from the electronic health record. Incident diabetes mellitus was defined using the 2010 American Diabetes Association criteria or physician‐established diagnosis. Time‐varying Cox proportional hazards regression models were used to adjust for age, sex, race, BMI, rheumatoid factor (RF) and anti–cyclic citrullinated peptide antibodies (anti‐CCP), erythrocyte sedimentation rate (ESR), and use of nonsteroidal antiinflammatory drugs (NSAIDs), glucocorticoids, hydroxychloroquine, and methotrexate.

Results

A total of 1,587 incident RA patients without diabetes mellitus were included. The anti‐TNFα users (n = 522) had a lower median age but greater baseline BMI; maximum ESR, RF, and anti‐CCP positivity; and NSAID, glucocorticoid, or methotrexate use. The median followup time for the ever and never TNFα inhibitor users was 44.9 months (interquartile range [IQR] 23.7–73.0 months) and 37.1 months (IQR 16.3–65.1 months), respectively (P < 0.001). Of the 91 patients developing diabetes mellitus, 16 were ever and 75 were never TNFα inhibitor users, yielding incidence rates of 8.6 and 17.2 per 1,000 person‐years (P = 0.048), respectively. Adjusting for covariates, the hazard ratio for incident diabetes mellitus in TNFα inhibitor users was 0.49 (95% confidence interval 0.24–0.99, P = 0.049) compared to the never users.

Conclusion

In this inception RA cohort, anti‐TNFα use was associated with a 51% reduction in risk of developing diabetes mellitus.