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Lege Artis Medicinae

OCTOBER 21, 2020

[Atherosclerosis: an ancient process in a new interpretation]

REIBER István

[The progress of atherosclerosis starts in childhood and lasts until the body dies. Most cardiovascular diseases and deaths can be traced back to atherosclerotic vascular changes. The process is thousands of years old, but its complex pathophysiology becomes recognized and realised only nowadays. Based on the evidence available today, atherosclerosis is such a chronic inflammatory disease of large- and medium-sized arteries, which is characterized by lipoproteins and immune cells transformed through oxidative and other changes and subendothelial accumulation of extracellular matrix. Innate and adaptive immunity provide a complex regulating system of atherogenesis, which while directing specifically the pro-atherogenic inflammatory and atheroprotective anti-inflammatory processes intensify plaque progression or even stabilize them respectively. With our growing knowledge about the pathology of atherogenesis, we can further improve the identification of cardiovascular risk conditions and apply more personalized therapeutic strategies.]

Lege Artis Medicinae

SEPTEMBER 30, 2020

[The pain-trigger role of cytokines in the nervous system – the direct analgesic effect of anti-cytokine therapy ]

HODINKA László, VERECKEI Edit

[Nociceptive, neuropathic and central me­chanisms are involved in the perception, transmission and processing of chronic pain and shaping of cerebral pain image. Alar­mins – molecules alarming defence and signing the presence of pathogens and tissue damage - trigger a series of pathogenic events resulting in inflammatory pain stimuli. Proinflammatory cytokines play a determining role in the pain perception at the level of the nervous system. Continuous inflammatory stimuli while sensitizing the periferic and central neurons activate the pain-related cerebral areas and develop the complex pain image, the pain matrix. Ce­reb­ral functional connections are operating in networks and can be visualized by functional MRI. Cytokines activate the neurons directly or indirectly by other neuromediators. Cytokine receptors are expressed on no­ciceptors and even on higher-level neurons and on various non-neural cells, such as microglia and astrocytes. The most ubiquitous cytokines are the Tumour Necrosis Factor and Interleukin 6 in the nervous sys­tem. The signaling pathways are the Nuclear Factor κB and the Janus-kinase enzyme system. The proinflammatory cytokines and the Janus-kinase are therefore primary therapeutic targets. Anti-cytokine biologicals and small molecular kinase inhibitors decrease the pain and improve functional activity in rheumatoid arthritis. Decrease of pain was more pronounced than expected only from the decrease of the clinical biomarkers of inflammation. The early and ra­pid painkiller effect of targeted biological and chemical-biological response modifiers is attributed to their direct analgesic effect on the brain.]

Hypertension and nephrology

SEPTEMBER 10, 2019

[Role of IL-10 family of cytokines in kidney fibrosis]

PAP Domonkos, VERES-SZÉKELY Apor, SZEBENI Beáta, SZIKSZ Erna, KISS József Zoltán, TAKÁCS István Márton, REUSZ György, SZABÓ J. Attila, VANNAY Ádám

[Chronic renal failure is a major health problem, affecting 8 to 16% of the population. Regardless of the etiology the common hallmark of chronic renal failure is inflammation, leading to the activation of renal myofibroblasts. Chronic activation of myofibroblasts lead to abnormal accumulation of extracellular matrix, disruption of the architecture of the kidney and finally to reduced renal function. Although our knowledge is rapidly expanding about the pathomechanism of chronic renal failure, we still have no drug to treat or hinder the progression of the disease. In our present review article, we summarize the role of the cytokines of the IL-10 family in renal scarring.]

Lege Artis Medicinae

OCTOBER 20, 2018

[Gene modified T cells against cancer]

SZÖŐR Árpád

[Chimeric antigen receptor modified (CAR) T cells are hailed as a revolutionary breakthrough in the field of oncology. CAR T cells were first applied, with outstanding success, in the treatment of various leukaemias, yielding unprecedented antitumor activity and long periods of disease free survival. Following the success of CAR T cell therapy in leukaemias, solid tumors should now be targeted. These are more complex targets, therefore CAR T cell therapy needs to be further optimized for this purpose. Also, some unfortunate side effects, including the potentially deadly global inflammation called cytokine storm have to be minimized and possibly even eradicated. The next decade will be an exciting time to define whether this therapy which is yet exclusively used for cancer patients is also successful in the treatment of other diseases. In a recent study, T cells reengineered with CAR derived chimeric autoantibody receptors (CAAR) efficiently prevented disease progression in pre-clinical animal models simulating the serious autoimmune disorder, pemphigus vulgaris. Therapy was based on CAAR constructs which have the unique ability to selectively recognize and eliminate the B-cell clones secreting autoantibodies against a self-protein, thus playing a key role in disease pathogenesis and progression. In this review, we would like to give an overview about the history of the CAR T-cell concept, summarize briefly the currently running clinical trials, and discuss the challenges and future prospects of CAR T-cell therapy.]

Clinical Oncology

SEPTEMBER 10, 2017

[Targeted therapy of the clear cell renal cancer ]

TORDAY László

[The renal cell cancer is among the ten most frequent cancers in developed countries. Its inci dence rate continuously increased until recently. On the other hand, survival parameters of renal cell cancer patients considerably improved in the last decade due to early diagnosis and developments in the treatment of irresectable disease. Huge progress had been made in understanding of the biological background of this chemo- and radiotherapy resistant disease, leading to the introduction of drugs in fi rst and further line treatment acting on VEGF and mTOR signal transduction pathways. Simultaneously, the era of widespread cytokine treatments had been ended. Recent studies had ensured the introduction of several drugs with new mechanism of action (MET, AXL; FGFR, PD-1 inhibition) into the therapy; these new advances completely changed the treatment landscape of RCC further improving progression free and overall survival. In this publication a review of data regarding the targeted treatment of clear cell renal cancer will be provided and as of our recent knowledge therapeutic positions of different drugs used will be discussed.]

Clinical Oncology

FEBRUARY 20, 2014

[Management of renal cancer]

MARÁZ Anikó, SZŰCS Miklós

[Targeted anti-cancer agents are used as standard therapies in case of advanced or metastatic clear cell renal carcinoma. Neovascularisation plays an important role in the progression of hypervascularized cancers. Vascular endothelial growth factor (VEGF) is the key molecule in this mechanism. Most of the registered agents inhibit the angiogenesis by blocking the VEGF signalling pathway. It can occur if an antibody binds to the VEGF, so the linkage to the receptor is blocked. This happens in case of bevacizumab. Another mechanism is the inhibition of the intracellular compound of VEGF receptor by tyrosine kinase inhibitors (TKI). Sorafenib, sunitinib, pazopanib and axitinib belong to this group. Other well-known mechanism of action is the inhibition of mammalian target of rapamycin (mTOR) receptor, like temsirolimus and everolimus. Based on randomised controlled trials sunitinib, pazopanib or IFNα-bevacizumab combination is recommended fi rst-line according to the international recommendations in case of good and moderate prognosis. For patients with poor prognosis temsirolimus is the standard therapy. In second-line, after ineffective cytokine therapy, sorafenib, pazopanib and axitinib are the supported options. If TKI is ineffective, everolimus or axitinib can be administered. In the latest recommendations sorafenib is another possible option (off label). After two TKIs, only everolimus is registered for third-line therapy. Life expectancy of patients can further be improved as the number of targeted drugs increases, more effective agents appear and as appropriate sequences and their benefi cial effects are recognised.]

Hypertension and nephrology

MARCH 20, 2015

[Role of activated cells and local inflammatory mechanisms in the development of hypertension]

LELBACH Ádám, KOLLER Ákos

[In the past decades an increasing attention has been paid regarding the possible role of the immune system in the development of hypertension. In vitro and in vivo animal experiments, as well as human studies provided evidence for the role of the innate and adaptive immune systems in the development of hypertension, especially in connection with the perivascular adipose tissue, heart and kidney. Inflammatory mediators, cytokines, reactive oxygen metabolites have not only local pro-hypertensive effecting the vasculature, but also influence the development of hypertension through other regulatory mechanisms, such as the central nervous system. These findings provide a new understanding of the development of hypertension, as well as offer new potential mechanisms that can be targeted with novel the - rapies.]

Lege Artis Medicinae

SEPTEMBER 22, 2013

[A novel rapid IL-6 release assay using blood mononuclear cells of patients with various forms of drug induced skin injuries]

BALÓ-BANGA J. Mátyás, SCHWEITZER Katalin

[INTRODUCTION - IL-6 is a multifunctional cytokine with effects on the haematopoiesis on differentiation of T and B lymphocytes and on the regulation of both inflammatory and allergic reactions. The question arose whether this substance excreted by mononuclear cells could be used as a marker of allergy to drugs or not. Till now equivocal descriptions were lacking. METHOD - The preformed IL-6 present in the mononuclear cells released by any of four standard dilutions of pure substances upon 20 minutes incubation was determined from the supernatants by ELISA technique. In vivo patch, intradermal and provocation tests were carried out along with this assay (483 in vitro and 172 in vivo). RESULTS - Two different groups suspect for drug allergy (100 and 62 patients as well as their matching controls, 24 and 23 persons) were involved with these procedures. In some cases TNF-α, IL-2, IFN-γ and IL-4 was measured simultaneously by flow cytometric assay. Only TNF-α and IL-6 were present in the 20 min. supernatants. The comparisons with in vivo tests have confirmed that the amount of IL-6 release had not depended either on the clinical phenotype of allergy or on the structure of the tested drugs within the molecular mass range between 76-4000 Da. IL-6 released at the lowest or multiple concentrations of drugs coincided with more severe and widespread clinical forms. CONCLUSION - Based on the results we elaborated an in vitro method applicable clinically for detecting drug sensitisation and its differential diagnosis in patients with skin signs of drug sensitisation.]

Clinical Neuroscience

OCTOBER 05, 2013

[The impact of the vitamin D in neurological diseases and neurorehabilitation: from demencia to multiple sclerosis. Part I: The role of the vitamin D in the prevetion and treatment of multiple sclerosis]

SPEER Gábor

[The world-wide incidence of vitamin D deficiency is high, independently of age. Multiple sclerosis is a chronic disorder, occuring in those who possess or are exposed to a combination of genetic and environmental risk factors. One of the environmental factors associated with the development is vitamin D. Vitamin D is an immunomodulatory agent, its role is verified in many of autoimmune diseases. Vitamin D inhibits IL-6, IL-17 and IL-23 secretions which are crucial in Th1 and Th17 differentiation and also decreases proinflammatorical cytokine production. Moreover it enhances the immunosuppressive IL-10 cytokine secretion and inhibits the T-reg cell development. These cytokines and cells are essential for the pathomechanism of multiple sclerosis. Data have shown, that the vitamin D levels above 100 nmol/l (40 ng/ml) is essential for the prevention of multiple sclerosis. Below this level the vitamin D supplementation is reasonable. In pregnancy, the vitamin D deficiency at the last two semester increases the risk for the multiple sclerosis of the infant. The optimal vitamin D level for multiple sclerosis patients is 100-150 nmol/l (40-60 ng/ml). There is no consensus for the role of vitamin D in multiple sclerosis yet, but until the achieving this, the diagnosis and the treatment of the vitamin D deficiency is crucial for scelrosis multiplex patients and in cases of elevated risk. Data shows, that in patient with multiple sclerosis the normal vitamin D level is suboptimal, however the exact role of vitamin D and doses must be clarified by interventional studies.]

Hungarian Immunology

MARCH 20, 2006

[The role of nerve growth (NGF) factor in the immune and inflammatory events and in autoimmune thyroid diseases]

MOLNÁR Ildikó

[Nerve growth factor (NGF) is a neurotroph cytokine, and beside its effect on the central and peripheral nervous systems NGF plays an important role in the inflammatory and autoimmune processes. There are two types of NGF receptors, the high-affinity (TrkA) and the low-affinity (p75), which activations via signal transduction could lead to the inhibition or induction of apoptosis. Suppression of apoptosis could be induced by cytokines, hormones, antioxidans and increased intracellular Ca2+-levels. In the pathogenesis of many autoimmune diseases (systemic lupus erythematosus, 1-type diabetes mellitus, multiple sclerosis) could detect elevated serum levels of NGF associated with the disease activity. Our study demonstrated increased levels of NGF in autoimmune thyroid diseases (Graves’ disease, Hashimoto’s thyroiditis) in comparison with the controls. Decreased serum levels of NGF were found in Graves’ ophthalmopathy suggesting the role of apoptosis in the development of the eye symptoms. Orbital tissues are characterized with the high expression of TrkA receptors. NGF plays an important role in the pathomechanisms of neuro-immuno-hormonal diseases and its knowledge may be helpful in the diagnosis and therapy.]