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The anti-proliferative effect of cation channel blockers in T lymphocytes depends on the strength of mitogenic stimulation.
Petho, Z, Balajthy, A, Bartok, A, Bene, K, Somodi, S, Szilagyi, O, Rajnavolgyi, E, Panyi, G, Varga, Z
Immunology letters. 2016;:60-9
Abstract
Ion channels are crucially important for the activation and proliferation of T lymphocytes, and thus, for the function of the immune system. Previous studies on the effects of channel blockers on T cell proliferation reported variable effectiveness due to differing experimental systems. Therefore our aim was to investigate how the strength of the mitogenic stimulation influences the efficiency of cation channel blockers in inhibiting activation, cytokine secretion and proliferation of T cells under standardized conditions. Human peripheral blood lymphocytes were activated via monoclonal antibodies targeting the TCR-CD3 complex and the co-stimulator CD28. We applied the blockers of Kv1.3 (Anuroctoxin), KCa3.1 (TRAM-34) and CRAC (2-Apb) channels of T cells either alone or in combination with rapamycin, the inhibitor of the mammalian target of rapamycin (mTOR). Five days after the stimulation ELISA and flow cytometric measurements were performed to determine IL-10 and IFN-γ secretion, cellular viability and proliferation. Our results showed that ion channel blockers and rapamycin inhibit IL-10 and IFN-γ secretion and cell division in a dose-dependent manner. Simultaneous application of the blockers for each channel along with rapamycin was the most effective, indicating synergy among the various activation pathways. Upon increasing the extent of mitogenic stimulation the anti-proliferative effect of the ion channel blockers diminished. This phenomenon may be important in understanding the fine-tuning of T cell activation.
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State-dependent blocking mechanism of Kv 1.3 channels by the antimycobacterial drug clofazimine.
Faouzi, M, Starkus, J, Penner, R
British journal of pharmacology. 2015;(21):5161-73
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Abstract
BACKGROUND AND PURPOSE Kv 1.3 potassium channels are promising pharmaceutical targets for treating immune diseases as they modulate Ca(2+) signalling in T cells by regulating the membrane potential and with it the driving force for Ca(2+) influx. The antimycobacterial drug clofazimine has been demonstrated to attenuate antigen-induced Ca(2+) oscillations, suppress cytokine release and prevent skin graft rejection by inhibiting Kv 1.3 channels with high potency and selectivity. EXPERIMENTAL APPROACH We used patch-clamp methodology to investigate clofazimine's mechanism of action in Kv 1.3 channels expressed in HEK293 cells. KEY RESULTS Clofazimine blocked Kv 1.3 channels by involving two discrete mechanisms, both of which contribute to effective suppression of channels: (i) a use-dependent open-channel block during long depolarizations, resulting in accelerated K(+) current inactivation and (ii) a block of closed deactivated channels after channels were opened by brief depolarizations. Both modes of block were use-dependent and state-dependent in that they clearly required prior channel opening. The clofazimine-sensitive closed-deactivated state of the channel was distinct from the resting closed state because channels at hyperpolarized voltages were not inhibited by clofazimine. Neither were channels in the C-type inactivated state significantly affected. Kv 1.3 channels carrying the H399T mutation and lacking C-type inactivation were insensitive to clofazimine block of the closed-deactivated state, but retained their susceptibility to open-channel block. CONCLUSIONS AND IMPLICATIONS Given the prominent role of Kv 1.3 in shaping Ca(2+) oscillations, the use-dependent and state-dependent block of Kv 1.3 channels by clofazimine offers therapeutic potential for selective immunosuppression in the context of autoimmune diseases in which Kv 1.3-expressing T cells play a significant role.
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[Raynaud's phenomenon; diagnosis and treatment].
Hofstee, HM, Voskuyl, AE, Serné, EH, Smulders, YM
Nederlands tijdschrift voor geneeskunde. 2009;:B216
Abstract
Primary Raynaud's phenomenon (RP) is a relatively common disorder. Most patients with primary RP have only mild symptoms and do not develop complications. Distinguishing primary from secondary RP is important with respect to complications, and for prognosis and treatment. Secondary RP mainly manifests as part of systemic connective tissue disease. About 13% of patients diagnosed initially as having primary RP develop a systemic disorder within the following few years. Both auto-immune serology including antinuclear antibodies (ANA), and capillaroscopy are important diagnostic tools if one suspects the existence or development of a systemic disorder. Calcium antagonists are the cornerstone of RP pharmacotherapy.
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Treatment of systemic sclerosis.
Allanore, Y, Kahan, A
Joint bone spine. 2006;(4):363-8
Abstract
Systemic sclerosis is the most severe of all connective tissue diseases. The distinctive pathogenic process involves sequential or concomitant abnormalities in blood vessel function, immunity and, ultimately, fibroblast function. These specific characteristics may explain the results of treatment evaluations. The decrease in excess mortality shown in recent studies seems chiefly ascribable to the use of cardiovascular drugs. Angiotensin-converting enzyme (ACE) inhibitors are effective in resolving renal crisis, prostacyclins and endothelin antagonists improve pulmonary hypertension, and calcium antagonists and ACE inhibitors benefit patients with myocardial involvement. On the other hand, immunomodulatory drugs and other agents investigated for their disease-modifying potential failed to influence skin fibrosis in controlled trials. Trials of immunosuppressants are ongoing. Available results indicate that emphasis should be put on cardiovascular drugs. The development of criteria for disease activity and severity would facilitate future research on the treatment of systemic sclerosis.
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Addition of isradipine (Lomir) results in a better renal function after kidney transplantation: a double-blind, randomized, placebo-controlled, multi-center study.
van Riemsdijk, IC, Mulder, PG, de Fijter, JW, Bruijn, JA, van Hooff, JP, Hoitsma, AJ, Tegzess, AM, Weimar, W
Transplantation. 2000;(1):122-6
Abstract
BACKGROUND After successful kidney transplantation patients may suffer from the adverse effects due to the use of calcineurin inhibitors. Calcium channel blockers are effective in the treatment of hypertension and may ameliorate cyclosporine- (CsA) induced impairment of renal function after kidney transplantation. Calcium channel blockers may also modulate the immune-system which may result in reduction of acute rejection episodes. PATIENTS AND METHODS From June 1995 till 1997 the effect of isradipine (Lomir) on renal function, incidence and severity of delayed graft function (DGF), and acute rejection after kidney transplantation, was studied in 210 renal transplant recipients, who were randomized to receive isradipine (n=98) or placebo (n=112) after renal transplantation in a double-blind fashion. RESULTS In the isradipine group renal function was significantly better at 3 and 12 months (P=0.002 and P=0.021) compared with the placebo group. DGF was present in both groups: isradipine: (28+6)/98 (35%); placebo: (35+9)/112 (40%), P=0.57. Severity of DGF was comparable in both groups (isradipine: 9.1+/-8.7 vs. placebo: 9.3+/-8.1 days). No statistical difference was found in incidence or severity of biopsy-proven acute rejection [isradipine: (42+6)/98 (49%) versus placebo: (46+9)/112 (49%), P=1.00]. Renal vein thrombosis was observed in eight patients. This proved to be associated with the route of administration of the study medication [6/45 (13%) on i.v. medication versus 2/165 (1%) on oral medication, P<0.001]. CONCLUSIONS Addition of isradipine results in a better renal function after kidney transplantation, without effect on incidence or severity of DGF or acute rejection.