Type Of Desensitization Research Articles

Optimal Immunosuppression Strategy in the Sensitized Kidney Transplant Recipient.

Patients with previous sensitization events against anti-human leukocyte antigens (HLA) often have circulating anti-HLA antibodies. Following organ transplantation, sensitized patients have higher rates of antibody-mediated rejection (AMR) compared to those who are non-sensitized. More stringent donor matching is required for these patients, which results in a reduced donor pool and increased time on the waitlist. Current approaches for sensitized patients focus on reducing preformed antibodies that preclude transplantation; however, this type of desensitization does not modulate the primed immune response in sensitized patients. Thus, an optimized maintenance immunosuppressive regimen is necessary for highly sensitized patients, which may be distinct from non-sensitized patients. In this review, we will discuss the currently available therapeutic options for induction, maintenance, and adjuvant immunosuppression for sensitized patients.

Effect of New Type of Desensitization on the Microleakage of Pure Titanium Crown

This study was conducted to observe surface morphology changes of dentin surface coated with potassium doped nano hydroxyapatite (K-nHA) on the surface of isolated teeth. The surface morphology of isolated molars was coated with K-nHA, nano-hydroxyapatite (nHA), and Gluma desensitizers to observe changes in surface morphology. The effects ofK-nHA, nHA, and Gluma desensitizers on microleakage of pure titanium crowns after bonding with zinc polycarboxylate cement (ZPCC) were measured. Three different treatment methods can effectively close the dentin tubules. Depth into the dentin tubule of K-nHA was higher than the other two groups. K-nHA reduces the microleakage of ZPCC bonded pure titanium crown. The microleakage value of the K-nHA group was lower than that of the nHA group, but there was no statistical difference. K-nHA is better than the simple nHA in closing the dentinal tubules. It has better curative effect on dentin hypersensitivity, and has a better sealing effect.

Recovery from tachyphylaxis of TRPV1 coincides with recycling to the surface membrane.

The transient receptor potential vanilloid-1 (TRPV1) ion channel is essential for sensation of thermal and chemical pain. TRPV1 activation is accompanied by Ca2+-dependent desensitization; acute desensitization reflects rapid reduction in channel activity during stimulation, whereas tachyphylaxis denotes the diminution in TRPV1 responses to repetitive stimulation. Acute desensitization has been attributed to conformational changes of the TRPV1 channel; however, the mechanisms underlying the establishment of tachyphylaxis remain to be defined. Here, we report that the degree of whole-cell TRPV1 tachyphylaxis is regulated by the strength of inducing stimulation. Using light-sheet microscopy and pH-sensitive sensor pHluorin to follow TRPV1 endocytosis and exocytosis trafficking, we provide real-time information that tachyphylaxis of different degrees concurs with TRPV1 recycling to the plasma membrane in a proportional manner. This process controls TRPV1 surface expression level thereby the whole-cell nociceptive response. We further show that activity-gated TRPV1 trafficking associates with intracellular Ca2+ signals of distinct kinetics, and recruits recycling routes mediated by synaptotagmin 1 and 7, respectively. These results suggest that activity-dependent TRPV1 recycling contributes to the establishment of tachyphylaxis.

Regulation of Ca2+-dependent Desensitization in the Vanilloid Receptor TRPV1 by Calcineurin and cAMP-dependent Protein Kinase

The vanilloid receptor TRPV1 is a polymodal nonselective cation channel of nociceptive sensory neurons involved in the perception of inflammatory pain. TRPV1 exhibits desensitization in a Ca2+-dependent manner upon repeated activation by capsaicin or protons. The cAMP-dependent protein kinase (PKA) decreases desensitization of TRPV1 by directly phosphorylating the channel presumably at sites Ser116 and Thr370. In the present study we investigated the influence of protein phosphatase 2B (calcineurin) on Ca2+-dependent desensitization of capsaicin- and proton-activated currents. By using site-directed mutagenesis, we generated point mutations at PKA and protein kinase C consensus sites and studied wild type (WT) and mutant channels transiently expressed in HEK293t or HeLa cells under whole cell voltage clamp. We found that intracellular application of the cyclosporin A.cyclophilin A complex (CsA.CyP), a specific inhibitor of calcineurin, significantly decreased desensitization of capsaicin- or proton-activated TRPV1-WT currents. This effect was similar to that obtained by extracellular application of forskolin (FSK), an indirect activator of PKA. Simultaneous applications of CsA.CyP and FSK in varying concentrations suggested that these substances acted independently from each other. In mutation T370A, application of CsA.CyP did not reduce desensitization of capsaicin-activated currents as compared with WT and to mutant channels S116A and T144A. In a double mutation at candidate protein kinase C phosphorylation sites, application of CsA.CyP or FSK decreased desensitization of capsaicin-activated currents similar to WT channels. We conclude that Ca2+-dependent desensitization of TRPV1 might be in part regulated through channel dephosphorylation by calcineurin and channel phosphorylation by PKA possibly involving Thr370 as a key amino acid residue.

Rapid down regulation of Ca 2+ signals induced by endothelin-1 in a human bronchial epithelial cell line

Ca 2+ transients evoked by endothelin-1 (ET-1) were measured in single cells of an immortalized human tracheal epithelial cell line using Fura-2. ET-induced Ca 2+ transients were compared to signals evoked via established phospholipase-C linked receptors (H 1 histamine; P 2y purinergic, ATP). Saturating concentrations of histamine (100 μM) and ATP (10 μM) caused Ca 2+ transients of identical amplitude, whereas a saturating concentration of ET-1 (10 nM) on average resulted in a slightly smaller change in fluorescence ratio (80 ± 27%). H 1 and PZY induced Ca 2+ signals caused by brief (10–30 s) application of the agonists were highly reproducible. No desensitization to these ligands was observed, if between two exposures cells were superfused with agonist-free solution for ≥ 200 s. A single exposure to ET-1 (10 nM) for ≥ 6 s reduced sensitivity of the cell to a second exposure to ET-1. On average, the signal upon a second application of 10 nM ET-1 had an amplitude of 30% of the first ET-1 induced signal in that cell. After two 10 s exposures to the peptide, less than 10% of the initial amplitude was measured. This desensitization did not affect responsiveness to histamine or ATP. No recovery from desensitization to ET-1 was observed for 12 h after a single brief treatment with the peptide. Thereafter, responsiveness to ET-1 re-appeared with a half time of about 5 h and was complete by about 20 h. Ca 2+ signals to all three agonists were absent in thapsigargin treated cells. Their amplitude was not affected by superfusion of the cells with Ca i2+-free solution. Under conditions of store-depletion either by ET-1 or by thapsigargin, a change from Ca 2+-free to Ca 2+-containing solution induced a slow rise in [Ca 2+ i, suggesting the existence of a capacitative Ca 2+ entry pathway. ET-receptors most likely of the ET A subtype are subject to a novel type of desensitization — at least with regard to Ca 2+ signalling — which might reflect a signal transduction mechanism specific to ET receptors.

Downregulation of muscarinic M2 receptors linked to K+ current in cultured guinea-pig atrial myocytes.

1. Desensitization of muscarinic K+ current (IK(ACh)) was studied in cultured atrial myocytes from guinea-pig hearts using whole-cell voltage clamp. 2. Three different types of desensitization could be identified. A fast component which upon rapid superfusion with ACh resulted in a partial relaxation of IK(ACh) within a few seconds to a plateau which was maintained in the presence of ACh. Recovery from this type of desensitization paralleled the decay of IK(ACh) after washout of the agonist. A second type of desensitization was observed within minutes. This was reversed around 10 min after washout of ACh. Both types were heterologous with regard to the A1 receptor and the novel phospholipid (Pl) receptor, both of which activate IK(ACh) via the same signalling pathway. 3. A third type of desensitization (downregulation) occurred upon exposure of the cultures for 24-48 h to the muscarinic agonist carbachol (CCh). The level of downregulation depended on the concentration of CCh (0.1 microM < or = [CCh] < or = 10 microM). No recovery was observed within 5 h after washout of CCh. Thereafter sensitivity to ACh slowly returned (half-time (t1/2), approximately 20 h). 4. Downregulation by CCh (0.1-5 microM) was characterized by an increase in EC50 for ACh with no reduction in maximum IK(ACh). With 5 microM CCh, EC50 was increased from 0.1 to 3.7 microM. At 10 microM CCh EC50 was increased to 15 microM and maximal current that could be evoked by ACh was reduced to 15%. 5. Downregulation by CCh was homologous with regard to A1 and Pl receptors. Maximum IK(ACh), assayed by a saturating concentration of Pl, was not reduced in downregulated cells, suggesting a mechanism localized at the M2 receptor. 6. The changes in the concentration-response curves can be accounted for by assuming an excess of M2 receptors relative to the subsequent component of the signalling pathway. 7. As the intact heart is under tonic vagal control, downregulation is likely to contribute to controlling the sensitivity of the heart to vagal activity in situ.