A randomized controlled trial with a delayed-type hypersensitivity model using keyhole limpet haemocyanin to evaluate adaptive immune responses in man

Aims Keyhole limpet haemocyanin (KLH) immunization is a clinical model for the evaluation of human antibody responses. The current study evaluated the anti-KLH antibody response after KLH immunization and the delayed-type hypersensitivity response following intradermal KLH administration, using objective imaging techniques.Methods Healthy male subjects aged 24.5 +/- 5.4 years were randomized to intramuscular immunization with 100 mu g KLH (n = 12) or placebo (n = 3). Anti-KLH antibody (Ig) M and IgG titres were determined before and every 7 days after KLH immunization for a total of 28 days. Twenty-one days after the immunization, all subjects received 1 mu g KLH intradermally. Prior to and 2 days after intradermal KLH administration, skin blood perfusion, erythema and oedema were quantified using noninvasive imaging tools. Repeated measures ANCOVAs were used to analyse data.Results Anti-KLH IgM and IgG titres increased after KLH immunization compared to placebo (estimated difference [ED]: 37%, 95% confidence interval [CI]: 19-51% and ED: 68%, 95% CI: 56-76% respectively). Upon intradermal KLH administration an increase in skin blood perfusion (ED: 10.9 arbitrary units (AU), 95% CI: 1.4-20.4 AU) and erythema (ED: 0.3 AU, 95% CI: 0.1-0.5 AU) was observed in KLH-immunized subjects compared to placebo.Conclusion KLH immunization followed by intradermal KLH administration resulted in increased anti-KLH IgM and IgG titres and a delayed-type hypersensitivity response quantified by an increase in skin blood perfusion and erythema. Using noninvasive imaging tools the KLH model has the potential to serve as an objective tool to study the pharmacodynamics of T-cell-directed immunomodulatory drugs.Drug Delivery Technolog

OX40L Inhibition suppresses KLH-driven immune responses in healthy volunteers: a randomized controlled trial demonstrating proof-of-pharmacology for KY1005

The safety, tolerability, immunogenicity, and pharmacokinetic (PK) profile of an anti-OX40L monoclonal antibody (KY1005, currently amlitelimab) were evaluated. Pharmacodynamic (PD) effects were explored using keyhole limpet hemocyanin (KLH) and tetanus toxoid (TT) immunizations. Sixty-four healthy male subjects (26.5 +/- 6.0 years) were randomized to single doses of 0.006, 0.018, or 0.05 mg/kg, or multiple doses of 0.15, 0.45, 1.35, 4, or 12 mg/kg KY1005, or placebo (6:2). Serum KY1005 concentrations were measured. Antibody responses upon KLH and TT immunizations and skin response upon intradermal KLH administration were performed. PD data were analyzed using repeated measures analysis of covariances (ANCOVAs) and post hoc exposure-response modeling. No serious adverse events occurred and all adverse events were temporary and of mild or moderate severity. A nonlinear increase in mean serum KY1005 concentrations was observed (median time to maximum concentration (T-max) similar to 4 hours, geometric mean terminal half-life (t1/2) similar to 24 days). Cutaneous blood perfusion (estimated difference (ED) -13.4 arbitrary unit (AU), 95% confidence interval (CI) -23.0 AU to -3.8 AU) and erythema quantified as average redness (ED -0.23 AU, 95% CI -0.35 AU to -0.11 AU) decreased after KY1005 treatment at doses of 0.45 mg/kg and above. Exposure-response analysis displayed a statistically significant treatment effect on anti-KLH antibody titers (IgG maximum effect (E-max) -0.58 AU, 95% CI -1.10 AU to -0.06 AU) and skin response (erythema E-max -0.20 AU, 95% CI -0.29 AU to -0.11 AU). Administration of KY1005 demonstrated an acceptable safety and tolerability profile and PK analyses displayed a nonlinear profile of KY1005. Despite the observed variability, skin challenge response after KY1005 treatment indicated pharmacological activity of KY1005. Therefore, KY1005 shows potential as a novel pharmacological treatment in immune-mediated disorders.Drug Delivery Technolog

Immunomonitoring of Tacrolimus in Healthy Volunteers: The First Step from PK- to PD-Based Therapeutic Drug Monitoring?

Therapeutic drug monitoring is routinely performed to maintain optimal tacrolimus concentrations in kidney transplant recipients. Nonetheless, toxicity and rejection still occur within an acceptable concentration-range. To have a better understanding of the relationship between tacrolimus dose, tacrolimus concentration, and its effect on the target cell, we developed functional immune tests for the quantification of the tacrolimus effect. Twelve healthy volunteers received a single dose of tacrolimus, after which intracellular and whole blood tacrolimus concentrations were measured and were related to T cell functionality. A significant correlation was found between tacrolimus concentrations in T cells and whole blood concentrations (r = 0.71, p = 0.009), while no correlation was found between tacrolimus concentrations in peripheral blood mononuclear cells (PBMCs) and whole blood (r = 0.35, p = 0.27). Phytohemagglutinin (PHA) induced the production of IL-2 and IFNγ, as well as the inhibition of CD71 and CD154 expression on T cells at 1.5 h post-dose, when maximum tacrolimus levels were observed. Moreover, the in vitro tacrolimus effect of the mentioned markers corresponded with the ex vivo effect after dosing. In conclusion, our results showed that intracellular tacrolimus concentrations mimic whole blood concentrations, and that PHA-induced cytokine production (IL-2 and IFNγ) and activation marker expression (CD71 and CD154) are suitable readout measures to measure the immunosuppressive effect of tacrolimus on the T cell

Performance evaluation of multiple-bit delay detection with majority vote decision rule in optical DPSK systems

Due to copyright restrictions, the access to the full text of this article is only available via subscription.In this paper, the performance of multiple-bit delay detection (MBDD) systems in optical differential phase shift keying (DPSK) is investigated. Assuming that the dominant noise in the system is originated by the optical amplifier and using Gaussian approximation, we present a closed form equation which predicts the overall bit-error-rate (BER) performance of the system as a function of the number of delay segments, optical signal-to-noise ratio (OSNR) at the receiver, and bandwidth of the optical bandpass filter. It is shown that with a large number of delay segments, the performance of MBDD system approaches to the performance of homodyne coherent detection

PDP46 Experimental Demonstration of an Interference-Avoidance- Based Protocol for O-CDMA Networks

Abstract: We demonstrate the transmission scheduling algorithm in an O-CDMA network to avoid congestion collapse in an O-CDMA network. Our result shows that transmission scheduling increases the performance of the system by orders of magnitude. ©2006 Optical Society of America OCIS codes: (060.2330) Fiber optics communication, (060.2360) Fiber optics links and subsystem

Investigating the impact of recommender systems on user-based and item-based popularity bias

Abstract Recommender Systems are decision support tools that adopt advanced algorithms in order to help users to find less-explored items that can be interesting for them. While recommender systems may offer a range of attractive benefits, they may also intensify undesired effects, such as the Popularity Bias, where a few popular users/items get more popular and many unpopular users/items get more unpopular. In this paper, we study the impact of different recommender algorithms on the popularity bias in different application domains and recommendation scenarios. We have designed a comprehensive evaluation methodology by considering two different recommendation scenarios, i.e., the user-based scenario (e.g., recommending users to users to follow), and the item-based scenario (e.g., recommending items to users to consume). We have used two large datasets, Twitter and Movielens, and compared a wide range of classical and modern recommender algorithms by considering a diverse range of metrics, such as PR-AUC, RCE, Gini index, and Entropy Score. The results have shown a substantial difference between different scenarios and different recommendation domains. According to our observations, while the recommendation of users to users may increase the popularity bias in the system, the recommendation of items to users may indeed decrease it. Moreover, while we have measured a different level of popularity bias in different languages (i.e., English, Spanish, Portuguese, and Japaneses), the above-noted phenomena has been consistently observed in all of these languages