A series of 19 congener derivatives and conjugates of histamine was synthesized and tested to determine whether the ligands would alter the conventional histamine activity in various tissues. The derivatives, which contained either branched or unbranched aliphatic groups, aromatic amide groups, or dipeptides, exhibited affinities for histamine type 1 and/or type 2 receptors that were widely different from the progenitor. The p-trifluoromethyl derivative of histamine with an intermediate chain length of four methylenes (compound 13) was the most potent lymphocytes H2 receptor agonist but was inactive on guinea pig myocardium H2 receptors. The deletion of a single methylene chain (compound 12) from this compound resulted in total loss of its H2 activity on lymphocytes and its H1 activity on aorta. Compound 12 became an exclusive H1 agonist on lymphocytes H1 receptors. The dipeptide conjugate (compound 17) and the aliphatic congener derivative (compound 18), both with four methylenes, retained some of the activity on guinea pig myocardium H2 receptors, but lost their activity on lymphocytes H2 receptors. Therefore, histamine can be modified at sites that are at a distance from the imidazole moiety, resulting in tissue selective histamine receptor agonists.

This study investigated cytokine release by T-cell lines from atopic and nonatopic individuals in the presence of specific aeroallergen. Cell lines from atopic and nonatopic individuals secreted IL-2 for less than 14 and more than 21 days, respectively. All of the atopic, but not the nonatopic, cell lines exhibited a biphasic peak in IL-4 and IL-5 secretion. Flow cytometry revealed that, after 35 days, 89.3% of the atopic cells were T helpers and 73.2% were activated. Only 7.4% of the nonatopic cells displayed activation markers. In conclusion, T-cell differentiation may be controlled by other factors in addition to stimulation by aeroallergens.

The occurrence of cephalothin induced neutropenia in 3 patients with infective endocarditis is described. In each patient, withdrawal of cephalothin was followed by rapid haematological recovery. It is apparent that granulocytopenia may frequently occur in patients receiving prolonged, high dose, intravenous cephalothin for the treatment of bacterial endocarditis.

T-cells are sentinels of adaptive cell-mediated immune responses. T-cell activation, proliferation and differentiation involves metabolic reprogramming involving the interplay of genes, proteins and metabolites. Here, we aim to understand the metabolic pathways involved in the activation and functional differentiation of human CD4+ T-cell subsets (Th1, Th2, Th17 and iTregs). We combined genome-scale metabolic modeling, gene expression data, targeted and non-targeted lipidomics experiments, together with in vitro gene knockdown experiments and showed that human CD4+ T-cells undergo specific metabolic changes during activation and functional differentiation. In addition, we identified and confirmed the importance of ceramide and glycosphingolipid synthesis pathways in Th17 differentiation and effector functions. Finally, through in vitro gene knockdown experiments, we substantiated the requirement of serine palmitoyl transferase (SPT), a de novo sphingolipid pathway in the expression of proinflammatory cytokine (IL17A and IL17F) by Th17 cells. Our findings may provide a comprehensive resource for identifying CD4+ T-cell-specific targets for their selective manipulation under disease conditions, particularly, diseases characterized by an imbalance of Treg / Th17 cells. Our data also suggest a role for elevated levels of ceramides in conditions comorbid with these diseases, e.g., obesity and insulin resistance.

No abstract