Immunotherapy of spontaneous type 1 diabetes in nonobese diabetic mice by systemic interleukin-4 treatment employing adenovirus vector-mediated gene transfer.

We have previously shown that systemic injection of multiple low doses of recombinant murine interleukin-4 (mIL-4) can prevent type 1 diabetes (T1D) in nonobese diabetic (NOD) mice by activating regulatory T helper (Th) 2 cells in vivo. Here, we have developed a gene transfer approach to the prevention of T1D by testing the therapeutic potential of an adenovirus gene transfer vector engineered to express mIL-4. We found that only two systemic injections of a recombinant adenovirus type 5 vector-expressing mIL-4 (Ad5mIL-4) reduces destructive insulitis and protects NOD mice from the onset of diabetes by eliciting intrapancreatic Th2 cell responses. Host immune responses against the adenovirus vector were detectable; however, the levels of antibody production were insufficient to preclude Ad5mIL-4 treatment as a possible therapeutic agent against T1D. Thus, adenovirus-mediated delivery of IL-4 provides protection of NOD mice from T1D and represents a clinically viable therapeutic approach.

Adverse drug reactions from birth to early childhood.

Neonates and older infants are a diverse group of children, quite different from their older counterparts. Adverse drug reactions may have profound immediate, delayed, and long-term implications for their neurologic and somatic development. The intrauterine, neonatal, and infancy periods are the only stages in life in which one is exposed to and affected by drugs administered to another person, the mother. In addition, because of the fragility of the neonate and the complexity of their illnesses, their pharmacotherapy is frequently complicated with misadventure and adverse drug reactions that are unavoidable or difficult to assess. Because of their differences in morphology and disease process and treatments, infants and children experience a different range of adverse drug reactions. These reactions are not necessarily predictable from the adult experience. Despite the advances made in the field of pediatric adverse drug reactions and the lessons learned through the misfortunes involving children, children continue to suffer. Sixty years after the Elixir of Sulfanilamide-Massengill disaster, children continue to be given medications with diethylene glycol in developing countries. Pediatricians, pharmacologists, and others must continue to be vigilant and active in preventing, monitoring, and treating adverse drug reactions in children. Learning from mistakes of the past will improve the health of children by preventing mistakes in the future.

Antibodies to myeloperoxidase in propylthiouracil-induced autoimmune disease in the cat.

Cats are known to develop a lupus-like syndrome similar to that observed in humans when treated with propylthiouracil. We have previously demonstrated that propylthiouracil and other drugs associated with lupus are oxidized in the presence of myeloperoxidase to reactive intermediates. We postulated that these reactive metabolites could modify myeloperoxidase resulting in anti-myeloperoxidase antibodies and possibly be responsible for the lupus-like syndrome. Five cats were treated with propylthiouracil and 2 developed the lupus-like syndrome as well as anti-myeloperoxidase antibodies. These appeared to correlate better with disease than antinuclear antibodies. The antibodies were true autoantibodies because the myeloperoxidase used to detect the antibodies did not require treatment with propylthiouracil. In a subsequent study in which the cat food contained a higher level of taurine, none of the animals developed the autoimmune syndrome. It is possible that diet also plays an important role in the development of such adverse reactions.

Oxidation of propylthiouracil to reactive metabolites by activated neutrophils. Implications for agranulocytosis.

Propylthiouracil (PTU) is associated with idiosyncratic agranulocytosis that may be due to reactive metabolites generated from oxidative metabolism by neutrophils. Therefore, the metabolism of PTU was investigated in activated neutrophils. Three oxidized metabolites were observed on HPLC: PTU-disulfide, propyluracil-2-sulfinate, and propyluracil-2-sulfonate (PTU-SO3-). No metabolism was detected in cells that had not been activated. Metabolism was inhibited by sodium azide and by catalase. The same products were produced by myeloperoxidase (MPO) in an MPO/H2O2/Cl- system. PTU inhibited its own metabolism; however, complete conversion to PTU-SO3- could be achieved with optimal PTU concentrations. MPO/H2O2 without Cl- produced only slight metabolism. The PTU-sulfenyl chloride is a postulated intermediate. In the absence of chloride, oxidation might proceed through propyluracil-2-sulfenic acid. The sulfenyl chloride and PTU-SO3- are both chemically reactive with sulfhydryl compounds such as N-acetylcysteine. Such reactive metabolites, generated by activated neutrophils, may be involved in hypersensitivity reactions associated with PTU, such as agranulocytosis.