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Purpose: As previous data had shown that only two-thirds of patients had the predicted activity time courses when PEG-asparaginase 1000 U/m2 was used in reinduction after native E. coli asparaginase in induction treatment of acute lymphoblastic leukaemia (ALL), drug monitoring was performed with the use of a higher dose. Methods: Because one-third of patients had insufficient serum asparaginase activity time courses after a single dose of 1000 U/m2 PEG-asparaginase during reinduction treatment, a dose of 2500 U/m2 PEG-asparaginase, which is the approved dosage in Germany, was used in 39 reinduction and 20 relapse patients to determine whether prolongation of the activity time course may be possible with this higher dose, and to look for significant differences between reinduction and relapse patients. Results: After 1, 2 and 3 weeks, the mean activities were 1113±699 U/l, 231±259 U/l, and 13±35 U/l in the reinduction patients, and 1078±649 U/l, 165±195 U/l and 19±28 U/l in the relapse patients, respectively. There were a considerable number of patients with a substantially shortened activity time course in both groups. In 10 of 39 reinduction patients and in 7 of 24 doses during relapse treatment, only activities

Hypersensitivity reactions are relevant adverse effects of asparaginase therapy. Therefore, children treated with native Escherichia coli asparaginase in induction therapy of acute lymphoblastic leukaemia (ALL) or non-Hodgkin's lymphoma (NHL) were switched to the pegylated enzyme for reinduction under drug monitoring. Seventy children, including four patients with allergic reactions during induction, were given one dose of Oncaspar 1,000 U/m2 intravenously. Activity was determined every third or fourth day until it dropped below the limit of quantification. In current reinduction protocols [ALL/NHL-Berlin-Frankfurt-Munster (BFM) 95 trials], four doses of 10,000 U/m2 E. coli asparaginase deplete asparagine for about 2-3 weeks, therefore activities of >/= 100 U/l up to day 14 and >/= 50 U/l up to day 21 were targeted. In 66 patients without an allergic reaction during induction, the mean activity was 606 +/- 313 U/l, 232 +/- 211 U/l and 44 +/- 50 U/l after 1, 2 and 3 weeks respectively. In 44/66 patients, activity was >/= 100 U/l after 14 d. A rapid decline in activity was seen in the remaining 22 patients, including 8/22 patients who showed no activity after 1 week. Toxicity was low and comparable to the native enzymes but, in contrast to about 30% of hypersensitivity reactions with conventional reinduction therapy, no allergic reaction was seen. Substituting 4 x 10,000 U/m2 asparaginase medac for one dose of 1,000 U/m2 Oncaspar was safe and well tolerated. Comparable pharmacokinetic treatment intensity was achieved in about two-thirds of patients.

SJL mice have been extensively characterized as "low-responder" animals in terms of IgE-dependent immediate-type hypersensitivity responses. Since these mice are genetically deficient in certain TCR Vbeta gene segments, we asked whether this might be the reason for the "low-responder" status. Specifically in H-2d mice the TCR-Vbeta8.2 gene element has been shown to play an important role in Th2 immune responses to ovalbumin (OVA). Utilizing a TCR Vbeta8. 2-transgenic SJL (SJL Vbeta8+/+) mouse, we examined whether the H-2s -bearing "low-responder" mouse could be converted into a "high-responder" animal. Remarkably, non-sensitized SJL Vbeta8+/+ mice demonstrated strongly elevated levels of total IgE antibody. Mitogen-stimulated T cells from these mice released high amounts of IL-4 as compared to SJL wild-type (wt) mice. In addition, sensitization to OVA via the airways resulted in the development of increased airway responsiveness in SJL Vbeta8+/+ mice, but not in SJL wt animals. The results indicate that the capacity to produce IgE and IL-4 and to develop increased airway responsiveness can be restored in SJL wt mice by introducing the Vbeta8.2 gene segment into the TCR repertoire.

Bronchial asthma (BA) develops on the basis of a genetic predisposition and involves a characteristic sequence of changes in immune functions. In the immunopathogenesis, several phases can be distinguished: the initial stage is defined as the development of allergic sensitization. This step is dependent on: (i) T cell activation; (ii) IL-4 production; (iii) IgE synthesis; and (iv) mediator release by effector cells. The second phase of allergic inflammation as a consequence of the T cell dependent sensitization is characterized by IL-5 production and eosinophil activation and recruitment. Airway mucosa remodelling is the consequence of chronic inflammatory processes and represents the final stage of BA. In this article animal models will be discussed with regard to their relevance for these different phases in development of chronic allergic BA.