Differential OVA-induced pulmonary inflammation and unspecific reaction in Dark Agouti (DA) rats contingent on CD26/DPPIV deficiency.

Many disease models have shown that, within the species rat, different strains are differentially susceptible to asthma-induced inflammation depending on the genetic background. Likewise, CD26/DPPIV-deficiency in asthmatic F344 rats has been shown to result in a less pronounced inflammation and in increased Treg cell influx into the lung compared to wild-types. The aim of the present study was to investigate whether the genetic background of the animals interferes with CD26/DPPIV-deficiency in a model of allergic-like inflammation, or whether the deficiency per se is the predominant regulator of the inflammation. Therefore, we hypothesised that CD26/DPPIV-deficient Dark Agouti (DA) rats also exhibit a less pronounced ovalbumin (OVA)-induced inflammation compared to wild-types. After sensitisation with OVA, Al(OH)3 and heat-killed Bordetella pertussis bacilli, animals were challenged three times with 5% aerosolized OVA at intervals of 24h, i.e., on three consecutive days. 24h after the third challenge, animals were sacrificed and examined. In both wild-type and CD26/DPPIV-deficient rat groups, asthma induction led to (1) lung inflammation, (2) significantly increased eosinophil infiltration in the BALF, (3) significantly increased IgE serum levels, (4) a significant increase of inflammatory cytokines, (5) a significant increase of different T cell populations in the lungs and in their draining lymph nodes, as well as to (6) a significantly higher number of all T lymphocyte subtypes in the blood. Thus, the degree of the OVA-induced Th2-driven pulmonary inflammation was similarly pronounced in both wild-type and CD26/DPPIV-deficient DA rats.

Effects of dipeptidyl peptidase-4 inhibition in an animal model of experimental asthma: a matter of dose, route, and time.

The CD26-associated enzymatic activity of dipeptidyl peptidase-4 (DPP4) as well as the recruitment of CD26(+) T cells increase under allergic airway inflammation. Furthermore, genetic deficiency of CD26/DPP4 exerts protective effects in experimental asthma. Therefore, CD26/DPP4 might represent a novel therapeutic target in asthma. To study the effects of pharmacological inhibition of DPP4 on allergic airway inflammation the DPP4-inhibitor isoleucine thiazolidide was tested using different doses at different time points (at sensitization, immediately before and simultaneously with the allergen challenge, as well as continuously via drinking water), and different routes (intraperitoneal, oral, and by inhalation). Allergic-like airway inflammation was induced in Fischer 344 rats (Charles River) sensitized against ovalbumin (OVA) using OVA aerosols. Intraperitoneal application of the DPP4 inhibitor showed effects neither at sensitization nor at challenge, whereas a continuous application via drinking water using high doses of the inhibitor led to an aggravation of the histomorphological signs of airway inflammation. In contrast, aerosolization of the DPP4 inhibitor simultaneously with the allergen significantly reduced airway hyperresponsiveness and ameliorated histopathological signs compared to controls. In addition, this treatment resulted in increased mRNA levels of surfactant proteins, suggesting an involvement of DPP4 inhibitors in surfactant metabolism in OVA-challenged rats. Continuous systemic inhibition of DPP4 via the oral route aggravates allergic airway inflammation. In contrast, topical inhibition of DPP4 exerts potential protective effects, and further research in humans is needed.