Peptide immunotherapy in allergic asthma generates IL-10-dependent immunological tolerance associated with linked epitope suppression.

Treatment of patients with allergic asthma using low doses of peptides containing T cell epitopes from Fel d 1, the major cat allergen, reduces allergic sensitization and improves surrogate markers of disease. Here, we demonstrate a key immunological mechanism, linked epitope suppression, associated with this therapeutic effect. Treatment with selected epitopes from a single allergen resulted in suppression of responses to other ("linked") epitopes within the same molecule. This phenomenon was induced after peptide immunotherapy in human asthmatic subjects and in a novel HLA-DR1 transgenic mouse model of asthma. Tracking of allergen-specific T cells using DR1 tetramers determined that suppression was associated with the induction of interleukin (IL)-10(+) T cells that were more abundant than T cells specific for the single-treatment peptide and was reversed by anti-IL-10 receptor administration. Resolution of airway pathophysiology in this model was associated with reduced recruitment, proliferation, and effector function of allergen-specific Th2 cells. Our results provide, for the first time, in vivo evidence of linked epitope suppression and IL-10 induction in both human allergic disease and a mouse model designed to closely mimic peptide therapy in humans.

Rapidly progressive Bronchiolitis Obliterans Organising Pneumonia presenting with pneumothorax, persistent air leak, acute respiratory distress syndrome and multi-organ dysfunction: a case report.

INTRODUCTION: Bronchiolitis Obliterans Organising Pneumonia (BOOP) may often present initially as a recurrent spontaneous pneumothorax and then develop multi-system complications. CASE PRESENTATION: A 17-year-old boy presented with a pneumothorax, which developed into rapidly progressive Bronchiolitis Obliterans Organising Pneumonia (BOOP). He developed multi-organ dysfunction (including adult respiratory distress syndrome, oliguric renal failure, acute coronary syndrome, cardiac failure and a right atrial thrombus) which necessitated prolonged intensive care. Diagnosis was confirmed on open lung biopsy and he responded well to treatment with corticosteroids. CONCLUSION: BOOP is exquisitely sensitive to oral corticosteroids but if the diagnosis is not considered in such patients and appropriate treatment instituted early, BOOP may often lead to prolonged hospital admission with considerable morbidity.

Development of respiratory control instability in heart failure: a novel approach to dissect the pathophysiological mechanisms.

Observational data suggest that periodic breathing is more common in subjects with low F(ETCO(2)), high apnoeic thresholds or high chemoreflex sensitivity. It is, however, difficult to determine the individual effect of each variable because they are intrinsically related. To distinguish the effect of isolated changes in chemoreflex sensitivity, mean F(ETCO(2)) and apnoeic threshold, we employed a modelling approach to break their obligatory in vivo interrelationship. We found that a change in mean CO(2) fraction from 0.035 to 0.045 increased loop gain by 70 +/- 0.083% (P < 0.0001), irrespective of chemoreflex gain or apnoea threshold. A 100% increase in the chemoreflex gain (from 800 l min(-1) (fraction CO(2))(-1)) resulted in an increase in loop gain of 275 +/- 6% (P < 0.0001) across a wide range of values of steady state CO(2) and apnoea thresholds. Increasing the apnoea threshold F(ETCO(2)) from 0.02 to 0.03 had no effect on system stability. Therefore, of the three variables the only two destabilizing factors were high gain and high mean CO(2); the apnoea threshold did not independently influence system stability. Although our results support the idea that high chemoreflex gain destabilizes ventilatory control, there are two additional potentially controversial findings. First, it is high (rather than low) mean CO(2) that favours instability. Second, high apnoea threshold itself does not create instability. Clinically the apnoea threshold appears important only because of its associations with the true determinants of stability: chemoreflex gain and mean CO(2).

Late asthmatic reactions induced by inhalation of allergen-derived T cell peptides.

In individuals with atopy and asthma, allergen-derived T cell peptides injected intradermally induce isolated late asthmatic reactions (LARs) followed by bronchial hyporesponsiveness to peptide, inhibition of the allergen-induced cutaneous late-phase reaction, and altered T cell function in vitro. Laboratory animal data indicate that "activation" and "tolerance" also occur if peptides are inhaled. In this study, we show that inhalation of Fel d 1-derived peptides induced isolated LAR in individuals with asthma sensitive to cat allergen comparable with that previously demonstrated using intradermal injection. LARs were accompanied by eosinophilia and nonsignificant elevations of total cysteinyl leukotrienes in the sputum. Unlike the intradermal route, repeated inhalation of peptides was not associated with abrogation of the LAR and produced a sputum eosinophilia comparable with the first exposure. In addition, there was no inhibition of the cutaneous late-phase reaction to whole cat dander. Thus, isolated LAR induced by inhaled, allergen-derived peptides represent a novel model of provoked asthma and are not associated with the induction of hyporesponsiveness ("tolerance") in the skin or lung.