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Background/AbstractImmune responses initiated by T cell receptor (TCR) and costimulatory molecule mediated signaling culminate in maximal cytokine mRNA production and stability. The transcriptional responses to co-stimulatory T cell signalling involve calcineurin and NF-AT, which can be antagonized by interference with the cis-trans peptidyl-prolyl isomerases (PPIase), cyclophilin A and FKBP. Signalling molecules downstream of CD28 which are essential for the stabilization of cytokine mRNAs are largely unknown.Methodology/Principal FindingsWe now show that Pin1, a third member of the PPIase family mediates the post-transcriptional regulation of Th1 cytokines by activated T cells. Blockade of Pin1 by pharmacologic or genetic means greatly attenuated IFN-γ, IL-2 and CXCL-10 mRNA stability, accumulation and protein expression after cell activation. In vivo, Pin1 blockade prevented both the acute and chronic rejection of MHC mismatched, orthotopic rat lung transplants by reducing the expression of IFN-γ and CXCL-10. Combined transcriptional and post-transcriptional blockade with cyclosporine A and the Pin1 inhibitor, juglone, was synergistic.Conclusions/SignificanceThese data suggest Pin1 inhibitors should be explored for use as immunosuppressants and employed with available calcineurin inhibitors to reduce toxicity and enhance effectiveness.

Background Rat lung allograft rejection is mediated by collagen type V (col(V)) specific Th17 cells. Adoptive transfer of these cells is sufficient to induce rejection pathology in isografts, whereas tolerance to col(V) suppresses allograft rejection. We therefore tested if regulatory T cells from tolerant rats could suppress the Th17 mediated rejection in the syngeneic model of lung transplantation. Methods Rats were subjected to syngeneic left lung transplantation and acute rejection was induced by adoptive transfer of lymph node cells from col(V)-immunized rats. Tolerance was induced by intravenous (iv) injection of col(V) and spleen lymphocytes were used for adoptive transfer. CD4+ T cells were depleted using magnetic beads. Lung isografts were analyzed using micro-PET imaging and histochemistry. The transvivo delayed type hypersensitivity (TV-DTH) assay was used to analyze the Th17 response. Results Adoptive co-transfer of col(V)-specific effector cells with cells from col(V) tolerized rats suppressed severe vasculitis and bronchiolitis with parenchymal inflammation, and the expression of IL-17 transcripts in mediastinal lymph nodes induced by effector cells alone. Analysis by TV-DTH showed that the reactivity to col(V) was dependent on the presence of TNF-α and IL-17, but not IFN-γ. Depletion of CD4+ T cells from the suppressor cell population abrogated the col(V)-specific protection. Conclusion Th17 mediated acute rejection after lung transplantation is ameliorated by CD4+ col(V)-specific regulatory T cells. The mechanism for this Th17 suppression is consistent with tolerance induction to col(V). The goal of transplantation treatment therefore should target Th17 development and not suppression of T cell activation by suppressing IL-2.

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We examined whether lung inflammatory mediators are increased during exercise and whether pharmacological blockade can prevent exercise-induced arterial hypoxemia (EIAH) in young athletes. Seventeen healthy athletes (9 men, 8 women; age 23 +/- 3 yr) with varying degrees of EIAH completed maximal incremental treadmill exercise tests after administration of fexofenadine, zileuton, and nedocromil sodium or placebo in a randomized double-blind crossover study. Lung function, arterial blood gases, and inflammatory metabolites in plasma, urine, and induced sputum were assessed. Drug administration did not improve EIAH or gas exchange during exercise. At maximal exercise, oxygen saturation fell to 91.4 +/- 2.6% (drug trial) and 91.9 +/- 2.1% (placebo trial) and alveolar-arterial oxygen difference widened to 28.1 +/- 6.3 Torr (drug trial) and 29.3 +/- 5.7 Torr (placebo trial). Oxygen consumption, ventilation, and other exercise variables were similarly unaffected by drug treatment. Although plasma histamine increased with exercise, values did not differ between trials, and urinary leukotriene E(4) and 11beta-prostaglandin F(2alpha) levels were unchanged after exercise. Postexercise sputum revealed no significant changes in markers of inflammation. These results demonstrate that EIAH in young athletes is not attenuated with acute administration of drugs targeting histamine and bioactive lipids. We conclude that airway inflammation is of insufficient magnitude to cause impairments in gas exchange and does not appear to be linked to EIAH in healthy young athletes.