Inhaled vasoactive intestinal peptide exerts immunoregulatory effects in sarcoidosis.
BACKGROUND
Previous studies suggest an important immunoregulatory role of vasoactive intestinal peptide (VIP) in experimental models of chronic noninfectious inflammation. Sarcoidosis is characterized by noncaseating epitheloid cell granulomas, where excessive tumor necrosis factor-alpha production by pulmonary macrophages plays a critical role in granuloma formation and disease progression, which may lead to fatal organ dysfunction.


OBJECTIVE
To test whether inhaled VIP has an immunoregulatory role. Sarcoid alveolitis was used as a prototype of immune-mediated chronic lung inflammation.


METHODS
In an open clinical phase II study, we treated 20 patients with histologically proved sarcoidosis and active disease with nebulized VIP for 4 weeks.


RESULTS
VIP inhalation was safe, well-tolerated, and significantly reduced the production of tumor necrosis factor-alpha by cells isolated from bronchoalveolar lavage fluids of these patients. VIP treatment significantly increased the numbers of bronchoalveolar lavage CD4(+)CD127(-)CD25(+) T cells, which showed regulatory activities on conventional effector T cells. In vitro experiments demonstrated the capacity of VIP to convert naive CD4(+)CD25(-) T cells into CD4(+)CD25(+)FoxP3(+) regulatory T cells, suggesting the generation of peripheral regulatory T cells by VIP treatment.


CONCLUSIONS
This study is the first to show the immunoregulatory effect of VIP in humans, and supports the notion of inhaled VIP as an attractive future therapy to dampen exaggerated immune responses in lung disorders. Thus, the inhalation of neuropeptides may be developed into a new therapeutic principle for chronic inflammatory lung disorders in humans.
Prasse
Antje
A
Department of Pneumology, University Hospital, Freiburg, Germany. antje.prasse@uniklinik-freiburg.de
Zissel
Gernot
G
Lützen
Niklas
N
Schupp
Jonas
J
Schmiedlin
Rene
R
Gonzalez-Rey
Elena
E
Rensing-Ehl
Anne
A
Bacher
Gerald
G
Cavalli
Vera
V
Bevec
Dorian
D
Delgado
Mario
M
Müller-Quernheim
Joachim
J
D000280:Administration, Inhalation; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D017565:Sarcoidosis, Pulmonary / Q000188:drug therapy* / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000276:immunology; D014660:Vasoactive Intestinal Peptide / Q000276:immunology* / Q000494:pharmacology* / Q000627:therapeutic use; D014665:Vasodilator Agents / Q000276:immunology* / Q000494:pharmacology* / Q000627:therapeutic use
D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; D014660:Vasoactive Intestinal Peptide