A novel low molecular weight inhibitor of dendritic cells and B cells blocks allergic inflammation.
OBJECTIVE
During allergic lung inflammation dendritic cells (DCs) direct the generation and function of effector T-helper type 2 cells. T-helper type 2 cells not only orchestrate the inflammatory processes in the tissue by inducing the accumulation and activation of proinflammatory cells but also induce IgE production by B cells. Thus, inhibitors of DC function should have therapeutic benefits in patients with allergies.


METHODS
VAF347, a novel low molecular weight immunomodulator, is described and acts as an antiinflammatory compound by a dual mode of action.


RESULTS
VAF347 inhibited the function of human monocyte-derived DCs to induce T-cell proliferation and cytokine production. Mechanistically, this effect may be due to reduced expression of CD86, HLA-DR, and interleukin 6 by DCs. In addition, the compound inhibited IgE synthesis in an isotype-specific fashion by human B lymphocytes. In a mouse model of antigen-induced eosinophilic inflammation, VAF347 blocked lung eosinophilia, mucus hyperplasia, and serum IgE levels, representing the hallmarks of allergic lung inflammation. The biological effects in vivo are most likely mediated by the immunoregulatory role of VAF347 on DCs because allergic lung inflammation was also inhibited in B-cell-deficient mice.


CONCLUSIONS
VAF347 represents a novel type of immunomodulator by affecting two major pathways in allergic airway pathogenesis: dendritic cell-mediated T-helper-cell activation and induction of IgE production by human B lymphocytes.
Ettmayer
Peter
P
Novartis Institutes for Biomedical Research Vienna, Brunnerstrasse 59, A-1230 Vienna, Austria.
Mayer
Peter
P
Kalthoff
Frank
F
Neruda
Wolfgang
W
Harrer
Nathalie
N
Hartmann
Gabriella
G
Epstein
Michelle M
MM
Brinkmann
Volker
V
Heusser
Christoph
C
Woisetschläger
Maximilian
M
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D051940:B7-2 Antigen / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D004195:Disease Models, Animal; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis / Q000187:drug effects; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D011743:Pyrimidines / Q000494:pharmacology*; D012130:Respiratory Hypersensitivity / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D051940:B7-2 Antigen; D006684:HLA-DR Antigens; D015850:Interleukin-6; D011743:Pyrimidines; C509596:VAF347; D007073:Immunoglobulin E