Delivery of granulocyte-macrophage colony-stimulating factor in bioadhesive hydrogel stimulates migration of dendritic cells in models of human papillomavirus-associated (pre)neoplastic epithelial lesions.
Because of the central role of dendritic cells and/or Langerhans cells(DC/LC) in the induction of cellular immune responses, pharmacological agents that modulate the recruitment of these cells might have a clinical interest. The present study was designed to evaluate the capacity of several pharmaceutical formulations to topically deliver granulocyte-macrophage colony-stimulating factor (GM-CSF) on human papillomavirus (HPV)-associated genital (pre)neoplastic lesions. The formulations were evaluated for their bioactivity and for their potential to recruit DC in organotypic cultures of HPV-transformed keratinocytes. We found that a bioadhesive polycarbophil gel (Noveon) at pH 5.5 is able to maintain the bioactivity of GM-CSF at 4 or 37 degrees C for at least 7 days, whereas a decreased activity of GM-CSF was observed when the molecule is included in other polymer gels. GM-CSF incorporated in the polycarbophil gel was also a potent factor in enhancing the colonization of DC into organotypic cultures of HPV-transformed keratinocytes since the infiltration of DC in the in vitro-formed (pre)neoplastic epithelium was very low under basal conditions and dramatically increased in the presence of GM-CSF gel. We next demonstrated that GM-CSF incorporated in polycarbophil gel induces the recruitment of human DC in a human (pre)neoplastic epithelium grafted into NOD/SCID mice. The efficacy of GM-CSF in this formulation was equivalent to that observed with liquid GM-CSF. These results suggest that GM-CSF incorporated in polycarbophil gel could play an important role in the recruitment of DC/LC in mucosal surfaces and be useful as a new immunotherapeutic approach for genital HPV-associated (pre)neoplastic lesions.
Hubert
Pascale
P
Department of Pathology B35, CHU Sart Tilman, 4000 Liege, Belgium. P.Hubert@ulg.ac.be
Evrard
Brigitte
B
Maillard
Catherine
C
Franzen-Detrooz
Elizabeth
E
Delattre
Luc
L
Foidart
Jean-Michel
JM
Noël
Agnes
A
Boniver
Jacques
J
Delvenne
Philippe
P
D000180:Acrylic Resins; D000269:Adhesives; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects*; D004848:Epithelium / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D005456:Fluorescent Dyes; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage* / Q000494:pharmacology*; D006801:Humans; D020100:Hydrogels; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009924:Organ Culture Techniques; D027383:Papillomaviridae; D030361:Papillomavirus Infections / Q000473:pathology*; D011230:Precancerous Conditions / Q000473:pathology*
D000180:Acrylic Resins; D000269:Adhesives; D005456:Fluorescent Dyes; D020100:Hydrogels; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C030312:calcium polycarbophil