Modulation of IFN-gamma-induced immunogenicity by phosphatidylethanolamine-linked hyaluronic acid.
BACKGROUND
The present study was conducted to examine the possibility of modulating interferon (IFN-gamma)-induced immunogenicity by a novel compound that is composed of a PLA2 inhibitor linked to hyaluronic acid (HYPE).


METHODS
HYPE was tested for its effect on IFN-gamma-induced expression of MHC class I, class II, and intercellular adhesion molecule (ICAM-1) in cultured endothelial and renal proximal tubular cells by flow cytometric analysis (FACS) as well as its ability to influence T cell activation in mixed lymphocyte reaction (MLR) or after mitogen stimulation.


RESULTS
In FACS, a profound inhibition in MHC class I and ICAM-1 staining was observed in stimulated or unstimulated cells that were incubated with HYPE. This was not due to down-regulation of antigen expression and only occurred when monoclonal antibodies, but not when polyclonal antibodies, were used. HYPE inhibited the induction of MHC class II in both cell types after IFN-gamma stimulation in a dose-dependent manner. Moreover, the induction of class II transactivator (CIITA) was completely inhibited under these conditions, most likely because it blocked the binding of IFN-gamma to the cell membrane. Addition of HYPE to MLR inhibited the proliferation of T cells and the secretion of interleukin (IL)-2, IFN-gamma, and IL-10. This was not observed when HYPE was added together with anti-CD3 or phytohemagglutinin (PHA).


CONCLUSIONS
Our study provides experimental evidence that HYPE has immunosuppressive features. This makes the compound an interesting candidate as an immunosuppressive drug, not only in organ transplantation, but also in diseases where IFN-gamma is overexpressed.
Yard
Benito A
BA
V. Medizinische Klinik, Klinikum Mannheim, University of Heidelberg, Germany.
Yedgar
Saul
S
Scheele
Martin
M
van der Woude
Diane
D
Beck
Grietje
G
Heidrich
Bärbel
B
Krimsky
Miron
M
van der Woude
Fokko J
FJ
Post
Stefan
S
D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology; D006801:Humans; D006820:Hyaluronic Acid / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects / Q000235:genetics; D007371:Interferon-gamma / Q000276:immunology* / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000276:immunology*; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008285:Major Histocompatibility Complex / Q000187:drug effects; D010714:Phosphatidylethanolamines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D019459:Urothelium / Q000187:drug effects / Q000276:immunology
D016895:Culture Media, Serum-Free; D010714:Phosphatidylethanolamines; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma; D006820:Hyaluronic Acid