"Accomodated" pig endothelial cells promote nitric oxide-dependent Th-2 cytokine responses from human T cells.
BACKGROUND
Cardiac and renal allo- and xenografts can become naturally resistant to vascular rejection. Understanding this process of "accommodation" would enhance our understanding of vascular inflammatory responses and have implications for immune manipulation and tolerance induction. A feature of these grafts is infiltration by leukocytes secreting a Th-2 pattern of cytokines.


METHODS
HLA-DR-1-transfected, immortalized porcine endothelial cells (IPEC) were incubated with polyclonal human immunoglobulin G (IgG) for 6 days before incubation with purified human CD4+ T cells.


RESULTS
IgG-incubated IPEC stimulated a normal proliferative response from alloreactive T cells. However, interferon (IFN)-gamma levels were significantly reduced, whereas interleukin (IL)-5 and IL-10 were maintained at levels equivalent to those stimulated by control IPEC. Cognate interaction between T cells and IPEC was not required for this effect, because IgG-incubated, MHC-class II-negative IPEC caused reduced IFN-gamma secretion during a response to human Epstein-Barr virus-transformed B cells. Experiments with the nitric oxide (NO) donor, (z)-1-2-[2-Aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NO), and the NO synthase inhibitor, NG-monomethyl-L-arginine.monoacetate (L-NMMA), showed that NO released by the IgG-incubated IPEC was actively involved in the development of this phenotype.


CONCLUSIONS
These data suggest a novel, IgG-mediated, NO-dependent mechanism by which endothelial cells (EC) influence T cell responsiveness and that the Th-2 cytokine skewing seen in "accommodated" grafts may be a secondary phenomenon, resulting from the T-EC interactions.
Dorling
A
A
Department of Immunology, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN United Kingdom. a.dorling@ic.ac.uk
Jordan
W
W
Brookes
P
P
Delikouras
A
A
Lechler
R I
RI
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D006801:Humans; D007074:Immunoglobulin G / Q000502:physiology; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D015848:Interleukin-5 / Q000096:biosynthesis; D009569:Nitric Oxide / Q000502:physiology*; D013552:Swine; D013601:T-Lymphocytes / Q000276:immunology*
D016207:Cytokines; D007074:Immunoglobulin G; D015848:Interleukin-5; D016753:Interleukin-10; D009569:Nitric Oxide; D007371:Interferon-gamma