Antitumour necrosis factor-alpha chimeric antibody (infliximab) inhibits activation of skin-homing CD4+ and CD8+ T lymphocytes and impairs dendritic cell function.
BACKGROUND
Psoriasis is a chronic inflammatory skin disease characterized by hyperproliferation and altered differentiation of keratinocytes in reply to cytokines such as interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha, provided by infiltrating CD4+ and CD8+ T cells and natural killer cells. Infliximab is a chimeric monoclonal antibody that neutralizes both soluble and membrane-bound TNF-alpha, and that may give a long-term disease remission.


OBJECTIVE
To determine the in vitro effects of infliximab on CD4+ and CD8+ T cells derived from lesional skin, and on dendritic cells (DCs).


METHODS
Psoriatic T-cell lines were isolated from lesional skin of four patients with psoriasis and assayed for their proliferation, cytokine release and susceptibility to apoptotic stimuli in the presence of graded (1-100 microg mL(-1)) concentrations of infliximab. DCs were differentiated in the presence of infliximab from peripheral blood monocytes. Phenotype was assessed by fluorescence-activated cell sorting and antigen-presenting capacity in functional assays.


RESULTS
In vitro activation of psoriatic as well as antigen (nickel)-specific skin-homing T cells was strongly and dose-dependently impaired by infliximab, in terms both of proliferation and of IFN-gamma release. Despite the significant reduction of IFN-gamma secretion, infliximab only marginally affected the release of interleukin (IL)-10 by skin T cells, thus determining a reduction of the IFN-gamma/IL-10 ratio at the site of inflammation. The effects were maximal when T-cell activation occurred in the absence of costimulation, or when T cells were activated by immature compared with mature DCs. In addition, skin-homing CD8+ T cells were more prominently affected by infliximab compared with CD4+ T lymphocytes, both in terms of inhibition of activation and in their susceptibility to apoptosis. Finally, infliximab directly affected the differentiation of monocyte-derived DCs, by inhibiting the expression of CD1a and CD86, and strongly impaired the antigen-presenting capacity of immature and, to a lesser extent, mature DCs.


CONCLUSIONS
Infliximab directly affects psoriatic T cells and impairs the antigen-presenting capacity of DCs. These effects may help to explain the long-term disease remission obtained with the drug.
Bedini
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C
Laboratory of Immunology and Allergology, Istituto Dermopatico dell'Immacolata, IRCCS, via dei Monti di Creta 104, 00167 Rome, Italy.
Nasorri
F
F
Girolomoni
G
G
Pità
O de
Od
Cavani
A
A
D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017951:Antigen Presentation / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D000069285:Infliximab; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000032:analysis; D008213:Lymphocyte Activation / Q000187:drug effects; D011565:Psoriasis / Q000276:immunology*; D012867:Skin / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D000911:Antibodies, Monoclonal; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma; D000069285:Infliximab; D017493:Leukocyte Common Antigens