Targeting TNFalpha rapidly reduces density of dendritic cells and macrophages in psoriatic plaques with restoration of epidermal keratinocyte differentiation.
BACKGROUND
The cytokine network theory for psoriasis postulates a key role for TNFalpha in mediating inflammation and altered epidermal differentiation.


OBJECTIVE
This study defines responses following administration of adalimumab, a TNFalpha inhibitor, in pre-psoriatic skin (PN) and lesional psoriatic plaques (PP) skin.


METHODS
PN and PP skin before and after treatment were biopsied at days 2, 7, 28 and 84 (n=6 different patients). Cryosections were immunohistochemically stained to detect TNFalpha and other relevant markers in epidermal and dermal compartments. Detection of apoptosis utilized antibody specific for activated caspase 3. Semiquantitative assessments and statistical analysis was performed for each staining profile.


RESULTS
TNFalpha+ cells were increased in PP skin. PP skin was also characterized by a four-fold increase in number of CD68+ macrophages as well as eight-fold increase in CD11c+ dermal dendritic cells (DCs) compared to PN skin. By two-color immunofluorescence staining, both CD68+ cells as well as CD11c+ cells expressed TNFalpha. Following initiation of adalimumab therapy, CD11c+ cells, significantly decreased in PP skin at days 7, 28, and 84, while CD68+ and CD14+ cells decreased at days 28 and 84. Other markers for DCs (CD83, CD86) showed decreases at days 7, 28, and 84. Reduction in DCs, macrophages or T cells was not accompanied by increased activated caspase 3-positive cells. When a keratinocyte terminal differentiation marker was examined, adalimumab triggered rapid restoration of loricrin expression (beginning on day 2), with loss of aberrant differentiation marker, keratin 17 (K17).


CONCLUSIONS
Adalimumab impacts dermal-based immunocytes, and the epidermal compartment also responds by restoration of normal differentiation without detectable apoptosis.
Marble
Deborah J
DJ
Department of Medicine, Division of Dermatology, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL 60153, United States.
Gordon
Kenneth B
KB
Nickoloff
Brian J
BJ
D000068879:Adalimumab; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis / Q000187:drug effects; D001706:Biopsy; D002454:Cell Differentiation / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects; D004311:Double-Blind Method; D006801:Humans; D007107:Immune System / Q000187:drug effects* / Q000378:metabolism; D016130:Immunophenotyping; D015603:Keratinocytes / Q000187:drug effects* / Q000473:pathology; D008264:Macrophages / Q000187:drug effects; D011565:Psoriasis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014409:Tumor Necrosis Factor-alpha; D000068879:Adalimumab
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