Programmed cell death of keratinocytes in infliximab-treated plaque-type psoriasis.
BACKGROUND
Tumour necrosis factor (TNF)-alpha blockade using infliximab, a chimeric anti-TNF-alpha antibody, is an effective treatment for plaque-type psoriasis, inducing remission in about 80% of patients.


OBJECTIVE
To examine infliximab-induced programmed cell death (PCD) of keratinocytes in psoriatic plaques on serial skin biopsy samples.


METHODS
Five patients with moderate to severe plaque-type psoriasis received infliximab infusions intravenously (5 mg kg(-1)) at weeks 0, 2 and 6. Biopsies of nonlesional and lesional skin (days 0, 5, 14 and 21) were obtained. Conventional microscopy was used to examine the morphology of the psoriatic keratinocytes. In situ detection of apoptosis was performed by electron microscopy and by immunohistochemical staining with anti-p53 and anti-caspase-3 antibodies. Results Infusion of infliximab induced a clinical response in all five patients with psoriasis, with a mean Psoriasis Area and Severity Index improvement of 24.8% already at day 5. This was accompanied by significant histopathological changes in the skin biopsy samples after infliximab treatment. Light and electron microscopic evaluation revealed apoptosis-like morphological changes in lesional keratinocytes, i.e. nuclear condensation, chromatin fragmentation and cytoplasmic vesiculation, visible already after the first infusion. These damaged keratinocytes stained positively for p53, but not for active caspase-3.


CONCLUSIONS
The effects of infliximab in psoriasis extend beyond merely anti-inflammatory actions, and may include caspase-independent PCD of lesional keratinocytes. The PCD of keratinocytes may be an important mechanism that could explain at least in part the rapid and sustained therapeutic effect of infliximab in psoriasis.
Krüger-Krasagakis
S
S
Department of Biology, University Hospital of Heraklion, University of Crete, Greece. krkras@med.uoc.gr
Galanopoulos
V K
VK
Giannikaki
L
L
Stefanidou
M
M
Tosca
A D
AD
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001706:Biopsy; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003879:Dermatologic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007124:Immunoenzyme Techniques; D000069285:Infliximab; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008854:Microscopy, Electron; D008875:Middle Aged; D011565:Psoriasis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D012720:Severity of Illness Index; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000911:Antibodies, Monoclonal; D003879:Dermatologic Agents; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D000069285:Infliximab; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases