Interleukin-11 therapy selectively downregulates type I cytokine proinflammatory pathways in psoriasis lesions.
Psoriasis is a chronic inflammatory skin disease in which epidermal hyperplasia results from skin infiltration by type I T lymphocytes and release of associated cytokines. A multifunctional cytokine, rhIL-11, modulates macrophage and type I T-lymphocyte function in cell culture and shows anti-inflammatory activity in animal models. We are testing subcutaneous delivery of rhIL-11 to patients with psoriasis in a phase 1 open-label dose-escalation clinical trial. Tissue was obtained from lesional and uninvolved skin before and during treatment with rhIL-11 and was examined by histology/immunohistochemistry and quantitative RT-PCR. Expression of over 35 genes was examined in all patients, and multiple genetic markers of psoriasis were identified. Expression of numerous proinflammatory genes was elevated in psoriatic tissue compared with nonlesional skin. Seven of 12 patients responded well to rhIL-11 treatment. Amelioration of disease by rhIL-11, as shown by reduced keratinocyte proliferation and cutaneous inflammation, was associated with decreased expression of products of disease-related genes, including K16, iNOS, IFN-gamma, IL-8, IL-12, TNF-alpha, IL-1beta, and CD8, and with increased expression of endogenous IL-11. We believe that this is the first study in humans to indicate that type I cytokines can be selectively suppressed by an exogenous immune-modifying therapy. The study highlights the utility of pharmacogenomic monitoring to track patient responsiveness and to elucidate anti-inflammatory mechanisms.
Trepicchio
W L
WL
Department of Molecular Medicine, Genetics Institute, Cambridge, Massachusetts 01810, USA.
Ozawa
M
M
Walters
I B
IB
Kikuchi
T
T
Gilleaudeau
P
P
Bliss
J L
JL
Schwertschlag
U
U
Dorner
A J
AJ
Krueger
J G
JG
D000954:Antigens, Surface / Q000032:analysis; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000187:drug effects; D005819:Genetic Markers; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D007279:Injections, Subcutaneous; D017370:Interleukin-11 / Q000627:therapeutic use*; D015603:Keratinocytes / Q000187:drug effects; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology; D011565:Psoriasis / Q000188:drug therapy* / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000187:drug effects / Q000473:pathology; D013997:Time Factors
D000954:Antigens, Surface; D016207:Cytokines; D005819:Genetic Markers; D017370:Interleukin-11; D012333:RNA, Messenger; D011994:Recombinant Proteins