title: Blockade of CD11a by efalizumab in psoriasis patients induces a unique state of T-cell hyporesponsiveness.
abstract: Efalizumab (anti-CD11a) interferes with LFA-1/ICAM-1 binding and inhibits several key steps in psoriasis pathogenesis. This study characterizes the effects of efalizumab on T-cell activation responses and expression of surface markers on human circulating psoriatic T cells during a therapeutic trial. Our data suggest that efalizumab may induce a unique type of T-cell hyporesponsiveness, directly induced by LFA-1 binding, which is distinct from conventional anergy described in animal models. Direct activation of T cells through different activating receptors (CD2, CD3, CD3/28) is reduced, despite T cells being fully viable. This hyporesponsiveness was spontaneously reversible after withdrawal of the drug, and by IL-2 in vitro. In contrast to the state of anergy, Ca(+2) release is intact during efalizumab binding. Furthermore, lymphocyte function-associated antigen-1 (LFA-1) blockade resulted in an unexpected downregulation of a broad range of surface molecules, including the T-cell receptor complex, co-stimulatory molecules, and integrins unrelated to LFA-1, both in the peripheral circulation and in diseased skin tissue. These observations provide evidence for the mechanism of action of efalizumab. The nature of this T-cell hyporesponsiveness suggests that T-cell responses may be reduced during efalizumab therapy, but are reversible after ceasing efalizumab treatment.
authors.affiliation: Laboratory for Investigative Dermatology, The Rockefeller University, New York, New York 10065, USA.
authors.forename: Emma
authors.initials: E
authors.lastname: Guttman-Yassky
authors.forename: Yulia
authors.initials: Y
authors.lastname: Vugmeyster
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Lowes
authors.forename: Francesca
authors.initials: F
authors.lastname: Chamian
authors.forename: Toyoko
authors.initials: T
authors.lastname: Kikuchi
authors.forename: Mark
authors.initials: M
authors.lastname: Kagen
authors.forename: Patricia
authors.initials: P
authors.lastname: Gilleaudeau
authors.forename: Edmund
authors.initials: E
authors.lastname: Lee
authors.forename: Brisdell
authors.initials: B
authors.lastname: Hunte
authors.forename: Kathy
authors.initials: K
authors.lastname: Howell
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dummer
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Bodary
authors.forename: James G
authors.initials: JG
authors.lastname: Krueger
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D040881:CD11a Antigen / Q000276:immunology*; D018801:CD2 Antigens / Q000378:metabolism; D018106:CD28 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D005260:Female; D006801:Humans; D039041:Integrin alpha4beta1 / Q000378:metabolism; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011565:Psoriasis / Q000188:drug therapy* / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D040881:CD11a Antigen; D018801:CD2 Antigens; D018106:CD28 Antigens; D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D039041:Integrin alpha4beta1; D007376:Interleukin-2; D016169:Lymphocyte Function-Associated Antigen-1; D011948:Receptors, Antigen, T-Cell; C472181:efalizumab