Blockade of CD11a by efalizumab in psoriasis patients induces a unique state of T-cell hyporesponsiveness.
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.
Guttman-Yassky
Emma
E
Laboratory for Investigative Dermatology, The Rockefeller University, New York, New York 10065, USA.
Vugmeyster
Yulia
Y
Lowes
Michelle A
MA
Chamian
Francesca
F
Kikuchi
Toyoko
T
Kagen
Mark
M
Gilleaudeau
Patricia
P
Lee
Edmund
E
Hunte
Brisdell
B
Howell
Kathy
K
Dummer
Wolfgang
W
Bodary
Sarah C
SC
Krueger
James G
JG
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
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