TY - JOUR
T1 - Blockade of CD11a by efalizumab in psoriasis patients induces a unique state of T-cell hyporesponsiveness
AU - Guttman-Yassky, Emma
AU - Vugmeyster, Yulia
AU - Lowes, Michelle A.
AU - Chamian, Francesca
AU - Kikuchi, Toyoko
AU - Kagen, Mark
AU - Gilleaudeau, Patricia
AU - Lee, Edmund
AU - Hunte, Brisdell
AU - Howell, Kathy
AU - Dummer, Wolfgang
AU - Bodary, Sarah C.
AU - Krueger, James G.
N1 - Funding Information:
This research was supported in part by a General Clinical Research Center grant (M01-RR00102) from the National Center for Research Resources at the National Institutes of Health. JGK is supported by the following National Institutes of Health (NIH) grants: R01 AI-49572 and AI-49832. MAL is the recipient of the NIH/NIAMS grant K23 AR052404-01A1.
PY - 2008/5
Y1 - 2008/5
N2 - 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.
AB - 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.
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U2 - 10.1038/jid.2008.4
DO - 10.1038/jid.2008.4
M3 - Article
C2 - 18239614
AN - SCOPUS:42149156689
SN - 0022-202X
VL - 128
SP - 1182
EP - 1191
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 5
ER -