1. ¹Laboratory for Investigative Dermatology, The Rockefeller University, New York, New York, USA
2. ²Genentech Inc., South San Francisco, California, USA

Correspondence: Dr JG Krueger, Laboratory for Investigative Dermatology, The Rockefeller University, 1230 York Avenue, NY, PO Box 178, New York 10065, USA. E-mail: jgk@rockefeller.edu

³These authors contributed equally to this work

⁴Current address: Wyeth-Research Inc., Andover, Massachusetts, USA

⁵Current address: Schering Plough Biopharma, Palo Alto, California, USA

Received 7 June 2007; Revised 1 November 2007; Accepted 27 November 2007; Published online 31 January 2008.

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.