41.3T Cell Targeted Therapies

Adhesion molecules participate in many stages of the immune response, regulating leukocyte circulation, lymphoid cell homing to tissues and inflammatory sites, migration across endothelial cells, and T cell stimulation. During the T cell immune response, adhesion molecules form a specialized junction between the T cell and the antigen-presenting cell. For this reason, in the search for new therapeutic agents, many researchers have focused their attention on targeting adhesion molecules. Most of these efforts are intended to develop drugs for autoimmune diseases. Therapeutic agents such as efalizumab and alefacept have been approved by the FDA for the treatment of some inflammatory autoimmune diseases such as psoriasis [32].

After the initiation of the autoimmune process in primary SS, autoantigens are expressed on the surface of epithelial cells, with T lymphocytes migrating to exocrine tissue and being activated in situ and B cells producing autoantibodies locally [33]. Several studies have recently analyzed the role of T cell dysfunction in the pathogenesis of primary SS.

41.3.1Efalizumab

Efalizumab (Raptiva®) is a humanized monoclonal antibody that targets the CD11a component of leukocyte function–associated antigen-1 (LFA-1), preventing its binding to intercellular adhesion molecules. Blocking this interaction results in interference with T cell activation and reactivation, inhibition of leukocyte extravasation, and adherence to keratinocytes in psoriatic epidermis. Some studies have suggested a potential role for LFA-1 in controlling the migration of lymphocytes to exocrine glands in SS [34, 35], with the implication that efalizumab might be a treatment strategy worth testing.

Efalizumab was approved by the FDA and EMEA for the treatment of psoriasis [36]. Unfortunately, it has recently been withdrawn after 5 years of use because of three cases of progressive multifocal leukoencephalopathy [37]. An ongoing phase II study sponsored by the National Institute of Dental and Craniofacial Research, which had been recruiting patients since 2006, had to be suspended.

41.3.2Alefacept

Alefacept (Amevive®) is a selective immunomodulating drug that blocks the LFA–3/ CD2 interaction necessary for the activation and proliferation of memory effector T cells by binding to the CD2 expressed on the T cell surface. Among biological agents, alefacept has demonstrated the longest remission in psoriasis [38], and appears to be well tolerated, even with long-term use. Alefacept was approved by the FDA in January 2003 for the treatment of chronic plaque psoriasis [39]. However, the primary concern with alefacept is T lymphocyte depletion. Because the CD4+ count is reduced