Adhesion Molecules Involved in Leukocyte Recruitment and Lymphocyte Recirculation

¹ The University of Michigan, Ann Arbor.

In summary, adhesion molecules on the leukocyte and endothelium initiate both lymphocyte recirculation and leukocyte recruitment. Adhesive interactions are necessary for both the arrest of circulating cells at the apical endothelial surface and the subsequent migration across the vessel wall. Chemotaxins may influence both processes through rapid up-regulation of integrin-mediated adhesion, direct effects on leukocyte orientation and enhanced leukocyte motility. Inflammatory cytokines influence multiple steps in the recruitment cascade including expression of endothelial adhesion molecules and secretion of chemotaxins from multiple cell types. Finally, the microenvironment in which lymphocytes undergo antigen-driven proliferation can influence the, trafficking pattern of resulting memory cells through changes in multiple adhesion molecules at the cell surface. The interplay of these factors determines the specficity and rate of leukocyte extravasation during both recruitment and recirculation.

Blockade of adhesion receptors involved in recruitment can limit tissue destruction in model systems of both acute and chronic inflammatory disease. However, the existence of multiple receptors capable of mediating each step in recruitment suggests that blockade of single receptors will not provide optimal anti-inflammatory therapy. Blockade of multiple adhesion receptors, inhibition of receptor synthesis or translocation, and blockade of signals leading to conversion of receptors to a high avidity state may be required. The search continues for selective recruitment pathways such as those governing lymphocyte recirculation through peripheral lymph nodes and Peyer's patches. However, the evidence to date shows more similarities than differences in the soluble mediators and adhesion receptors mediating recruitment in different tissues. In fact, receptors such as L-selectin, LFA-1, and VLA-4 may participate in both leukocyte recruitment and immune surveillance (ie, lymphocyte recirculation). Therefore, therapies targeting recruitment are likely to influence inflammatory/immune responses in both diseased and uninvolved tissues. On the other hand, agents which act directly at the level of recruitment may provide effective, broad-spectrum anti-inflammatory activity with minimal systemic toxicity. The next 5 years will tell whether the explosion in our understanding of leukocyte recruitment and lymphocyte recirculation will result in the development of novel therapeutic agents.