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CHaPTEr 11 Lymphocyte Adhesion and Trafficking 179

form of LAD-1 (<10% of normal β 2 integrins) demonstrate as L-selectin, PSGL-1, and E- and P-selectins, fails to yield a
impairment in leukocyte migration and suffer from frequent consistent effect on EAE. It should also be noted that although
infections as well, but they usually survive until adulthood. In α 4 β 1 integrin is very important for lymphocyte homing to brain,
these patients, lymphocyte migration to inflammatory sites is it is not a brain-specific destination. It is also involved in leukocyte
close to normal, probably because lymphocytes can utilize the trafficking to other organs, such as the pancreas and the gut.
VLA-4–VCAM-1 pathway to compensate for the lack of β 2
integrins. LAD-1 variants with modestly reduced β 2 integrin Inflammatory Bowel Diseases
expression have been associated with mutations that create As described above, effector lymphocytes activated in the inductive
heterodimers but do not bind ligands. In all types of LAD I, sites (Peyer’s patches and mesenteric lymph node) of the intestine
granulocytes typically show normal rolling, but failure to arrest selectively migrate to the effector sites of the gut (mainly the
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on endothelial cells. lamina propria). The key tissue-specific adhesion code for the
intestinal entry is α 4 β 7 integrin on lymphocytes and its endothelial
LAD II counterreceptor MAdCAM-1. Although the canonical CCR9-
Patients with LAD II suffer from several abnormalities, including CCL25 interaction is important for attracting T and B lymphocytes
recurrent infections, neutrophilia, impaired pus formation, mental to the small intestine, the critical chemotactic receptors for the
retardation, growth defects, and deficiency in H blood group entry into the large intestine are GPR15 (on T cells except for
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antigen. The cause of the disease is impaired transport of Tregs) and CCR10 (on plasmablasts).
guanosine diphosphate (GDP)–fucose from the cytoplasm to
the Golgi lumen as a result of mutations in a GDP–fucose ON THE HOrIZON
transporter. The defect leads to impaired fucose modification
of selectin ligands, most notably that of PSGL-1. Consequently, Adhesion Molecules as Targets for Novel
these patents demonstrate a marked decrease in leukocyte rolling Diagnostic and Therapeutic Agents
under flow conditions. Interestingly, some patients respond to • Use of adhesion molecules as targets for the diagnosis of immune
treatment with oral fucose. deficiencies, inflammatory disorders, and cancers.
• Use of adhesion molecules as targets for imaging inflammatory
LAD III responses.
The third LAD syndrome involves defective inside-out signaling • Use of adhesion modulating therapies and other manipulations of
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of β 1 , β 2 , and β 3 integrins. In the leukocytes of these patients, lymphocyte trafficking, including small molecules, to treat infections,
activation of multiple leukocyte integrins, including LFA-1 and immune deficiencies, autoimmune disorders, transplant rejection,
ischemia­reperfusion injuries, and cancers.
VLA-4, by chemokine-triggered, G protein–coupled signals is
genetically defective. Concurrent defects in platelet integrins lead
to a bleeding diathesis. LAD III is caused by mutated Kindlin3, In humans, the homing of regulatory T cells to the colon is
which is a major cytoplasmic activator of integrins. GPR15 independent. This creates pathways by which the traf-
ficking of proinflammatory versus antiinflammatory lymphocyte
Autoimmune or Inflammatory Diseases subtypes in the large bowel can be altered. In inflammatory
Multiple Sclerosis bowel disease (IBD), the expression of MAdCAM-1 is upregulated
Migration of lymphocytes through the blood–brain barrier into in the vessels of lamina propria, together with other vascular
the central nervous system (CNS) is a key pathogenic event that adhesins, such as VCAM-1 and ICAM-1. Increased expression
occurs during the development of multiple sclerosis (MS) and of CCL20 in the IBD mucosa enhances the recruitment of both
its widely used animal model, experimental allergic encephalo- T and B cells to the inflamed gut through ligation of CCR6.
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myelitis (EAE) (Chapter 66). Under normal conditions, lym- Successful pharmacological and genetic targeting of these key
phocytes only patrol outside of the CNS parenchyma in the gut-selective lymphocyte trafficking alleviates inflammation in
leptomeningeal and perivascular compartments. Naïve lympho- multiple animal models of IBD.
cytes inefficiently bind to endothelial cells in meningeal microves-
sels without a rolling step using α 4 integrin and then extravasate Cancer
through the fenestrated choroid vessels using P-selectin and Immunoevasion is one of the main hallmarks of cancer, and insuf-
CCR6. Upon inflammation, meningeal and choroid vessels become ficient lymphocyte trafficking to solid tumors contributes to tumor
more adhesive, and the endothelial cells within the CNS paren- progression. In the neoangiogenic vessels of tumors, immature
chyma start to express ICAM-1 and VCAM-1. These alterations and disorganized endothelial cells often express insufficient
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allow effector lymphocytes, which have primarily been activated amounts of adhesion and attraction molecules. Moreover,
in the cervical lymph nodes that ultimately drain the CNS-derived tumor-derived factors often render the local endothelial cells
antigens, to penetrate the blood–brain barrier and enter the unresponsive to inflammatory cytokines. Nevertheless, chronic
CNS parenchyma. inflammation in tumors can induce the formation of HEV-
In vivo animal studies have shown that the disease course can like vessels, which show augmented expression of trafficking
be dramatically altered by blocking the function of leukocyte α 4 molecules.
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integrin. This treatment is able to prevent the disease and even Lymphocyte migration can be harnessed to improve the
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reverse the paralytic disease and lymphocytic infiltrations in the outcome of cellular immunotherapy for cancer. Infusion of
brain. Antibodies against α 4 β 1 integrin show this remarkable activated or genetically modified effector T cells, and cytotoxic
efficacy even if started a month after onset of the clinical disease. CD8 T cells in particular, would benefit from a more effective
Certain EAE models can also be blocked by targeting the α 4 targeting of the cells into the tumor. Homing of CAR-T cells to
integrin ligand VCAM-1 or by blocking the function of CD44. the tumors could be enhanced by transduction with adhesion
In contrast, inhibition of many other adhesion molecules, such molecules and chemokine receptors, possibly with simultaneous