Page 199 - Clinical Immunology_ Principles and Practice ( PDFDrive )

180 ParT ONE Principles of Immune Response

induction of tumor vessel normalization. However, anti-adhesive CLINICaL PEarLS
therapies targeting inappropriate accumulation of Tregs in the
tumor would also enhance anti-cancer immune responses. • Blocking of α 4 integrin with natalizumab ameliorates disease activity
in multiple sclerosis (MS) and in Crohn disease.
• Blocking of α 4 /β 7 with vedolizumab is an effective treatment for
THEraPEUTIC PrINCIPLES inflammatory bowel disease (IBD).
• Proadhesive strategies have been mainly developed using gene therapy. Therapeutic Applications of Adhesion
• Inappropriate inflammation associated with many diseases can be
dampened by antiadhesive therapeutics. Modulating Therapies
• Function blocking monoclonal antibodies (mAbs) are effective antiad­ Pro- and anti-adhesive therapies have long been an obvious
hesive molecules. pharmaceutical goal in the field of leukocyte trafficking.
• Cell migration can also be blocked by ligand and receptor ana­ Inflammation-promoting strategies would be beneficial for
logues, small­molecule inhibitors, and genetic means (e.g., RNA treating many immune deficiencies, persistent infections, or
interference).
cancers. Proadhesive control of lymphocyte traffic would benefit
specific areas, such as vaccine development and bone marrow
cell transplantation. In practice, lymphocyte recirculation
Adhesion Molecules as Diagnostic Targets routes are already being empirically exploited, for example, by
Immunodeficiency Disorders varying the anatomical site (skin vs. intestine) of vaccination to
In classic LAD I deficiency, a definitive diagnosis can be established optimize the immunization response. Anti-adhesive therapy, on
by flow-cytometric analysis of immunofluorescent-stained the other hand, can be seen as a form of treatment applicable to
32
CD18 integrin on blood leukocytes. In individuals without the all disease categories that involve an inflammatory component.
deficiency, practically all peripheral blood lymphocytes are CD18 In addition, it could provide novel precision drugs individually
positive. In severe cases of LAD I deficiency, there is a complete tailored for treating organ-specific inflammatory disorders, which
absence of this adhesion molecule, whereas in moderate deficiency would be predicted to diminish the problems of generalized
about 1–10% of control levels is seen. LAD II can be diagnosed immunosuppression.
with commercially available antibodies by documenting a lack
of fucosylated adhesion molecules (e.g., abnormal expression of Antibodies and Small-Molecular Drugs
sLeX on blood leukocytes). Diagnosis of LAD III requires activa- A number of specific antagonists of adhesion molecules have
37
tion of cells, the use of monoclonal antibodies (mAbs) that been developed. Function-blocking mAbs against adhesion
recognize specific activation epitopes, or functional assays. molecules and chemokines have often been the drug candi-
dates used for proof-of-principle experiments. In parallel, re-
Soluble Adhesion Molecules combinant ligand or receptor analogs have been developed.
Most adhesion molecules are found in soluble forms in body Ultimately, knowledge of the structure of the adhesion molecules
fluids. They can be generated by alternative splicing of messenger has allowed the design of rational, small-molecular drugs, such
RNA (mRNA) with deletion of transmembrane anchors, by as those affecting the conformational state of leukocyte integ-
proteolytic cleavage of cell-bound proteins by various sheddases rins. Possibilities to modulate mRNA expression of adhe-
(proteases), or by cleavage of the GPI linkage. Either of the soluble sion mol ecules through antisense oligonucleotides and RNA
forms can function as molecular sinks, competing for their specific interference have added another potential tool to the pharma-
ligand(s) with the membrane-bound forms. Alternatively, they ceutical armamentarium.
can trigger biological responses by interacting with their ligand-
bearing cells. Adhesion-Modulating Drugs in Clinical Use
The availability of commercial kits for measuring the levels Although all these forms of therapy have been enormously
of soluble adhesion molecules has led to numerous reports successful in a panoply of animal models, transfer to the clinic
describing an increase or a decrease of certain adhesion molecules has been difficult. However, a small number of very potent drugs
in different diseases. In most cases, there appears to be little or targeting adhesion molecules have been introduced.
no additional diagnostic or predictive value derived from the The first two selective adhesion molecule (SAM) inhibitors
use of these tests compared with more traditional parameters were natalizumab and efalizumab. The way for natalizumab, a
of inflammatory activity. Therefore at present, the indications humanized anti-α 4 integrin antibody, was paved by the excellent
for measurements of soluble adhesion molecules, or chemokines, results of α 4 –blocking in EAE (see above). In patients with
in inflammatory diseases and cancers remain to be defined. relapsing MS, a monthly intravenous injection of natalizumab
leads to a significant reduction in the numbers of new lesions,
Imaging numbers of relapses, and the risk of sustained disability. The
34
The use of neutrophil scans or radioactively labeled nonspecific beneficial effects of natalizumab treatment are evident also in
molecules to localize inflammatory foci is not satisfactory in patients who do not respond to interferon- (IFN-β) therapy.
terms of timing, expense, biohazards, specificity, or sensitivity. Because natalizumab also inhibits α 4 β 7 , the gut homing receptor,
Hence, there have been trials to radioactively or nonradioactively natalizumab also alleviates inflammation in the gut, and it has
label mAbs that recognize endothelial adhesion molecules, infuse been shown to be effective in patients with Crohn disease. 35
them intravenously, and monitor their accumulation by appropri- Efalizumab, a humanized, function-blocking antibody directed
ate imaging devices. Inflammation-inducible molecules, such as against CD11a, was the second antiintegrin antibody to enter
E-selectin and MAdCAM-1, have been used as target antigens. clinical application. It showed good efficacy in patients with
In the case of radioactively labeled E-selectin antibodies, the plaque psoriasis, but it was withdrawn from the market because
utility of this approach has been verified in patients. of an increased risk of an opportunistic infection (see below).