Page 1241 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 89 Biological Modifiers of Inflammatory Diseases 1203

C5b-9 terminal attack complex, and failure to generate C5a
On the Horizon: Recombinant Promoters of Treg Function diminishes complement pathway mediated recruitment of
IL-27 may modulate autoimmune inflammation via promotion phagocytic cells. Since both C5a and C5b-9 have potent proco-
of Treg lineage and function; it often opposes the action of IL-6 agulant activity at sites of inflammation, complement activation
and is the only member of the gp130-related cytokine family to is hypothesized to be critical to the generation of intravascular
predominantly signal via the latent transcription factor signal thrombi in thrombotic microangiopathy syndromes, including
transducer and activator of transcription 1 (STAT1) instead of atypical hemolytic–uremic syndrome (aHUS), catastrophic
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STAT3. In this context, IL-27 acts as a negative regulator of anti-phospholipid syndrome, and thrombotic microangiopathy
Th17 commitment, whereas the p28 subunit of IL-27 antagonizes that may be seen in SLE. Eculizumab is currently approved for
IL-6–STAT3-mediated T-cell responses. Treg function may also use in patients with aHUS but has also been reported to be of
be enhanced by recombinant IL-35. 54 benefit in patients with these other complement activation–
mediated thrombotic syndromes. 55-57
Complement Pathway Inhibitors Eculizumab inhibits terminal complement activation and
In addition to opsonization of microbial pathogens and products therefore renders patients vulnerable to infection with encap-
of apoptosis, products of complement activation play a significant sulated organisms. Life-threatening and fatal meningococcal
role in recruitment and activation of phagocytic cells (C3a, C5a), infections have occurred in patients who received eculizumab,
cell membrane damage (C5b-9), and have potent procoagulant and meningococcal vaccination is recommended at least 2 weeks
activity (C5a, C5b-9) (Table 89.3). Congenital deficiency of C3 prior to receiving eculizumab. In cases where the risks of delaying
or functional C3 impairment is typically associated with severe, eculizumab therapy outweigh the risk of developing a menin-
if not fatal, clinical phenotypes, rendering C3 or its cleavage gococcal infection, meningococcal vaccine should be administered
products unattractive targets for immunomodulation. However, as soon as possible. However, current meningococcal vaccines
inhibition of C5 appears to be well tolerated and may have do not protect against serogroup B strains of Meningococcus,
beneficial effects on disorders in which enhanced cleavage of C5 and thus immunized patients are still at risk of infection by this
contributes to disease manifestations (Table 89.3). strain.
KEY CONCEPTS Adhesion Molecule Inhibitors
Inhibitors of Complement Activation and Trafficking of phagocytic cells and lymphocytes across vascular
Cell Migration endothelium is critical to the development of inflammatory
lesions and associated tissue injury. The transmigration of cells
• Inhibition by eculizumab of C5 cleavage to its active products and across the endothelium is dependent on the upregulation of
resulting assembly of the membrane attack complex is of significant integrin/adhesion molecules, some of which have binding
benefit to patients who have complement-mediated thrombotic specificity for ligands (addressins) in specific organs, such as the
microangiopathy syndromes occurring with atypical hemolytic–uremic CNS or the enteric mucosa. Strategies to decrease the influx of
syndrome, catastrophic antiphospholipid syndrome, or severe flare-ups
of systemic lupus erythematosus (SLE). monocytes and/or T and B lymphocytes using biologicals that
• Immunization against Neisseria species is recommended for patients target adhesion molecules have, therefore, been deployed as
who require dosing with eculizumab. treatments for several inflammatory disorders, including MS
• Antibody targeting the lymphocyte integrin addressin α 4 β 1 (natalizumab) and IBD.
has been shown to be of benefit in managing multiple sclerosis (MS) Natalizumab is a humanized IgG4κ mAb with specificity for
and inflammatory bowel disease (IBD) but is associated with a risk the α 4 subunit of the very late activation antigen-4 (VLA-4)–
of central nervous system (CNS) JC virus activation (progressive
multifocal leukoencephalopathy [PML]). integrin molecule expressed on lymphocytes and monocytes.
• Antibody targeting the α 4 β 7 integrin (vedolizumab) selectively inhibits Natalizumab blocks association of the VLA-4 α 4 β 1 and α 4 β 7
trafficking of lymphocytes into the intestinal lamina propria and is of integrins with their respective vascular receptors, thereby limiting
benefit in the management of IBD. cell transmigration into tissue sites of inflammation in the CNS
and in the intestinal mucosa. On the basis of the premise that
Eculizumab, a humanized IgG2/4κ mAb with specificity for administration of natalizumab blocks the interaction of T-cell
C5, blocks the generation of C5a and C5b by the C5 convertase. α 4 β 1 with its addressin ligand on venules in the CNS, this thera-
The resulting failure to generate C5b impairs assembly of the peutic approach was validated in murine models of encephalo-
myelitis, and subsequent clinical trials confirmed natalizumab
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to be efficacious in decreasing the frequency of relapses of MS.
TABLE 89.3 recombinant Inhibitors of Natalizumab also inhibits the interaction of the α 4 β 7 integrin
Complement activation and Molecules with mucosal addressin cell adhesion molecule-1 (MAdCAM-1)
Mediating Cell Migration expressed on venules in the enteric mucosa and has been shown
to induce remissions and prevent flare-ups of Crohn disease in
Dosing patients who have failed to have an adequate response to anti–
Molecule Construct Half-Life (Maintenance) TNF-α therapy. 59
Eculizumab anti-C5 (humanized 8–15 days 300–1200 mg Recent additional work in experimental allergic encephalo-
IgG2/4κ) intravenously (IV) myelitis (EAE) models in different strains of mice suggests that
every 1–2 weeks natalizumab affects primarily the transmigration of Th1 cells,
Natalizumab anti-α 4 β 1 (humanized 7–15 days 300 mg IV every with much less of an inhibitory effect on the transmigration of
IgG4κ) 4 weeks Th17 cells. As such, there may be differential efficacy of natali-
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Vedolizumab anti-α 4 β 7 (humanized 25 days 300 mg IV every
IgG1κ) 8 weeks zumab in the treatment of Th1- versus Th17-driven subtypes
of MS and/or IBD.