Page 931 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPter 66 Multiple Sclerosis 899

screened for immunity to varicella zoster before commencing in patients with SPMS, it did not prevent clinical progression
treatment. In the postmarketing setting, there have been at least or progressive cerebral atrophy. 7
three cases of PML in fingolimod-treated patients with no or Despite causing a profound lymphopenia, alemtuzumab
only distant prior exposure to immunosuppressant drugs. Other therapy has only rarely been associated with opportunistic
potential side effects of fingolimod include macular edema, infections and has not been associated an increased incidence
bradycardia, and atrioventricular block. of malignancy. Surprisingly, the principal adverse effect of
alemtuzumab in MS is antibody-mediated autoimmune disease,
Natalizumab most commonly Graves disease. Idiopathic thrombocytopenic
Natalizumab is a humanized mAb reactive against the cell purpura, Goodpasture syndrome, and antiglomerular basement
adhesion molecule α 4 integrin, which is widely expressed on membrane disease have been reported less frequently. The
lymphocytes and monocytes. Natalizumab is believed to mediate underlying mechanism is not fully understood but may be a
its ameliorative effects in RRMS by blocking interactions between consequence of homeostatic T-cell proliferation following
the very late antigen-4 (VLA-4; a heterodimer composed of the lymphoablation, leading to the generation of chronically activated
α 4 and β 1 integrin chains) on leukocytes with its cognate ligand, oligoclonal CD4 and CD8 T cells capable of producing proinflam-
vascular cell adhesion molecule (VCAM)-1, on cerebrovascular matory cytokines. 58
endothelial cells. VLA-4–VCAM-1 interactions are required for the
passage of lymphocytes and monocytes past the BBB. Natalizumab Daclizumab
was approved by the FDA for relapsing MS in 2004 following Daclizumab is a humanized mAb reactive to CD25, the α subunit
a 2-year phase III trial. Natalizumab reduced the relapse rate of the IL-2 receptor. Daclizumab was originally proposed as a
at 1 year by 68% and the number of gadolinium-enhancing treatment for RRMS based on the hypothesis that it would block
MRI lesions at both 1 year and 2 years by over 90%, compared IL-2–dependent expansion of effector T cells. However, mecha-
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with placebo. Natalizumab also reduced the risk of sustained nistic studies have shown that daclizumab does not inhibit T-cell
progression of disability by 42% over 2 years. In an independent survival, proliferation, or cytokine production. Some patients
placebo-controlled trial, the addition of natalizumab to IFN-β-1a treated with daclizumab exhibit an expansion of circulating
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suppressed break through disease activity and reduced the risk CD56 bright NK cells, which correlates with treatment response.
of sustained disability in patients who were refractory to IFN-β CD56 bright NK cells have been shown to possess immunoregulatory
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alone. The effects of natalizumab on leukocyte trafficking are properties and to kill activated autologous T cells in vitro.
not specific to the CNS. In fact, in 2008, the FDA approved Daclizumab might also modulate lymphoid tissue inducer cells
natalizumab for the treatment of refractory Crohn disease. The in patients with MS and thereby suppress the development of
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most serious complication of natalizumab treatment is PML; meningeal lymphoid follicles. In a phase III randomized placebo-
there have been over 400 reported cases. Factors that increase the controlled clinical trial in RRMS, subcutaneous administration
risk of natalizumab-associated PML include John Cunningham of daclizumab reduced the annualized relapse rate by 45%, the
(JC) virus seropositivity, duration of treatment >2 years, and proportion of patients who relapsed by 41%, and new or newly
prior exposure to immunosuppressant drugs. enlarged T2-weighted MRI lesions by 54%, compared with
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intramuscular IFN-β-1a over 144 weeks. It was approved by
Alemtuzumab the FDA in 2016 for the treatment of relapsing MS in adults.
Alemtuzumab is a humanized anti-CD52 mAb that globally Side effects include an increased risk of infections, hepatotoxicity,
depletes circulating T and B lymphocytes via antibody-dependent noninfectious colitis, lymphadenopathy, and cutaneous events,
cell-mediated cytotoxicity, complement-dependent cytolysis, and such as rash and eczema. On the basis of its safety profile,
induction of apoptosis. CD52 is primarily expressed on the cell daclizumab is generally reserved for patients who have an
surface of T and B lymphocytes, but it is also expressed at lower inadequate response to ≥2 other disease modifying agents.
levels on macrophages, eosinophils, and natural killer (NK) cells.
The function of CD52 is unknown, although there is some B Cell–Depleting Monoclonal Antibodies
evidence that it is involved in T-cell activation. Hematopoietic A role of B cells in the pathogenesis of MS has been suspected
stem cells (HSCs) do not express CD52, allowing the subsequent since the discovery of unique oligoclonal bands in the CSF of
repopulation of circulating lymphocyte pools following alem- the majority of individuals with MS, indicative of intrathecal
tuzumab treatment, which occurs at variable rates between antibody synthesis. Nonetheless, B cells are not a prominent
lymphocyte subsets. Reconstituted circulating T-cell pools have component of the perivascular infiltrates in MS lesions. This
+
+
low
been found to be enriched in CD4 CD25 high CD127 FOXP3 apparent paradox has been resolved, at least in part, by the
regulatory T cells (Tregs) that might be responsible, in part, for discovery of lymphoid follicle–like structures, composed of
the long-lasting therapeutic effect of alemtuzumab, that has been proliferating B cells, antibody-producing plasma cells, Th cells,
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6
observed in some individuals. In a 2-year, rater-masked, random- and FDCs, in the meninges of some individuals with MS.
ized controlled phase III trial, previously untreated patients with Although meningeal lymphoid follicles have primarily been
RRMS were randomly allocated to receive intravenous alemtu- detected in autopsy specimens from persons with progressive
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zumab or subcutaneous IFN-β-1a. Alemtuzumab was given MS, it is possible that nascent immune cell aggregates develop
once per day for 5 days at baseline and once per day for 3 days in the RR stage but are disrupted during the dissection and
at 12 months. Relapse rates were reduced by 54.9% in the processing of CNS tissues. The most direct evidence for a role
alemtuzumab group compared with the IFN-β-1a group. In an of B cells as effector cells in MS pathogenesis comes from trials
independent study, alemtuzumab reduced relapse rates and the of mAbs directed against CD20, a B cell–specific surface molecule.
risk of sustained accumulation of disability in patients with CD20 is expressed on preB cells and mature B cells. It is not
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RRMS refractory to first-line DMAs. Although alemtuzumab expressed on antibody-secreting plasma cells. Rituximab, a
suppressed new MRI lesion formation and superimposed relapses genetically engineered chimeric anti-CD20 mAb, induces a rapid