Page 467 - Clinical Immunology_ Principles and Practice ( PDFDrive )

446 ParT ThrEE Host Defenses to Infectious Agents

have similar effects on DCs, with subsequent Th2 polarization animal models have revealed the protective effect of helminth
and inhibited responses to Th1-inducing TLR ligands. In addition, infections against atopy and asthma. Several mechanisms have
schistosomes modulate the activation of Nlrp3 (NLR family, been proposed for the helminth-induced protection, the chief
pyrin domain containing 3) inflammasome and thus IL-β produc- of which are the induction of Treg activity, regulatory B-cell
tion. Excretory/secretory antigens produced by helminths can activity, and immunosuppressive cytokines including IL-10 and
inhibit DC synthesis of proinflammatory cytokines, chemokines, TGF-β. Similarly, exposure to helminth parasites has been shown
and costimulatory molecules and promote DC production of to prevent the onset of Th1-mediated diseases, such as multiple
the regulatory cytokines IL-10 and TGF-β. Helminth infection sclerosis (MS), diabetes mellitus, and Crohn disease in experi-
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has also been shown to induce in vivo differentiation of a CD103 - mental animal models. Finally, recent studies in mice have
lo
CD11c population of regulatory DCs, which are inefficient in shown that type 2 immunity, induced by helminth infection,
priming effector T cells and instead favor the generation of Tregs. can maintain adipose tissue homeostasis and promote adipose
AAMs are able to markedly suppress target cell proliferation, as tissue beiging, protecting against obesity and metabolic dysfunc-
well as mediate repair of tissue that has been damaged by parasites. tion; that the immunomodulatory glycan LNFPIII, which is
In addition, human filarial infection is associated with the secreted by helminths, can alleviate hepatosteatosis and insulin
expansion of the nonclassic monocyte subset, as well as an resistance; and that there exists an inverse association between
immunoregulatory monocyte subset. Helminth antigens can the presence of helminth infections and the prevalence of type
modulate MHC class II and CD80/86 expression on “antigen- 2 diabetes.
presenting” basophils to induce the development of Th2 cells.
Finally, a heterogeneous population of immature myeloid cells HELMINTH THERAPY FOR
that share the common property of suppressing immune responses INFLAMMATORY DISEASES
are termed myeloid-derived suppressor cells (MDSCs). Although
these MDSCs have been well characterized in cancer immunology, To date, two species of helminths have been tested as clinical
their role in helminth infections is still being explored. treatment for therapy of inflammatory diseases: T. suis ova and
infection with N. americanus. Currently, 28 clinical trials of
Apoptosis helminth therapy in 10 autoimmune diseases and allergic or
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Another mechanism of immune evasion is the ability of some related conditions have been planned, started, or completed.
helminths to induce host cell apoptosis (Chapter 13). Apoptosis These include Crohn disease, ulcerative colitis, MS, celiac disease,
has been described as a host regulatory mechanism in various autism, plaque psoriasis, peanut and tree nut allergy, asthma,
helminth infections, including schistosomiasis, lymphatic filariasis, rhinoconjunctivitis, and rheumatoid arthritis. Although well
and onchocerciasis. tolerated, recent results suggested that this therapy did not achieve
improvement in disease activity or remission rates in Crohn
HELMINTHS AND THE MICROBIOTA disease. Studies using N. americanus include fairly small trials
with patients with Crohn disease or individuals with celiac disease
Recent work has highlighted the importance of the microbiota (gluten allergy). Additionally, a few studies have been performed
in influencing host immunological and metabolic functions examining the effect of helminth therapy on asthma/allergy. The
(Chapter 14). Helminths secrete a variety of products that can one minor success of helminth therapy in humans is in the
directly influence the composition and function of the microbiota, treatment of MS, wherein small trials have successfully demon-
whereas changes in microbiota can have an impact on susceptibil- strated lower relapses and lower magnetic resonance imaging
ity to helminth infection, indicating that helminth–microbiota (MRI) activity, prompting larger phase I or II trial involving
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cross-talk can regulate a variety of host processes. Recently, it either T. suis or N. americanus.
was reported that infection with helminths (H. polygyrus or T.
muris) results in alteration of the composition of the microbiota,
with expansion of Lactobacillacea and Enterobacteriacea in the ON ThE hOrIZON
gut, and that the removal of helminths resulted in restoration Identification and synthesis of helminth products that can be useful as
of the original composition of the microbiota. The consensus immune therapy in a variety of inflammatory disorders
in humans is yet to emerge, with some studies showing an effect Deciphering the three way cross-talk among host immunity, helminths,
of helminth infection on microbial diversity and others failing and the microbiota
to reveal any differences. Conversely, it has also been demonstrated Elucidation of the detailed mechanisms by which helminths manipulate
that introducing higher level of certain commensal microbes immune responses to bystander antigens
enhances susceptibility, whereas removal of microbiota by Development of clues to production of novel vaccine candidates to protect
against not only helminth infection but also helminth-induced
antibiotics decreases susceptibility to helminth infections. morbidity
Combined approaches involving genomics, transcriptomics, proteomics,
REGULATION OF ALLERGY, AUTOIMMUNITY, AND and metabolomics for assessment of host–helminth interactions
METABOLIC DISEASES IN HELMINTH INFECTION
VACCINES AGAINST HELMINTH PARASITES
The hygiene hypothesis postulates that the stimulation of the
immune system by microbes or microbial products protects from Vaccines against helminth infections are a necessary tool for
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the development of inflammatory and atopic disorders (Chapter their elimination and eradication for several different reasons.
1). Human studies have demonstrated that people living in areas Currently, a total of five human anthelmintic vaccines have
endemic for helminth infections have a decreased reactivity to advanced from discovery through manufacture and are now in
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skin tests for allergens and milder forms of asthma. Experimental phase I or II clinical testing. These include three Schistosome