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Published as: Curr Opin Immunol. 2010 October ; 22(5): 609–615.
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Antigen-specific immunotherapy of autoimmune and allergic
diseases
Catherine A Sabatos-Peyton*, Johan Verhagen*, and David C Wraith
David C Wraith: [email protected]
School of Cellular and Molecular Medicine, University of Bristol, Medical Sciences Building,
University Walk, Bristol, BS8 1TD, UK
Abstract
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Nearly a century has passed since the first report describing antigen-specific immunotherapy
(antigen-SIT) was published. Research into the use of antigen-SIT in the treatment of both allergic
and autoimmune disease has increased dramatically since, although its mechanism of action is only
slowly being unravelled. It is clear though, from recent studies, that success of antigen-SIT depends
on the induction of regulatory T (T reg) cell subsets that recognise potentially disease-inducing
epitopes. The major challenge remaining for the widespread use of antigen-SIT is to safely administer
high doses of immunodominant and potentially pathogenic epitopes in a manner that induces T cell
tolerance rather than activation. This review illustrates that intelligent design of treatment agents and
strategies can lead to the development of safe and effective antigen-SIT.
Introduction
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Current treatments for allergic and autoimmune disease treat disease symptoms or depend on
non-specific immune suppression. Treatment would be improved greatly by targeting the
fundamental cause of the disease, that is the loss of tolerance to an otherwise innocuous antigen
in allergy or self-antigen in autoimmune disease (AID). Much has been learned about the
mechanisms of peripheral tolerance in recent years. We now appreciate that antigen presenting
cells (APC) may be either immunogenic or tolerogenic, depending on their location,
environmental cues and activation state [1]. Furthermore, it is clear that both FoxP3+ and
FoxP3− cells with regulatory properties can be induced with specific antigen. This, therefore,
provides two guiding principles for the design of antigen-specific immunotherapeutic
strategies. First, antigen should be directed to tolerogenic rather than immunogenic APC;
secondly, administration of antigen should lead to the induction of regulatory T cells.
Allergen-specific immunotherapy
The application of allergen-SIT has become increasingly popular since first reported by
Leonard Noon in 1911. Subcutaneous (s.c.) or oral/sublingual administration of allergens has
been used for the successful treatment of a wide range of allergies including those to bee venom
[2], cow's milk [3], peanut [4] or birch pollen [5]. Typically, this starts with a build-up day
where the maximum tolerated dose is determined. This dose is then gradually escalated over
© 2010 Elsevier Ltd.
*These authors contributed equally to the writing of this review.
This document was posted here by permission of the publisher. At the time of deposit, it included all changes made during peer review,
copyediting, and publishing. The U.S. National Library of Medicine is responsible for all links within the document and for incorporating
any publisher-supplied amendments or retractions issued subsequently. The published journal article, guaranteed to be such by Elsevier,
is available for free, on ScienceDirect.
Sabatos-Peyton et al.
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a period of approximately two months to a high maintenance dose, which is administered
regularly for months to years. By escalating the treatment dose, a maintenance dose can be
reached that is far higher than the maximum tolerated dose at onset, with limited adverse effects.
Studies have shown that optimal results are achieved using the highest tolerable maintenance
dose [6] or a high cumulative dose, that is long-term treatment [7]. To further prevent adverse
effects and increase efficacy, a wide range of novel therapeutic strategies have been employed,
including the use of non-IgE binding allergen derivatives, adjuvants, alternative routes of
administration, fusion proteins, allergen-encoding cDNA and peptides that represent T cell
epitopes (reviewed in [8]). Hypoallergenic peptides, in particular, are an increasingly popular
alternative to whole proteins and have proven successful in animal models and human trials
[9,10,11••].
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Progress in the development of allergen-SIT has been hindered by a lack of understanding of
the underlying immunological mechanisms. In recent years, it has become clear that the ratio
of allergen-specific T cells secreting distinct cytokines plays a crucial role in the onset and
cessation of allergic diseases. First, it is important to realise that allergic and non-allergic
individuals recognise the same T cell epitopes of common allergens [12] and that only the
frequency of different subsets of CD4+ T cells specific for these epitopes differs. It is now clear
that the balance between effector T cell populations on the one hand and IL-10-secreting,
suppressive T cells on the other makes the difference between an atopic or healthy immune
response. In atopic individuals, the highest proportion of T cells recognising common
environmental allergens are IL-4-secreting T helper (Th) 2 cells, whereas IL-10-secreting T
cells prevail in healthy individuals [13]. The importance of the dominance of the IL-10secreting T cell population for a healthy immune response to allergens is elegantly
demonstrated in the case of beekeepers [14••]. During the season, beekeepers are stung
frequently, thus receiving repetitive high doses of allergen. Remarkably, their immune
response to the venom skews rapidly, with a dramatic shift in the dominant T cell subtype
towards IL-10-secreting cells. This induction of IL-10-secreting cells has now also been shown
to be a dominant feature of successful allergen-SIT in a range of allergies (Table 1) [4,5,11••,
15,16]. Allergen-SIT is successful at any age but early treatment of a single allergy may prevent
epitope spreading and hence limit the atopic march in later life [17].
Autoantigen-specific immunotherapy
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The use of SIT for AID has lagged behind SIT for allergy. This may be because AIDs are more
heterogeneous than allergic diseases; the disease-initiating or target antigen may not be known;
and/or the immune pathogenesis of AID is associated with epitope spreading [18] and
substantial tissue damage may have occurred before an effective diagnosis has been made.
Effective SIT for AID will, therefore, require the induction of cells capable of ‘bystander’
regulation or suppression at the earliest stage of disease [19,20].
First attempts at SIT, in diseases such as multiple sclerosis (MS), were not successful [21–
23]. Weiner and colleagues extended these studies by testing the phenomenon of mucosal
tolerisation in various experimental models [24]. This was universally effective and revealed
that a relatively low dose of antigen, delivered by the oral route, would induce ‘bystander
suppression’ whereby the administration of antigen A would induce cells capable of
suppressing responses to antigens B and C. Clinical trials proved that oral tolerance induction
is safe but not as effective as expected from studies in animal models.
The administration of self-antigen via plasmid DNA is an attractive approach since coexpression of cytokines and immune modulators can be used to enhance mechanisms of
tolerance induction. Early examples of DNA vaccination in AID models produced conflicting
results; disease could be either suppressed [25] or enhanced [26,27], depending on the disease
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Sabatos-Peyton et al.
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model or antigen expressed. Various approaches have been taken to enhance tolerance
induction. CpG motifs in plasmid DNA contribute to the Th1 response; this is reduced by coadministration of an oligonucleotide expressing GpG in place of CpG [28]. A DNA vaccine
encoding myelin basic protein, with CpG motifs replaced by GpG, was recently tested in MS
patients [29•]. Treatment with a 0.5 mg dose of DNA resulted in the reduction of new lesions
in the CNS, coinciding with a decrease in the Th1 response to myelin antigens. Co-expression
of cytokines designed to reduce the Th1 response to antigen enhanced the efficacy of
tolerogenic DNA vaccination in both EAE [30] and type I diabetes (T1D) models [31]. An
intriguing, novel approach involves the introduction of the microRNA miR-142 into the
antigen-expressing vector [32••]. The microRNA suppressed antigen expression in professional
APC and led to the induction of antigen-specific FoxP3+ cells in the liver. Expression of antigen
in the liver generally enhances the generation of induced FoxP3+ Treg cells and has proven
effective in models of uveitis and MS [33•,34•].
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Although antigenic protein therapy has been successful in pre-clinical models, the approach
has not translated well into the clinic. Nevertheless, there has been success in the use of an
alum-based islet-antigen vaccine. GAD-alum treatment led to the preservation of residual
insulin secretion in patients with recent-onset T1D [35•]. One approach, designed to improve
the safety of self-antigen delivery in AID, involves the coupling of intact antigen to APC using
chemical fixatives [36]. This is based on the concept that fixation promotes a tolerogenic
response to the APC. A systematic study of this approach, however, revealed that efficacy is
not dependent on the delivery of antigen on autologous cells; in fact, cells may be replaced
with antigen-coated beads [37]. This implies that the fixed cells themselves are not directly
involved in tolerance induction; rather, they carry intact antigen to tolerogenic APC for
processing and presentation. A phase I trial of fixed autologous peripheral blood leukocytes
coupled with a cocktail of seven encephalitogenic myelin peptides is underway in early
relapsing-remitting MS patients [38].
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The alternative to coupling antigen to APC is simply to administer soluble peptide via a
tolerogenic route. Much has been learned about the nature of the peptide, dose, route of delivery
and timing. The peptide must mimic the naturally processed antigen when bound to major
histocompatibility complex (MHC) [39]; post-translational modification of the peptide may
be required [40], and treatment must be initiated as soon as possible following definite
diagnosis (e.g., a single peptide could suppress diabetes at an early stage of disease while
treatment of late stage disease required administration of a combination of peptides [41]). One
approach to improving the safety and efficacy of peptide therapy has included the development
of recombinant MHC–peptide complexes. Treatment with sIAg7–pGAD65 complexes
effectively blocked the development of diabetes in the NOD mouse; suppression was dependent
on induction of islet-cell-specific IL-10-secreting CD4+ T cells [42]. Similarly, treatment with
a single recombinant MHC–peptide complex could reverse EAE through induction of IL-10secreting regulatory cells [43]. Clinical trials of peptide therapy have shown promising results
in a range of AID (Table 2) with various routes of administration and dosing schedules under
investigation. Importantly, as in many pre-clinical models, IL-10 is frequently associated with
effective peptide therapy.
The importance of antigen dose and IL-10 production for the success of
antigen-SIT
IL-10 secretion is a common self-regulatory property for the major CD4+ T helper subsets,
with Th1, Th2, Th9 and Th17 cells all shown to secrete IL-10 in the face of chronic exposure
to antigen (reviewed in [44•,45]). Both allergen-SIT and autoantigen-SIT exploit this natural
IL-10-secreting phenotype of highly differentiated effector cells with repeated exposure to
high-dose antigen converting effector T cells to IL-10-secreting regulatory populations (Figure
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1). The greatest hazard of high-dose peptide-specific therapy, however, is a harmful immune
response due to the initial burst of cell activation with subsequent proliferation and excessive
cytokine release. This became evident in trials of altered peptide ligand (APL) therapy in MS.
Treatment was terminated when it became evident that an allergic response to the peptide had
been induced at the highest dose [46,47]. Importantly, this problem was not observed at lower
doses of peptide. We have recently shown, using peptide analogues, that anergy, suppression
and IL-10 secretion are dose or affinity dependent, with lower signal strength leading to anergy
and higher signal strength driving IL-10 secretion and effective regulation of the inflammatory
immune response [48•]. Combined with the body of knowledge from allergen-SIT, these data
suggest that initiating treatment with lower doses and building to the highest maintenance dose
allows the full benefit of tolerance induction while also protecting the recipient from harmful
side effects. We propose, therefore, that for antigen-SIT in both allergy and AID, a stepwise
approach, with dose escalation activating T cells through increasing strength of signal to a
higher maintenance dose, will induce tolerogenic IL-10-secreting cells, capable of suppressing
the effector properties of their initiating population (Figure 2).
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Some studies suggest that IL-10 secretion is a transitory property of highly stimulated cells,
dependent on tissue-specific environmental cues for its maintenance, while others suggest that
the IL-10 locus can be genetically modified in terminal differentiation. Recent evidence has
shown that sustained high-dose TCR signalling and high levels of IL-12 were required for the
induction and maintenance of IL-10 secretion in Th1 cells, through sustained ERK1 and ERK2
MAP kinase phosphorylation [49••]. However, for Th2 cells, epigenetic modification of
chromatin at the IL-10 locus has been demonstrated [50,51]. Thus, the mechanistic details of
IL-10 regulation in T cells and the crucial question of whether IL-10 secretion can be imprinted
remain open.
Conclusion
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This review has highlighted recent advances in specific immunotherapy for allergic and
autoimmune disease. One overriding conclusion is that regulatory mechanisms involving IL-10
are important for effective therapy. Our belief is that basic research should focus on means to
target tolerogenic APC; to promote, for example through the use of appropriate adjuvants,
secretion of IL-10 from both APC and T cells; and to investigate the mechanisms of dose
escalation tolerance. Future clinical trials should focus on patient groups that are most likely
to benefit from the treatment, for example major changes should not be expected in advanced
stages of disease [38]; no SIT trial should be undertaken without detailed investigation of
immunological changes arising from the treatment; and intervention should be undertaken as
early after diagnosis as possible. Finally, the dose of antigen required for SIT is the most critical
consideration; dose escalation should allow for a safe increase in dose until an effective,
tolerogenic dose is achieved.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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Acknowledgments
The authors wish to thank Bronwen R. Burton for useful discussions during the writing of this review. CASP receives
a fellowship from the MS Society of GB & NI; JV and DCW are supported by a Wellcome Trust Programme Grant.
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Figure 1.
Self-regulatory properties of effector Th populations through chronic/repetitive stimulation.
Differentiation of naïve CD4+ T cells into effector Th1, Th2 and Th17 populations is well
established. Recent evidence from viral-infection and helminth-infection models, as well as
numerous allergen-specific and autoantigen-specific peptide therapy trials, suggests that
upregulation of IL-10 occurs during chronic or repetitive stimulation and can serve as a selflimiting mechanism [43,44•]. Shown are the potential cytokines/transcription factors/signalling
molecules that mediate the switch from effector T (T eff) to IL-10-secreting regulatory
populations. Note that Th2 cells produce IL-10 upon initial differentiation, and while evidence
does suggest that IL-10 helps host survival during helminth infection [44•], whether this is a
general feature of well-differentiated Th2 cells remains unclear.
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Figure 2.
Dosing strategy for antigen-SIT. Repeated administration of high-dose/affinity antigen has the
potential to induce the highest level of anergy and tolerance, but the first few treatments may
induce acute and sometimes severe side effects. Low-dose antigen does not carry a risk of side
effects, nor does it induce robust tolerance. The low dose does, however, allow for the gradual
increase of the dose without the adverse effects normally associated with the higher dose.
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Published as: Curr Opin Immunol. 2010 October ; 22(5): 609–615.
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Table 1
Studies demonstrating the importance of IL-10 induction for successful allergen-SIT.
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Allergen
Treatment
Patients
Outcome
Ref.
Peanut
Titrated oral administration of peanut protein
up to 1800 mg (total 36 months)
29
Reduction in IgE; increased IgG4; increase in
IL-10, IL-5, IFN-γ and TNF-α. Increase in
antigen-specific FoxP3+ cells until 12 months
[4]
Birch pollen
Incremental weekly doses of s.c. standard
quality birch pollen allergen up to 100,000
units, followed by monthly maintenance dose
13
Increase in antigen-specific IL-10-secreting
cells; increase in allergen-specific IgG
antibodies
[5]
Fel d 1 (cat)
Asthma patients received intradermal (i.d.)
fel d 1 peptides in increments up to a 90 μg
total over two weeks
16
Reduced late reaction to cat dander; increased
IL-10, with linked epitope suppression
[11••,15]
Japanese cedar pollen
Sublingual application of a pool of 7 Cry j 1
and 2 derived peptides
75
Increase in IL-10-secreting regulatory cells;
reduction in allergy symptoms to cedar pollen
and other allergens
[16,17]
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Table 2
Studies demonstrating the efficacy of self-antigenic peptide SIT in autoimmune diseases.
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AID
Treatment
Patients
Outcome
Ref.
Rheumatoid Arthritis
DNAJP1 peptide
peroral, 25 mg/day
over six months
160
Immune deviation from TNF-α to IL-10; combination of
peptide and hydroxychloroquine most effective
[52]
Systemic Lupus Erythematosus
Three s.c. doses of
spliceosomal
peptide P140 at twoweek intervals
20
Anti-dsDNA antibody levels reduced in 200 μg group
[53]
T1D
Three i.d. doses of
proinsulin peptide at
monthly intervals
48
Increase of IL-10-secreting T cells in patients receiving
10 μg dose
[54]
T1D
DiaPep 277, hsp60
peptide, range of
doses around 1 mg
>300
IL-10 production in response to therapy associated with
preservation of C-peptide
[55,56]
Primary Progressive MS/Secondary
Progressive MS
MBP8298, 500 mg
i.v. every six months
32
Reduction in CSF anti-MBP. Delay to progression in
DR2/DR4 subgroup
[57]
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Published as: Curr Opin Immunol. 2010 October ; 22(5): 609–615.