Mechanisms of remission in oral immunotherapy
Interferons have diverse and often opposing roles in orchestrating
immunological pathways. Recent studies from our group and others using a
network analysis approach have found that type I interferons may also be
important regulatory drivers in redirecting the allergic response
towards remission of allergy following oral
immunotherapy28,29 and may be negative regulators of
the allergic CD4+ T cells response both in and outside of the treatment
setting30,31. We examined gene co-expression networks
in CD4+ T cells at study entry and following 18-months of Probiotic and
Peanut Oral Immunotherapy in children who achieved remission following
active treatment and placebo-treated controls who remained allergic.
Results showed that remission following treatment was characterised by
changes in the antigen-specific response to peanut, with loss of Th2
driven gene connectivity and replacement by a large integrated type I
interferon network that incorporated Th2 genes within the
module18. In contrast, a Th2 dominant module persisted
in allergic children who received placebo treatment. Notably, the role
of type I interferons has also been highlighted in the setting of
subcutaneous immunotherapy (SCIT) for allergic rhinitis in adults.
Persistent reduction of house dust mite (HDM) associated symptoms after
SCIT treatment was associated with progressive integration of previously
distinct type I interferon and Th2 gene modules, resulting in a rewired
module in which the top nodes, ranked by degree of connectivity, were
made up of type I interferon genes19. It is noteworthy
that the same immune mechanisms were associated with disease remission
across multiple allergen immunotherapy studies, despite major
differences in the studies, including disease states and treatment
modalities. This supports a role for type I interferon pathways as a
fundamental mechanism through which lasting attenuation of allergen
responsiveness is achieved following allergen immunotherapy. Both of
these studies were conducted by profiling the total CD4+ T cell
compartment, and future studies are needed to determine if the Th2 and
IFN modules operate within a single CD4+ T cell population or whether
these signals reflect changes in discrete cell subpopulations. In this
context it is noteworthy that scRNAseq studies of CD4+ T cell memory
responses to HDM have identified novel subsets of T-helper and
T-regulatory cells, which express a type I interferon response
signature, and are expanded in healthy non-allergic subjects, suggesting
they may play a role in dampening allergic
responses32. Further studies applying similar systems
biology approaches to compare the effects of different therapies and
clinical outcomes following treatment will further elucidate the
underlying processes.
The precise mechanisms governing the interplay between type I IFN and
Th2 responses in the context of allergen immunotherapy are unknown.
Previous studies have demonstrated that type I IFNs can abrogate both
the production of Th2 cytokines in antigen stimulated
PBMC33 and expression of the high affinity IgE
receptor34. Furthermore, type I interferons suppress
the expression of GATA3 during differentiation of CD4+ T cells down a
Th2 path and in fully committed CD4+ Th2 cells, and promotes epigenetic
silencing of non-coding regions in the Th2 locus that controls Th2
cytokine expression35. Interferon genes (type I and
type II) have also been shown to regulate a cluster of genes associated
with levels of component resolved egg sIgG4 and sIgA after 8-months of
egg OIT17.
Another regulatory mechanism that has been reported with OIT is T cell
anergy. Expansion of the anergic (CD28-/CD38-/IFN-γ/IL4-/IL13-/IL10-)
non-cytokine secreting T cell subset, as well as non-allergic (IFN-γ+) T
cell types has been detected in those who achieve remission/SU (defined
as absence of clinical reactivity at 3 months post treatment).
Conversely, in those desensitised without remission/SU CD4+ T cell
subsets were scattered across multiple CD4+ T cell phenotypes with only
slight increases in anergic and non-allergic T cell
phenotypes36. However, this finding was not replicated
in a subsequent study by the same group when the frequency of
peanut-specific T cells over the course of OIT was measured using
Dextramers37. While shifts in the frequency of
peanut-reactive T cell clonotypes may not be clearly linked to outcomes
following OIT, the application of scRNAseq to this population has
demonstrated a link between dampened Th2 and Th1 signatures in effector
cells and remission21. Findings from this study were
consistent with the findings that clonal anergy is linked with positive
outcomes following OIT. Conversely, baseline inflammatory signals in Th1
and Th17 effector cells were associated with poorer outcomes following
OIT21.
Another signal linked with clinical outcome following treatment is an
early transient increase in TGF-β producing cells at one year into
treatment37. This signal was detected in a mixed group
of patients who either avoided the allergen in their diet leading up to
the 3 month remission/SU challenge or continued on 300mg
doses37. Therefore, it is unclear whether the finding
relates to remission/SU or to desensitisation without remission/SU.
T regulatory cells play an instrumental role in the development and
maintenance of oral tolerance38 and accordingly it is
generally assumed that Treg must also play a role in remission of
allergy in OIT39. Notably, pathogenic Tregs with a
Th2-like phenotype have been described in murine models of food allergy
and were also found to be circulating in the periphery of children with
food allergy40. Functional studies from this work
highlight that modulation of this population may promote the
establishment of oral tolerance in food allergic individuals. Yet,
evidence establishing Treg as primary mediators of remission following
OIT in humans remains limited. Although two studies report changes to
the antigen-specific Treg population following peanut
OIT41,42, a more recent study profiling
antigen-specific T cells with single-cell sequencing found no change in
peanut-reactive Treg with OIT21. Moreover, a subset of
peanut-reactive Treg with a Th2-like phenotype (Th2reg-like), matching a
previously described population found in food allergic
children40, was identified in this study. There is no
evidence to support modulation of the frequency or phenotype of these
cells with OIT, even in those who passed a food challenge 3-months after
treatment and were classified as tolerant
(remission)21. Induction of FOXP3 gene
expression via demethylation of the FOXP3 has been linked with
remission (defined as absence of clinical reactivity 3 months after
treatment cessation, n=7) compared to those who failed to achieve
remission (n=13), and this was reversed in those who lost their
protection (n=4 participants who failed a challenge at six months
post-treatment regained methylation of the FOXP3locus)41. These findings suggest that persistent
activation of FOXP3 may be a critical requirement for lasting
persistence of remission.