Targeted immunotherapy for hair regrowth and regeneration

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TYPE Opinion
PUBLISHED 10 October 2023
DOI 10.3389/fmed.2023.1285452
OPEN ACCESS
EDITED BY
Satoshi Nakamizo,
Agency for Science, Technology and Research
(A∗STAR), Singapore
REVIEWED BY
Toshiaki Kogame,
Kyoto University, Japan
*CORRESPONDENCE
Etienne C. E. Wang
etienne@nsc.com.sg
RECEIVED 30 August 2023
ACCEPTED 26 September 2023
PUBLISHED 10 October 2023
CITATION
Toh EQ and Wang ECE (2023) Targeted
immunotherapy for hair regrowth and
regeneration. Front. Med. 10:1285452.
doi: 10.3389/fmed.2023.1285452
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©2023 Toh and Wang. This is an open-access
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Targeted immunotherapy for hair
regrowth and regeneration
En Qi Toh1and Etienne C. E. Wang2*
1Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore, 2National
Skin Centre, Singapore, Singapore
KEYWORDS
targeted, immunotherapy, hair, alopecia, regrowth, regeneration
1. Introduction
Immunotherapy for skin conditions has a long and successful history. While the main
strategy for treating inflammatory conditions is local or systemic immunosuppression,
immunotherapy aims to stimulate parts or all of the immune system to bring about a
therapeutic response. The immune system contains multiple, redundant avenues of checks
and balances, and some immune cells have immunomodulatory or regulatory roles. These
cells are targeted by immunotherapy in inflammatory skin conditions. Immunotherapy is
effective in treating some hair loss disorders, supporting recent findings that the hair cycle is
influenced by immune cells (1,2).
The normal hair cycle consists of sequential growth (anagen), regression (catagen) and
rest (telogen) phases. In humans, the anagen phase (9–10 years) reflects the growing hair
shaft, while the end of telogen (2–3 months) is marked by hair shedding. When the hair
cycle is disrupted, premature anagen-to-catagen transition results in majority of hair follicles
(HFs) entering telogen and shedding concurrently, causing significant, noticeable hair loss.
The immune system is closely associated with the HF, with macrophages and mast cells
described in the perifollicular dermis (3,4). Skin-resident macrophages clear apoptotic cell
fragments following catagen (5) and may also interact with hair follicle stem cells (HFSC)
to maintain quiescence during telogen (1). The dynamic nature of the hair cycle results in a
constant flux of antigens, both self and non-self, from the manufacture of the hair shaft and
the infundibular connection to the outside world, respectively. To protect the hair bulb from
inappropriate immune attack, the HF has evolved a status of relative “immune privilege”
(IP). This was demonstrated elegantly by Billingham et al. decades ago showing that the
presence of HFs in allografts was sufficient to prevent immune rejection of melanocytes
in transplantation experiments on guinea pigs (6). Various mechanisms have since been
proposed for the IP of the HF, with the most prominent one being a downregulation of
MHC Class I expression (7). Hair loss disorders are associated with disruptions and changes
in the immune milieu of the HF (8,9), and conversely, immunotherapy has been utilized to
promote HF regrowth and regeneration.
2. The immune system interaction with the hair
follicle niche
With evidence of immune cells being associated with the HF, it is reasonable to
hypothesize that changes in immune cell composition and activity around HFs can affect
HFSC and the hair cycle. However, the direct influence of immune cells in promoting hair
regrowth and regeneration in humans is still unknown. In mice, regulatory T-cells (T-regs)
promote anagen re-entry via Notch signaling (10), and macrophages may release Wnt factors
to stimulate anagen under certain conditions (11). Wound-induced HF neogenesis (WIHN)
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Toh and Wang 10.3389/fmed.2023.1285452
is another phenomenon in rodents whereby brand-new HFs arise
from scar tissue of a wound. Cotsarelis and Ito showed that
relatively large wounds in the back skin of mice initially heal
without HFs, but these scars are soon populated by de novo HFs
via WIHN (12). Small cutaneous wounds in mice upregulate Wnt
and Shh pathways (13), while larger wounds recruit dermal γδ-T-
cells (14) and M2 macrophages (15) to promote WIHN. While the
mouse’s fur coat and human scalp hair differ in their stage of hair
cycle, fundamental processes and pathways are likely conserved,
and human HFs may respond in a similar manner to microtrauma.
In humans, crude immune stimulation has been shown to
induce hair growth. Friction and irritation are known causes of
hypertrichosis, and excessive hair growth occurs after limb fixation
with plaster cast application (16,17), and on burned skin borders
(18). Allergic contact dermatitis to wig adhesives is reported to have
a therapeutic effect in alopecia areata (AA) (19), forming the basis
of topical immunotherapy for AA. Contact dermatitis introduces
“antigenic competition” which recruits suppressor T-cells and
macrophages, producing an immunomodulatory environment and
dampening the autoimmune attack on HFs (20). These reports
point to a role for microtrauma to elicit a permissive environment
for hair regrowth and regeneration.
Newer treatment modalities for AGA harnessing the effects
of microtrauma include platelet-rich plasma (PRP), microneedling
and ablative and non-ablative lasers, which aim to reproduce
the effects of wounding in areas of alopecia. In PRP, intra-
dermal injection of activated platelets release growth factors
near HFs (21), including transforming growth factor-β(TGF-β),
epidermal growth factor, basic fibroblast growth factor (FGF),
vascular endothelial growth factor (VEGF), platelet-derived growth
factor (PDGF), and insulin-like growth factor-1, which support
the anagen phase of the hair cycle. The efficacy of PRP
appears operator- and protocol-dependent, but has been shown
in systematic reviews to promote hair regrowth modestly (22). In
randomized, split-scalp studies of PRP vs. sham injections, hair
density also increased among the controls, suggesting microtrauma
alone may stimulate hair regrowth (23). Indeed, several groups
have demonstrated that microneedling may be effective in treating
AGA (24) and AA (25). Both ablative and non-ablative settings of
Er:YAG lasers have been used in AGA and AA, with promising
results (26–28).
The efficacy of these treatments supports the hypothesis that
the microenvironment of HFSC can be manipulated to promote
hair regrowth. Immune cells are likely involved in the process
of microtrauma. The treatments above, however, are non-specific.
They induce an irritant, allergic or wounding response that varies
between patients, resulting in inconsistent effectiveness. We are
still in the process of understanding this process, and fine tuning
the procedures and patient selection to obtain the best possible
clinical outcomes.
3. Targeted immunotherapy for hair
regrowth
Targeted immunotherapy in promoting hair regeneration
is expected to grow with understanding of the detailed
control of the human hair cycle. The first mode of targeted
immunotherapy has been applied for AA, as we know most about
its immunopathology.
3.1. Immunosuppressive therapies with
stimulatory action in other parts of the
immune system or HFSC
3.1.1. JAK inhibitors
Janus kinase (JAK) inhibitors have revolutionized therapeutics
in dermatology, successfully utilized in many inflammatory skin
conditions including atopic dermatitis. The JAK-STAT pathway
is an integral component of AA pathophysiology, downstream of
interferon-gamma (IFN-γ) and interleukin (IL)-15 signaling.
Baricitinib is the first FDA-approved drug for AA in 2022. In
two concurrent phase III randomized controlled trials (BRAVE-
AA1 and BRAVE-AA2), baricitinib achieved SALT scores <20 at
52 weeks with a good safety profile (29). Baricitinib, which inhibits
JAK1 and JAK2 signaling is effective in long-standing AA resistant
to traditional therapies (30), besides being safe and effective in
pediatric AA (31). Increasingly specific JAK inhibitors (JAK1
ivarmacitinib, JAK3 ritlecitinib, and JAK1/Tyk2 beprocitinib)
(29,32) are investigated for use in AA, making treatment
more targeted.
Topical JAK inhibition not only reverses hair loss in AA mice,
but also induces the telogen-to-anagen transition in disease-free
C56Bl/6 mice (33). This suggests that the JAK-STAT pathway is
also involved in normal hair cycles (34), leading to the discovery
of a distinct subset of TREM2+macrophages that maintain
HFSC quiescence by secreting oncostatin M (1). Pharmacological,
immunological and genetic inhibition of these macrophages
sufficiently induced anagen in mice. Whether a similar mechanism
is present in the human HF niche is unknown, but STAT3 is
upregulated in AGA scalps (35).
The Wnt/β-catenin signaling pathway is the major pathway
in activating DPCs, which are crucial in the hair bulb and
bulge interaction for anagen initiation. Treatment of HFs with
ruxolitinib, a JAK1/2 inhibitor, stimulates the expression of β-
catenin mRNA, upregulating Wnt/β-catenin signaling. Further,
proinflammatory cytokines of AA, namely IFN-γ-induced caspase-
1, IL-1β, IL-15 and IL-18 are also suppressed by JAK1/2 inhibition
(36). JAK inhibition in AA thus may have more than an
immunosuppressive role, and may have immunotherapeutic roles
in stimulation of DP and/or HFSC.
In IFN-treated dermal papilla (DP) culture, ruxolitinib was also
shown to downregulate MHC class I expression, contributing to
partial IP restoration. In addition, ruxolitinib stimulated several
growth factors, including FGF7, that supported DP cell survival
which translates to a hair growth-permissive microenviroment
independent of its immunosuppressive properties (36).
The in vivo effects of JAK inhibition have yet to be evaluated,
partly due to the challenges in analyzing and quantifying the hair
cycle, as follicular units are asynchronous and hair cycle phases
last months to years. Existing JAK inhibitors also penetrate skin
insufficiently (37).
Other challenges to JAK inhibition include disease recurrence
after discontinuation and balancing long-term usage against side
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Toh and Wang 10.3389/fmed.2023.1285452
effects of infections, marrow suppression, transaminitis, and lipid
abnormalities (38).
3.1.2. Statins
Statins have been proposed for treating various dermatologic
conditions characterized by ingress of activated leukocytes into
the skin, including AA (39). In a pilot study, a combination
of simvastatin and ezetimibe reduced hair loss and resulted
in stable remission in AA mice model, with an increase in
FOXP3+T-regs (40). Simvastatin may improve AA through
multidirectional pro- and anti-inflammatory activities. These
include increasing Th2 cytokine secretion, upregulating T-reg cells
in mice (39), downregulating Th1 cytokine secretion via JAK-
STAT pathway modulation (41), inhibiting leukocyte activation,
adhesion and migration (42), activating Wnt/β-catenin signaling
pathway (43), and downregulating reactive oxygen species
production (44). However, larger placebo-controlled trials are still
required, as these findings were not always reproducible by other
authors (45).
3.2. Biologic therapies
Monoclonal antibody therapy is not as well established for AA
as for dermatological conditions like psoriasis and eczema. Most
TNF inhibitors are ineffective for AA, while dupilumab was found
to be modestly effective in a Phase IIa trial (46). Although AA is
associated with atopic dermatitis and psoriasis, treatment for the
latter does not always improve AA (47), and may sometimes worsen
hair loss (48).
The contrasting effects of biological therapies and JAK
inhibitors in AA suggest that current targets of monoclonal
antibodies (TNF-α, IL-17, IL-23 and IL-4 signaling) may support
the HF immune privileged microenvironment, and an unbalanced
blockade of these pathways leads to cytokine imbalance and AA
(49). JAK-inhibition is more focused on immune mechanisms that
share JAK-STAT pathways, which are more frequently associated
with “active” T-cell directives on the HF.
Nivolumab is an anti-PD1 (programmed cell death-1)
monoclonal antibody effective in many cancers, including
melanoma. It releases the inhibition of autoreactive T-cells,
allowing immune system clearance of tumor cells. This same
mechanism has been reported to cause AA in these patients
(50). The PD-1/PD-L1 pathway has also been implicated in
T-cell exhaustion accompanying response to AA treatment with
JAK-inhibitors (51). Exploring this pathway in AA may lead to
new targets for biological therapy.
3.3. IL-2 complex treatment
A pilot study using low dose IL-2 to expand T-reg populations
in severe AA showed initial promise (52). T-regs suppress
autoreactive NKG2D+T-cells that attack HFs and promote
hair regrowth by inducing anagen. In mice models, intradermal
injection of IL-2/anti-IL-2 antibody complex (IL-2c) efficiently
stimulates T-reg proliferation by 8- to 10-fold in the skin. T-
regs have also been shown to promote anagen via Jagged-1
expression (10).
A prospective randomized control study with low dose IL-2
was conducted which showed limited efficacy of this treatment
(53). In murine models, while the fold ratio of CD8 T-cells
over T-regs was also markedly reduced post-IL-2c treatment,
CD8 T-cells remained around HFs, including NKG2D+T-cells,
in established AA mouse models (54). Despite no significant
reduction in IL-10 or TGF-βsecretion, the expanded T-regs were
not sufficient to inhibit CD8 T-cell proliferation in established AA,
resulting in neither anagen induction nor AA reversal. Further
studies are warranted to investigate the role of IL-2/IL-2c in the
treatment of AA. Early IL-2c therapy has been hypothesized to
be effective in acute AA, which may slow disease progression
but may require adjunctive treatments for more chronic,
established cases.
3.4. Prevention or restoration of IP collapse
AA develops when the IP of the HF collapses, due to
ectopic MHC class-1 expression induced by IFN-γ(55). Ex vivo-
application of TGF-β1, α-MSH and the drug FK506 (Tacrolimus)
have been found to suppress MHC Class I expression in
cultured HF organ cultures, likely through suppressing mRNA
transcription (56). α-MSH, which also has immunosuppressive
properties, is also increased in AA lesional scalp post-UVA
phototherapy (57). While systemic calcineurin inhibitors like
ciclosporin have been effective in treating severe recalcitrant AA,
topical tacrolimus/FK506 has proven to be less reliable (58), and
exploring this method of restoring HF IP may further expand our
immunotherapy repertoire.
3.5. Harnessing microtrauma
For AGA, there is currently a wide variety of modalities
for inducing microtrauma to promote hair regrowth, including
fractional lasers and microneedling. While these may be non-
targeted, they enable more targeted drug delivery when combined
with topical treatments like minoxidil or PRP. Release of growth
factors with microtrauma [such as PDGF, VEGF, β-catenin, Wnt3a
and Wnt10b (59)] has been postulated to lead to angiogenesis,
dermal thickening, adipogenesis and HF stem cell activation to
promote anagen.
Identifying the key factors and signaling pathways that
promote microtrauma-induced hair regrowth will pave the way
to the next phase of targeted immunotherapy to treat hair
loss. Inclusion of these growth factors, or PRP, into customized
microneedles is currently explored as a delivery method for
treating AGA (60). These factors, as well as other signaling
molecules like nucleic acids, membrane receptors or co-factors,
can be packaged in exosomes to deliver a targeted signal of hair
regeneration (61,62).
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Toh and Wang 10.3389/fmed.2023.1285452
FIGURE 1
Summary of immunotherapy for hair loss disorders. (A) Current forms of immunotherapy are crude and non-targeted. Microtrauma produced by
microneedling or PRP treatments are eective in promoting HF regeneration in AGA, and topical immunotherapy causing allergic contact dermatitis
is an established treatment for AA. (B) Potential avenues for developing targeted immunotherapy for hair loss disorders. Some immunosuppressive
treatments may have mechanisms of action independent of their suppressive eects, or direct stimulatory roles on the HF itself, like JAK inhibitors.
JAK inhibition may have immunotherapeutic roles on the HF via upregulating the Wnt- β-catenin signaling pathway in DPCs, increasing FGF7 release
which supports DP survival, and downregulation of MHC Class I expression in the HF, partially restoring IP. Stimulation of T-regs in the vicinity of the
HF has both an immunomodulatory, as well as a direct pro-anagen eect on the HF. Targeted factors and signaling molecules can be packaged and
delivered with bespoke microneedle patches or systems to mimic the eects of microtrauma to stimulate HF regrowth and regeneration.
4. Conclusion
Targeted immunotherapy (Figure 1) is a promising form of
therapy for hair regrowth and regeneration, targeting immune
cells that support and influence the hair cycle. Refining our
current methods of immunotherapy will make these treatments
more accessible to a wider population of patients suffering hair
loss, with potentially fewer side effects. Further studies and
controlled trials are required before they can be incorporated
into clinical practice. If successful, targeted immunotherapy
will provide hope for patients struggling with or have failed
traditional treatments.
Author contributions
ET: Writing—original draft, Writing—review and editing.
EW: Conceptualization, Supervision, Writing—original draft,
Writing—review and editing.
Funding
The author(s) declare that no financial support was received for
the research, authorship, and/or publication of this article.
Conflict of interest
The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the
authors and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
claim that may be made by its manufacturer, is not guaranteed or
endorsed by the publisher.
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