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Hypothetical
treatment approaches for alopecia areata
While
the initiation of alopecia
areata may involve a succession of events, the
perpetuation
of alopecia
areata is likely to be a cycle of events and not a cascade. This
is particularly relevant when the morphological target, the hair
follicle, follows a cycle of proliferation and regression. Within
the cycle there are four key events; 1) hair follicle located
antigen
exposure (be it exogenous, endogenous, normal or aberrant expression)
to the immune system, 2) antigen presentation, co-stimulation,
and
activation of responsive lymphocytes by antigen presenting cells,
3) activated inflammatory cell migration to, and infiltration
of
hair follicles,
and 4)
the
action of the inflammatory cell infiltrate on the hair follicles.
Each of these events is vulnerable to therapeutic intervention.
In addition, peripheral to the disease cycle mechanism, the reactive
lymphocyte clones may be tolerized, deleted, or otherwise modulated.
If alopecia
areata pathogenesis is founded upon this basic inflammation mediated
concept, then there are several possible approaches to new treatment
development:
 1) Drug treatments for alopecia
areata are predominantly immunosuppressive
or immunomodulatory in their effect. Immunosuppressive agents
restrict
infiltration of the skin and hair follicles by activated inflammatory
cells while contact sensitizing agents alter the skin environment
such that the action of inflammatory cells on hair follicle growth
is downregulated. Remission of alopecia areata has been induced
using several immunomodulatory compounds. Intralesional injection
of triamcinolone acetonide,
PUVA
(methoxysporalen plus UV A light), and treatment with the topical
sensitizers dinitrochlorobenzene (DNCB), diphenylcyclopropenone
(DPCP), and squaric acid dibutyl ester (SADBE) have each induced
hair growth. These and other evidence demonstrate hair
loss may be due to inflammatory autoimmune mediated,
hair
follicle specific mechanisms.
2) Minoxidil, and also in part cyclosporin and
tacrolimus, have direct hair follicle growth promoting effects.
As such, an additional secondary alopecia areata therapeutic approach
is to treat the symptom of hair loss using
agents with direct action on the affected hair follicles.
However,
the relatively non-specific action, potential for side effects,
and limited response in many individuals
to current treatments means new therapeutic approaches are required.
In the short to mid term, new and improved drug treatments will
become available, primarily derived from pharmaceutical research
and developments in other autoimmune and inflammatory diseases.
With a greater understanding of immunosuppressive agents, contact
sensitizers and hair growth promoting drugs and their modes
of action,
more refined and potent drugs may become available that are
suitable for use in alopecia
areata.
3) Theoretically, autoimmune or inflammatory disease
mechanisms can be modulated in several ways. By extension of our
understanding of inflammatory mechanisms and drug action upon them,
specific pathways may be targeted. Observations on contact sensitization
treatment have led to speculation that future treatments could involve
modifying the skin and hair follicle biochemical environment. Injection
of interleukins or application of their respective cDNA sequences
may be used to block or modulate inflammatory cell infiltration
of the skin and hair follicles. Alternatively, similar approaches
may directly promote hair growth in spite of hair follicle inflammation.
4) Potentially, the most challenging
therapeutic approach is to define lymphocyte clones reactive for
hair follicle
antigen epitopes and either block their production (clonal deletion)
or promote tolerance (clonal anergy). Oral
tolerance has been one suggested approach in autoimmune disease
treatment; however, without knowledge of the antigenic targets
involved
in alopecia
areata, such treatment approaches are not yet viable.
5) The blockade or modulation of antigen presentation
and co-stimulation by antigen presenting cells to the responsive
lymphocyte clones involved in alopecia
areata may be a further focus of new treatment
approaches.
6) Once the lymphocytes are activated, it may still
be possible to block cell migration from sites of activation to
the skin and hair follicles. Preliminary investigations in which
CD44v10 was targeted with monoclonal antibodies suggest cell migration
inhibition may have potential alopecia
areata treatment benefit. Other activated
cell
surface markers and variants expressed
during migration may be additional targets. These approaches may
be employed as both treatment and preventative measures in alopecia
areata
susceptible
individuals.
7) Once hair follicle inflammation is underway
several treatment approaches are still possible. A potentially
complicated
therapeutic intervention may involve blocking or modulating antigens
expressed within anagen stage hair follicles that are the apparent
target for inflammatory cells or masking their expression. In
addition to modifying the inflammation inciting antigen expression,
inhibition
of MHC expression within hair follicles may also block alopecia
areata lesion perpetuation.
8) Finally, the mechanisms by which the inflammatory
cells adversely affect hair follicle activity may be targeted, including
disruption of Fas - Fas ligand interaction, prevention of granzyme
and perforin action, oxygen radical neutralization, and alteration
of the cytokine receptor and cytokine milieu.
Therapeutic intervention in the short term will involve
new and improved drug treatments to modulate hair follicle inflammation
and to promote hair growth. In the mid term, aspects of the disease
cycle may be targeted with cytokines, antigens, antibodies, and
other factors. In the long term, treatment may target genes directly
involved in the disease cycle mechanism or the contribution of general
susceptibility and severity modifying genes. |
