Table of contents :
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)
: body surface area (BSA) = 1.8-2 m2
,
and mammary glands).
It consists of :)
/ keratin filaments, the individual strands of which transverse the
cytoplasm in all directions and extend into the cell processes to converge
and insert on the desmosomes; they are thought to have a supportive or
cytoskeletal function and, to be the principal precursor of cytokeratin.
via hemidesmosomes :
of the epidermis that contain melanosomes (more represented in coloured
races), granules that contain tyrosinase and synthesize melanins
:,
photoprotective, whose synthesis is stimulated by binding of a-MSH
to MC1R,
contribute to UV-induced skin damage by generating free radicals upon UV
radiation. Gene mutations that lead to a loss in function of MC1R
are associated with increased pheomelanin production, which leads to lighter
skin and hair color. This receptor is a major determining factor in sun
sensitivity and is a genetic risk factor for skin
cancer.
Over 30 variant alleles have been identified which correlate with skin
and hair color, providing evidence that this gene is an important component
in determining normal human pigment variation,
endothelin-2,
endothelin
3,
a-MSH,
FGF-2
/ bFGF
and HGF / SF
produced by neighbouring basal keratinocytes
(1-2%) in stratum spinosum
and blood vessels,
nerves,
muscle
cells,
sweat and sebaceous glands and hair
follicles.
))
: the complex consisting of ....
The latter is a fine, non-pigmented hair (peach fuzz) that covers the body
of children and adults.
(both testosterone
incretion and peripheral conversion to DHT),
are the thick pigmented hairs found on the scalp, beard, armpits, and pubic
area
),
dermcidin,
...); its composition varies with many factors, e.g., fluid intake, external
temperature and humidity, and some hormonal activity
and connective tissue that houses larger blood vessels and nerves. This
layer is important is the regulation of temperature of the skin itself
and the body. The size of this layer varies throughout the body and from
person to person (see also diseases
of subcutis)
thermoregulation
: the regulation of heat
and infections when immune function is limited, for example in patients
with genetic
and acquired
immunodeficiency
disorders and in those receiving immunosuppressive therapy after organ
transplantationref1,
ref2.
The regulation of skin defence mechanisms is also crucial, as inappropriate
or misdirected immune activity is implicated in the pathogenesis of a large
variety of acquired inflammatory skin disorders, including psoriasisref,
atopic
dermatitisref1,
ref2,
ref3
and allergic
contact dermatitis,
lichen
planusref,
alopecia
areataref,
vitiligo
and other vesicobullous diseasesref.
The role of immune dysfunction in these conditions is emphasized by their
response to immunosuppressive therapeutic interventionsref1,
ref2,
ref3,
ref4.
Human skin is composed of 3 distinct compartments relevant to its immune
functions :
+
memory T cells.,
CCL17
/ TARC
and ICAM1. These support the margination and baseline emigration of CLA+
memory T cells into non-inflamed skin. CLA- T cells, including
both naive cells and memory/effector cells that are targeted to
other tissues, as well as granulocytes and other immune cells, lack the
appropriate receptors to attach to dermal vessels and emigrate into non-inflamed
skin.,
TNF-a,
IL-18ref
and a large number of chemokines and other immunoregulatory cytokinesref1,
ref2
and antimicrobial peptides such as b-defensins
in response to various stimuliref,
including kineticref
and thermal trauma, UV radiationref,
cytokines and neuropeptidesref.
IL-1a
(and IL-1b
from epidermal Langerhans cells), in turn, acts as a potent stimulator
of local immune functionref.
Keratinocytes also produce a large number of chemokines and other immunoregulatory
cytokines in response to stimulationref1,
ref2,
ref3,
ref4.
These products have various important effects on resident innate immune
cells in the skin, such as mast cells, DCs and macrophages, resulting in
the upregulation of expression of other inducible mediators and recruitment
of additional immune cells from the bloodref.
The induction of local inflammation through IL-1, however, depends on the
balance of agonists (IL-1a,
IL-1b,
caspase-1
and IL-1R1)
and antagonists (IL-1Ra
and IL-1R2
that are active in this pathwayref1,
ref2,
ref3.
Each of these molecules can be produced by keratinocytes under various
conditions, as well as by other cells that are resident in the skin, making
it difficult to predict the effects of specific interventions. New members
of the IL-1 family continue to be identified, adding to the complexity
of regulation of cutaneous inflammationref.
Keratinocytes secrete cytokines and can be induced to express class
II MHC molecules
(role in Ag presentation?). Epithelial-cell injury or pathogen invasion
leads to the release of primary cytokines and the activation of both skin
cells (keratinocytes and fibroblasts) and resident innate immune cells
(Langerhans cells (LCs), dermal dendritic cells (DCs) and mast cells),
stimulating downstream activation cascades.
and dermal DCs are stimulated to mature and emigrate from the tissue to
the draining lymph node, carrying antigen for presentation to naive and
memory T cells. The cytokines and chemokines produced in response to this
activation cascade act on the local endothelia through NFkB-mediated
pathways to upregulate the expression of adhesion molecules, including
E-selectin,
P-selectin and ICAM1, and direct the recruitment of additional innate immune
components according to the specific signals that are generated — for example,
neutrophils, eosinophils and NK cells. Both the epithelial barrier cells
and resident innate immune cells in the skin express PRRs
that recognize specific pathogen components and can trigger downstream
activation cascades. The NF-kB signalling pathway
is seen as a key link between the innate and adaptive immune systems. In
the skin, NF-kB regulates the expression of
numerous genes that are involved in the initiation of the inflammatory
response, including adhesion molecules, chemokines and cytokines (such
as IL-1 and TNF), MMPs,
NOS
and enzymes that control prostanoid synthesisref.
Beyond the direct effects of these compounds on pathogens and abnormal
cells, products of the innate immune response direct the recruitment of
additional leukocytes to the site of activation. In humans, genes regulated
by NF-kB include the endothelial adhesion molecules
E-selectin
and P-selectin, ICAM1, VCAM1, and various chemokines and cytokinesref.
Collectively, these molecules are considered to be both necessary and sufficient
for initiation of the leukocyte adhesion–extravasation cascade that recruits
circulating leukocytes from the peripheryref.
These include antigen non-specific leukocytes, such as neutrophils and
NK cells, as well as key components of the adaptive immune system, such
as effector T cells. Circulating CLA+ T cells represent a library
of memory T cells with TcRs specific for antigens previously encountered
in the skin. Cytokines released by keratinocytes, fibroblasts and resident
antigen-presenting cells stimulate the upregulation of expression of E-selectin
and ICAM1 through NF-kB-mediated activation
pathways. Production and presentation of T-cell-specific chemokines, such
as CCL17,
CCL22
and CCL27,
on the local endothelium results in the recruitment of CLA+
T cells in an antigen non-specific manner. T cells entering the tissue
that encounter their specific antigen presented by local macrophages or
DCs will be activated to proliferate and carry out their specific functions.
Those that do not encounter their cognate antigen, which might be most
of the cells that are recruited, will enter the lymphatics and return to
the general circulation. Mast cells are another crucial component of the
cutaneous immune response apparatus.,
IL-4,
IL-5,
IL-6,
IL-13,
TNF-a
and GM-CSF,
in response to various TLR
ligandsref1,
ref2,
ref3.
These and other mast-cell products have an important role in both the initiation
and modulation of innate immune responses and the generation of adaptive
immune responses.
)
: activated DCs, whether derived from epidermal Langerhans
cells (LCs)
or dermal DCsref1,
ref2,
are professional APCs with the capacity to present antigens efficiently
and to affect the maturation of naive T cells to a memory/effector
phenotyperef.
At sites of injury or pathogen invasion in the skin, these cells become
activated through innate mechanisms, including PRRs
and exposure to the pro-inflammatory cytokines (such as IL-1 and TNF) that
are released in response to tissue injury or infection. Activated APCs
rapidly engulf foreign particles and undergo maturation as they emigrate
through the afferent lymphatics to the local skin-draining lymph nodesref1,
ref2.
This maturation
process
enhances antigen processing and upregulates the expression of MHC molecules
and co-stimulatory molecules, including CD80 and CD86ref.
Antigens encountered in the skin are carried by activated DCs through the
afferent lymphatics to the draining lymph nodes, and presented to naive
and central memory T cells circulating through the node. This increases
the likelihood of encountering T cells that express the appropriate TcR.
The function of the local draining lymph nodes is to promote frequent and
supervised contact between antigens that are derived from a specific segment
of the skin (carried by DCs that have migrated through afferent lymphatics)
and the adaptive immune system (T cells entering the lymph node through
high endothelial venules). Naive T cells that encounter their cognate
antigen presented by an activated and mature DC will undergo proliferation
and clonal expansion, produce autocrine growth factors and differentiate
into memory/effector T cells expressing homing receptors for the tissue
served by that node,
which binds E-selectin.
Although CLA and a4b7
mediate specific tethering and rolling steps in distinct tissue vascular
beds, the activation of these rolling cells also proceeds in a tissue-specific
manner. Several chemokines and their receptors are associated with skin-homing
T cellsref1,
ref2,
ref3,
including CCR4
and its ligands CCL17
and CCL22.
Constitutive and inducible expression of CCL17 on the luminal aspect of
post-capillary venules in the skin has been shown, and CLA+
cells typically co-express CCR4. CCR4–CCL17 interactions can lead to the
arrest of rolling T cells if they are provided an integrin ligand. CCL27
has also been implicated in skin homing. This chemokine, preferentially
produced by epidermal keratinocytes, binds to CCR10
and is chemotactic for T cells in vitroref1,
ref2,
ref3.
CCR10 is expressed by a subset of CLA+ T cells only, and its
role in inducing the arrest of T cells on post-capillary venules in the
skin has not been shown. Other work indicates that CCR6
might be important for skin homingref,
though the expression of this chemokine receptor is more variable. In most
situations, it seems that skin-homing memory cells that express CLA,
CCR4
and LFA1 accumulate in the skin, where E-selectin,
CCL17
and ICAM1 are constitutively and inducibly expressed on post-capillary
venules. What role other receptor–ligand pairs will have in specific conditions
remains to be determined. Cytokines produced by T cells that are recruited
to sites of inflammation can influence the content of the ongoing infiltrate
by modifying the balance of chemokines produced. For example, IFN-g
can induce keratinocytes to produce a range of products, including CXCL10,
CXCL9
and CXCL11,
which act to recruit T cells that express the chemokine receptor CXCR3ref.
Many pathogens have evolved to use tissue-specific routes of entry. The
persistence of memory T cells with both antigen and tissue specificity
in the peripheral circulation prepares the immune system for possible future
interaction with the same pathogen, by providing a population of antigen-specific
effector cells pre-targeted to the site where exposure to that pathogen
would be most likely to recur. Although skin-homing T cells are a kind
of rapid deployment corps that can be called up to inflamed tissues, there
is also evidence for constitutive homing of such T cells to the skin. T
cells recovered from non-inflamed skin express high levels of CLA
and CCR4
as well as other chemokine receptorsref1,
ref2.
Even in the absence of inflammation, leukocytes are observed to tether
and roll constitutively on low levels of selectin expressed in dermal post-capillary
venulesref1,
ref2.
These cells can be thought of as continuously scanning the endothelial-cell
surfaces of their target tissue for activation signals and are poised to
respond to the slightest hint of danger. Constitutive expression of E-selectin
on cutaneous microvessels has been described in both humans and mice, as
has expression of CCL17
and ICAM1ref1,
ref2,
ref3.
Using these sequential interactions, an indeterminate fraction of these
T cells continuously enter the skin and traffic through it, seeking antigen-dependent
activation. Antigen-specific T cells can also be detected in the uninflamed
skin of patients with atopic dermatitisref.
It is unclear whether T cells that home constitutively to the skin are
responding to subclinical levels of inflammation or if alternative mechanisms
exist that support constitutive expression of endothelial homing components.
It is important to note that while they are in the skin, these cells can
be thought of as 'resident' T cells; how long they reside in the skin is
unknown at present. CLA+ T cells recruited to sites of inflammation
in the skin will encounter a range of inflammatory mediators triggered
by innate immune mechanisms, as well as activated dermal DCs and inflammatory
dendritic epidermal cells (IDEC) that can present antigen and provide costimulatory
signals to T cells that express appropriate counter-receptorsref1,
ref2,
that retain expression of L-selectin
and CCR7,
and the ability to circulate through lymph nodesref.
These cells can then emigrate from the lymph node in which they were originally
produced to lymph nodes throughout the body (including those draining non-cutaneous
epithelial-cell interfaces), where they may encounter DCs expressing the
same cognate antigen. In this way, the immune system hedges its bets, ensuring
a more rapid and effective response even if the next encounter occurs at
a different interface. Although the original description of central memory
cells suggested that they could home to lymph nodes only, it has become
clear that some T cells can express both central memory and tissue-homing
receptors. For example, cells that express CLA,
L-selectin,
CCR4
and CCR7
are well represented in peripheral bloodref.
One interesting question that awaits investigation is whether central memory
T cells that are generated in a skin-draining lymph node and resident in
a different tissue lymph node (for example, gut or respiratory system lymph
node) will, if exposed to antigen, give rise to new effectors of a skin-homing
phenotype or effectors that home to the current source tissue, or both.
also have an important, though less well characterized, role in dampening
exaggerated cutaneous immune responses, as well as in the maintenance of
immune tolerance to innocuous self or exogenous antigensref1,
ref2.
Recent reports have indicated that regulatory T-cell subsets might traffic
to the skin using pathways that are similar to those used by effector cellsref.
An imbalance in effector/regulatory T-cell recruitment or functions might
be a crucial factor in the development of inflammatory skin lesions. Conversely,
for those conditions in which the antigen (self or exogenous) can be identified,
induction of regulatory T cells to specific antigens could provide a powerful
mechanism for inducing specific toleranceref.
after therapeutic allogeneic bone-marrow transplantation. If these diseases
are viewed from our current perspective of cutaneous immune surveillance,
insights emerge that are useful to understanding their clinical and biological
behaviour. The evidence described earlier indicates that the cutaneous
immune-surveillance system responds to any cutaneous injury that produces
danger signals as if it was potentially infectious. Both innate and adaptive
immunity are mobilized, and their activities are synergistic. Inappropriate
adaptive immunity can be driven by non-specific activation of innate immune
pathways, for example, chronic trauma due to scratching of the skin. This
in turn can lead to autoinflammatory feedback loops through the recruitment
and activation of leukocytes independent of antigen-specific help. Different
populations of cells accumulate in specific disease states, reflecting
the patterns of expression of vascular adhesion molecules and chemoattractant
cytokines induced by the balance of stimuli in that target organ. This
has potential significance for the immunopathology of diseases in organs
other than the skin. Our continued understanding of mechanisms of cutaneous
immune surveillance will almost certainly provide important insights into
immune surveillance and diseases at other environmental epithelial-cell
interfaces, including the gut, lungs, oropharyngeal and genital mucosa.
,
which affects 1–2% of adults worldwide, is characterized by the formation
of erythematous cutaneous plaques covered with scale. Histologically, psoriatic
plaques show keratinocyte hyperproliferation and both neutrophil infiltration
of the upper epidermis and an infiltrate in the dermis and epidermis replete
with T cells, DCs and macrophages. Psoriasis has an obligate immunological
component; therapies directed against T-cell activation and function are
highly effective in this disease, and the disease can be initiated in xenograft
models by activated T cellsref.
Increasingly, it is being understood as an autoimmune disease, although
the autoantigen(s) has not been identifiedref.
The T cells in psoriatic lesions are CLA+ and produce a type 1 cytokine
profile. CD8+ T cells in particular have been identified in
the epidermis and are thought to have a key role in disease expression.
So far, nearly all successful therapeutic interventions for psoriasis target
T cells. These include corticosteroids, methotrexate, cyclosporine and
ultraviolet light (with or without the photosensitizer 8-methoxy psoralens)ref.
More recently, immunobiological therapy has come to the forefront in this
disease, with reports of polarizing therapies such as IL-4, IL-10 and IL-11,
which inhibit Th1 cells and/or enhance Th2-cell functions,
showing promiseref1,
ref2,
ref3.
Other biological agents that inhibit T-cell recruitment or activation,
including alefacept (an LFA3– immunoglobulin fusion protein), efalizumab
(a humanized antibody specific for CD11a) and CTLA4–immunoglobulin fusion
protein have shown efficacy in clinical trials; with alefacept and efalizumab
recently winning FDA approvalref.
Biological agents that inhibit TNF are also quite effective — etanercept
is a p75 TNF receptor–IgG Fc fusion protein and infliximab is a humanized
monoclonal antibody specific for TNF. Both of these compounds have been
shown to be effective in the treatment of psoriasisref.
Interestingly, short-term treatment with an antibody specific for E-selectin
was recently shown to be ineffective in psoriasis, indicating that once
lesions are established, blocking T-cell rolling on E-selectin is insufficient
to block disease activityref.
By contrast, Efomycin M — a small molecule inhibitor of selectin binding
— has recently been shown to be effective in animal models of psoriasis
and might indicate a further role for inhibition of selectins in the treatment
of human psoriasisref.
The interplay of innate and adaptive immune responses in psoriasis is seen
in the Koebner phenomenon, in which physical trauma provokes the development
of a psoriatic lesion. As discussed earlier, skin trauma leads to the release
of innate immune activators, such as IL-1 and TNF, and results in the upregulation
of E-selectin and ICAM1 expression on local dermal post-capillary venules.
This leads to the activation of resident T cells and the recruitment of
CLA+ T cells from the blood, including the presumed subpopulation
that is specific for psoriatic autoantigens. Innate immune activators also
induce the maturation of DCs in the dermis and epidermis, enhancing their
activity as APCs, and encouraging the activation and proliferation of the
recruited T cells and the development of a psoriatic plaque.
is a common disease that affects people of all age groups worldwideref1,
ref2.
The prevalence has been reported to vary between 7% and 17% for children,
and in 60% or more of these individuals the disease can persist into adulthoodref1,
ref2,
ref3,
ref4,
ref5.
Atopy is the hereditary predisposition to allergy or hypersensitivity,
with the term atopic dermatitis used to describe a group of skin diseases
associated with atopic conditions (allergic rhinitis, allergic keratoconjunctivitis,
asthma and eczema) that might be seen in all age groups. Clinically, atopic
dermatitis is characterized by the development of erythematous, exudative
lesions in skin folds that are associated with intense itching. Histopathological
sections show perivascular infiltration of the dermis and epidermis by
lymphocytes, monocytes and macrophages. Acute atopic dermatitis is mediated
by T cells specific for environmental antigens, although there are subgroups
of atopic dermatitis that might have different mechanisms of triggering
and maintaining inflammation (for example, extrinsic/allergic atopic dermatitis
versus intrinsic/non-allergic atopic dermatitis)ref1,
ref2,
ref3.
The house-dust mite Dermatophagoides pterynossinus is a common source of
extrinsic antigen, and T cells specific for this antigen can be identified
in lesional and non-lesional skin of selected individualsref.
Antigen presentation is enhanced by the presence of high-affinity IgE receptors
on Langerhans cells, which internalize antibody–antigen complexes, process
antigen and present it to T cells within evolving lesions. Interestingly,
as atopic dermatitis lesions become more chronic, the cytokine profile
they exhibit shifts from Th2 to Th1 typeref.
The mechanism behind this switch is incompletely understood. The interplay
between innate and acquired immunity emerges in this disease also. It is
well established that scratching of pruritic non-lesional skin can lead
to the emergence of new lesions. Presumably this occurs by the trauma of
scratching, as in the Koebner response described earlier. A second link
comes at the level of bacterial colonization and superinfection. Staphylococcus
aureus is readily cultured from atopic skin, particularly lesional
skin, and it might be that stimulation by bacterial superantigens or the
activation of TLRs on resident skin cells leads to chronic release of primary
cytokines. Recent studies have shown that atopic epidermis, unlike psoriatic
epidermis, does not produce the antibacterial peptides -defensin and cathelicidin
in response to such infectionref,
and that IL-4 blocks the induction of these antimicrobial peptides from
keratinocytesref.
So, a product of Th2 cells blocks one pathway of innate immune
activation, leading to bacterial overgrowth and the induction of another
innate immune pathway. This, in turn, facilitates the continued activation
of the adaptive immune system, including the recruitment and activation
of atopic Th2 cells, and perpetuation of the lesion.
is manifested by varying degrees of erythema, spongiosis (epidermal oedema)
and vesiculation. Most contact allergens are themselves irritants (for
example, uroshiol or poison ivy), and they therefore provide both antigen
and danger signals when they contact skin. The pathophysiology of this
disorder is multifactorial, but is characterized by the infiltration and
activation of both CD4+ and CD8+ T cellsref1,
ref2.
A general model in which allergen-specific Th1 CD4+
and CD8+ T cells act as effectors and Th2 cells act
as regulatory elements is supported by investigations in animal modelsref.
Accumulation of eosinophils and enhanced production of IgE can also be
seenref.
ACD requires a sensitization phase of 1–2 weeks after exposure, in which
small molecule components of the active agent bind to endogenous proteins
and act as haptens to induce the activation and proliferation of antigen-specific
T cells, which then mature into skin-homing effector memory cells. Subsequent
epicutaneous exposures result in symptoms that progress over hours to days
and reflect activation of resident antigen-specific effector T cells as
well as their further local accumulation from the blood. This is followed
by accumulation of CD4+ T cells that produce Th2-type
cytokines (for example, IL-5 and IL-13) in chronic and resolving lesions.
Recent studies have implicated IL-10, produced by CD4+CD25+
regulatory T cells, as a key factor in the down-modulation of allergic
responses in the skinref1,
ref2.
describes a distinctive syndrome of dermatitis, developing within 100 days
of allogeneic haematopoietic-cell transplantationref.
Chronic cutaneous GVHD describes a more indolent syndrome that develops
after day 100. Development of GVHD depends on the transfer of immunologically
competent cells, such as mature T cells included in bone-marrow transplants
or resident in solid organ transplants, the presence of alloantigens on
host tissues that can stimulate the graft cells and the lack of an effective
host immunological response to the graft. Acute cutaneous GVHD is characterized
initially by a rash or by a generalized redness of the skin and desquamation.
Chronic cutaneous GVHD can lead to areas of thickened skin or sclerodermatous
changes that sometimes cause contractures and limitation of joint mobility.
The predilection of GVHD for the skin and the gastrointestinal tract has
led to speculation that it is mediated in these respective tissues by antigen-specific
T cells with distinct skin- or gut-homing propertiesref1,
ref2.
This hypothesis has not been formally tested.
are malignancies of skin-homing T cellsref1,
ref2.
The most common form of this uncommon disease — mycosis fungoides — is
characterized by patches and plaques on the skin, often in non-sun-exposed
areas, which can resemble eczematous dermatitis. Histopathological features
of CTCL include the clustering of malignant T cells in the epidermis, often
around Langerhans cells. There is evidence that expression of homing molecules
determines the anatomic localization of these cellsref.
Tumour cells that are CLA
and CCR4 positive but lack expression
of either L-selectin or CCR7
can be found in the skin, whereas cells that express both L-selectin and
CCR7 are associated with lymph-node involvement. The CTCL cells almost
invariably produce TH2-type cytokinesref.
Recently, evidence has emerged that CTCL is associated with marked disruption
of the T-cell repertoire, indicating that it might be a systemic disease
rather than simply a clonal malignancy of skin-homing T cellsref.
is characterized by complete or partial depigmentation of the epidermis.
It is an acquired progressive disorder in which some or all of the melanocytes
that reside in the interfollicular epidermis and, occasionally, in the
hair follicles are selectively destroyedref.
Vitiligo is relatively frequent, occurring in 1–2% of the population. CD8+
T cells specific for antigens that are uniquely expressed by melanocytes
are frequently seen in these patients, leading to the suggestion that vitiligo
is a T-cell-mediated autoimmune disorderref.
Interestingly, vitiligo is most prominent in areas that are subject to
minor trauma, providing another disease-related link between innate and
acquired immunity in inflammatory skin diseases.,
as highlighted by the example of smallpox. Not only must the antigen be
administered in a manner that leads to DC maturation and migration to lymph
nodes (danger signals or adjuvant effects), but also the route of administration
might have marked qualitative and quantitative effects on the desired protective
immune response. Vaccination through the skin (intradermal) will be most
efficient at stimulating skin-homing effector cells, whereas alternative
routes (for example, oral and intramuscular) will most efficiently generate
effector memory T cells that are directed towards other sites. Although
aggressive stimulation with adjuvants might bypass the anatomically specific
elements of the immune response by driving broad production of central
memory cells, it might be preferable in some cases to limit responses to
a desired site to avoid potential complications in other tissues.
can evoke humoral and cellular immune responses in some patients. The radial
growth phase of primary melanoma, associated with slow and superficial
growth without prominent dermal invasion, is regularly associated with
a marked dermal lymphocytic reaction, sometimes resulting in partial tumour
destructionref1,
ref2,
ref3.
Clonal expansion of T cells occurs in regressing primary melanoma, and
lymphocytes explanted from such lesions are cytotoxic in vitro to
autologous melanoma cellsref1,
ref2,
ref3,
ref4.
Although a rapid lymphocytic infiltrate in the vertical growth phase (where
rapid growth and prominent dermal invasion occur) of primary melanoma occurs
less frequently, this response is correlated with prolonged survival and
a reduced incidence of metastatic diseaseref1,
ref2,
ref3.
Many strategies to enhance antimelanoma immunity are under investigation
at present, based on whole tumour cells or defined tumour antigensref1,
ref2,
ref3,
ref4,
ref5,
ref6,
ref7,
ref8,
ref9.
In the development of such protocols, relatively little attention has been
paid to the route of vaccination usedref1,
ref2,
ref3.
We
would predict that immunization through the skin would generate a skin-homing
effector T-cell response, but might not be expected to target metastatic
tumours in the lungs or gastrointestinal tract efficiently.
Under normal
circumstances, antimelanoma T-cell responses might first be expected to
develop in the local skin-draining lymph nodes and should lead to the generation
of skin-homing memory effector cells. Indeed, IL-2 therapy (which expands
and activates pre-existing memory effector cell populations) and DC vaccine
therapies result in more rapid responses to the cutaneous metastases of
melanoma than to metastases elsewhereref.
For immunization with melanoma-antigen-pulsed DCs, if they are injected
into the skin, they could traffic through afferent lymphatics to draining
lymph nodes, generating skin-homing memory effector cells. Injected intravenously,
however, their migration patterns remain largely unknown. Protocols to
enhance DC migration to peripheral lymph nodes are under investigationref.
It is also important to consider the effects of vaccination strategies
on DC activation, as antigen presentation by immature DCs has been shown
to stimulate antigen-specific inhibition of effector T-cell functionsref1,
ref2.
Copyright © 2001-2005 Daniele Focosi.
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