Section 8-a
Skin Rejection in Human Hand Allografts:
Histological Findings and Grading System
Jean Kanitakis
Introduction
Composite tissue allotransplantation, i.e. allotransplantation of heterogeneous non-organ tissues containing skin, muscles, bones, tendons
and vessels, has been experimentally performed
in animals for several decades, with reports dating back to the beginning of the twentieth century [1]. With the advent of cyclosporine, limb
allografts were tried again in primates in the
1980s but resulted invariably in more or less
rapid immunological rejection, manifesting
mainly on the skin [2, 3]. However, discovery of
safer and more efficient immunosuppressive
drugs, such as tacrolimus and mycophenolate
mofetil (MMF), along with advances in
(micro)surgical techniques, has made allotransplantation of composite tissues possible in
humans, opening a new era for replacement of
missing tissues due to traumatic or postoperative loss and congenital defects [4, 5]. Until now,
allografts of vascularised tendon [6], nerve [7],
veins [8], muscle [9], femur, knee [10, 11], larynx
[12], intestine and abdominal wall [13], facial
skin and ears [14] and tongue [15] have been
performed in humans. Very recently, a partial
allotransplantation of the face was performed in
France.
Successful allografting of hands in humans
was predicted to occur before the end of the
twentieth century [16]. In 1963, a hand allograft
was performed in Ecuador before the era of
modern immunosuppression but, not surpris-
ingly, it was rapidly rejected and amputated two
weeks posttransplantation [17]. The first successful (single) human hand allograft (HHA)
was performed in Lyon in 1998 by an international team headed by J.M. Dubernard [18, 19].
To date, 24 HHAs have been performed in eight
medical centres worldwide (11 monolateral and
four bilateral hand transplantations, two bilateral forearm transplantations and one thumb
transplantation) [20, 21]. HHA, by virtue of its
complex structure encompassing several tissues
of variable antigenicity (skin, muscles, vessels,
nerves, tendons, bones) can be considered the
“gold standard” of composite tissue allografts
(CTA).
The success of any CTA depends on adequate
functional recovery and prevention of allograft
rejection. The combined use of older immunosuppressants (such as steroids and azathioprine)
and more recent ones (such as cyclosporine A,
MMF, tacrolimus and rapamycin) can efficiently
prevent rejection of human CTA although the
balance between tolerance and rejection remains
subtle and needs to be continuously evaluated.
Experience obtained from limb allografts in animals suggests that each component of a CTA
interacts with the host immune system with a
special degree of antigenicity, with the skin
behaving as the most antigenic [22]. This was
subsequently confirmed by clinicopathological
observations of human-skin-containing CTA
(namely HHA), showing that skin is preferentially affected during periods of graft rejection [23].
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J. Kanitakis
Thus, the pathologic study of CTA is important
for at least two reasons. The primary one is early
detection of graft rejection; indeed, experience
obtained so far strongly suggests that clinical
and pathological monitoring of the skin is the
most reliable way to detect allograft rejection
and is more sensitive than clinical signs (inflammation, fever) or other biological tests [such as
C-reactive protein (CRP) and anti-human leukocyte antigen (HLA) antibodies]. The second is
that pathological study of the CTA may confirm
its structural integrity, which is a prerequisite
for good allograft function; it may also show
whether allograft cells (including immunologically relevant ones) are in the mid- or long-term
replaced by cells of recipient origin, therefore
rendering the allograft less antigenic towards its
host and allowing for tapering of immunosuppressive treatment.
We review here the main pathologic features
of HHA, based mainly on our own experience
obtained in six recipients allografted in Lyon
and Milan [18, 19, 24, 25] and followed up for up
to 5.5 years. Available data concern primarily
the skin since this is the most accessible tissue
for visual inspection and microscopic study.
Furthermore, skin biopsies are easy to obtain
and do not significantly impair the allograft
since the resulting wounds heal rapidly and
completely.
Fig. 1. Histological aspect of allografted skin in a human
hand allograft: the three layers of the normal skin are visible
(epidermis,dermis,hypodermis).The epidermis contains all its
normal layers, and the dermis contains sweat glands, pilosebaceous follicles and vessels (haematoxylin-eosin)
Nonrejection Conditions
Apart from periods of graft rejection (see further), skin contained in HHA maintains after
allografting a normal histological structure,
being composed of its three major layers (epidermis, dermis and hypodermis) (Fig. 1). The
epidermis is organised in four characteristic cell
layers (from bottom to top: basal, spinous, granular and horny) and contains all its normal cell
types, i.e. keratinocytes (KCs), melanocytes,
Langerhans (LC) and Merkel cells. KCs express
their characteristic antigens, such as keratins
(expressed in a characteristic pattern by all epidermal-layer KCs) (Fig. 2), involucrin (within
the upper epidermal layers) and filaggrin (with-
Fig. 2. Normal expression of high molecular weight keratins
1 & 10 in suprabasal epidermal keratinocytes of a human
hand allograft (immunoperoxidase revealed with aminoethyl
carbazole)
in the granular layer), reflecting a normal epidermal differentiation process. Basal-layer KCs
express normally the proliferation-associated
nuclear antigen Ki67, showing they are cycling
and capable of regeneration (Fig. 3), and the
nuclear p63 antigen involved in epidermal dif-
Skin Rejection in Human Hand Allografts: Histological Findings and Grading System
Fig. 3. Expression of the cell-cycle-associated nuclear antigen Ki67 in basal epidermal keratinocytes in a human hand
allograft (immunoperoxidase revealed with aminoethyl carbazole)
ferentiation. Biopsies taken from the junction
between donor and recipient skin show that epidermal KCs of donor and recipient origin blend
smoothly to produce a normal-looking epithelium, the respective origin of which can be differentiated thanks only to the expression of donoror recipient-specific antigens (such as HLA)
(Fig. 4). Nonkeratinocytic cells, detected thanks
to the expression of their specific antigens, are
also normally present in the epidermis and its
appendages. Melanocytes, expressing the
melanoma antigen recognised by T cells
(MART)-1 antigen, tyrosinase and S100 protein
are present in normal numbers in the basal cell
Fig. 4. Histological aspect of the skin of a human hand allograft taken at the junction between recipient (left) and donor
(right). Recipient (but not donor) epidermal keratinocytes
express the human leukocyte antigen (HLA)-A24
(immunoperoxidase revealed with aminoethyl carbazole)
251
layer (Fig. 5). LCs, the antigen-presenting cells
of the epidermis recognised thanks to the
expression of CD207/Langerin and CD1a antigens, are found in normal numbers within the
mid-stratum spinosum (Fig. 6). LCs are mobile
cells originating from CD34-positive bone-marrow precursors; their replacement by cells of
recipient origin could therefore be expected.
This possibility was monitored immunohistochemically with an antibody recognising a recipient-specific HLA antigen. In the first HHA, a
limited number of LCs (approximately 10%) of
recipient origin was detected in the allografted
epidermis during an episode of graft rejection
[24]. However, long-term follow-up (5.5 years) of
another HHA showed no epidermal LCs from
the recipient, suggesting that under steady-state
Fig. 5. The epidermis of a human hand allograft contains
normal numbers of (MART)-1+ melanocytes located within
the basal cell layer (immunoperoxidase revealed with
aminoethyl carbazole
Fig. 6. The epidermis of a human hand allograft contains
several dendritic CD1a+ Langerhans cells (immunoperoxidase revealed with aminoethyl carbazole)
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J. Kanitakis
conditions, the renewal of LCs in human epidermis is attributable to mitotic divisions of preexisting LCs or to local progenitors [26], in keeping
with experimental data obtained in mice [27].
Merkel cells, expressing namely keratin 20, are
also found in the basal epidermal layer. In the
dermis, epidermal adnexae (pilosebaceous follicles and sweat glands) are present and show normal histological structure; they normally
express their characteristic differentiation antigens, such as carcinoembryonic antigen (sweat
glands) and epithelial membrane antigen (sweat
and sebaceous glands) and contain basal cells
expressing Ki67 and p63, suggesting normal
growth. The dermis shows normal structure as
to the presence of collagen and elastic fibres and
contains all cell types found in normal conditions, such as perivascular factor XIIIa+ dermal
dendrocytes (Fig. 7), CD34+ deep dermal dendrocytes, tryptase+ mast cells and fibroblasts.
The dermal vasculature shows a normal structure, accounting for normal skin trophicity
(colour, temperature and healing process).
Endothelial cells express their characteristic
antigens (von Willebrand factor, CD31 and
CD34). Nerve bundles are also present in the
dermis and are made of (donor) perineurial
fibroblasts and Schwann cells, expressing their
characteristic antigens (epithelial membrane
antigen and S100 protein, respectively) (Fig. 8).
In the early postgraft period, cutaneous nerves
do not contain axons (due to their degeneration
Fig. 7. The upper dermis in a human hand allograft contains
several factor XIIIa+ dermal dendrocytes (immunoperoxidase
revealed with aminoethyl carbazole)
Fig. 8. A dermal nerve in a human hand allograft contains
Schwann cells, labelled by an antibody to S100 protein. This
antigen is also expressed by adjacent adipocytes
(immunoperoxidase revealed with aminoethyl carbazole)
following amputation during graft procurement); however, axons (presumably of recipient
origin), recognisable by their expression of neuronal markers [such as neurofilaments and protein gene product (PGP) 9.5] progressively reappear in dermal nerves [28] and also in the epidermis, vessel walls, arrector pili muscles and
around sweat glands (Fig. 8). The progressive
reinnervation of the skin completes its normal
histological appearance and parallels sensory
return. The hypodermis shows normal structure,
consisting of adipocytes arranged in lobules
separated by connective tissue septa; they normally express their characteristic antigens
(vimentin and S100 protein) (Fig. 9).
The deeper tissues (muscles, bones, tendons)
have not been studied histologically in nonrejection conditions; however, it can be reasonably
assumed that, similarly to the overlying skin,
they do not show obvious pathological changes.
Future studies are needed to show which, if any,
of the cellular constituents of these tissues are
replaced by host cells. This possibility does not
seem very likely in view of the fact that (similarly to the skin) the allografted tissues contain
their own stem cells, which are capable of dividing and maintaining tissue homeostasis, at least
under steady-state conditions.
Skin Rejection in Human Hand Allografts: Histological Findings and Grading System
Fig. 9. Neurofilament immunoreactivity showing the presence of axons is seen within a dermal nerve in a human hand
allograft at month 18 postgraft (immunoperoxidase revealed
with aminoethyl carbazole)
Allograft Rejection
Pathological features of allograft rejection manifesting in the skin in the setting of forelimb
allotransplantation have been studied in experimental animal (namely rat [29–31] and swine
[32]) models, and scoring systems for assessing
the severity of rejection have been proposed. In
these models, rejection manifests clinically with
redness, erosions, blisters and necrosis of the
skin.
In the case of HHA (and intestine with
abdominal-wall allografts), signs of allograft
rejection appear rather regularly in the early
posttransplant period, around the seventh to
ninth week postgraft. Clinically, they manifest as
erythematous asymptomatic macules that
appear insidiously over the skin of the HHA [13,
33]. These signs of acute rejection can be
reversed within 10–15 days with increased systemic immunosuppressive treatment and
adjunction of local immunosuppressants
(steroids and/or tacrolimus). If (as happened in
the first HHA) immunosuppression is discontinued, cutaneous lesions progress slowly to scaly,
erythematous or violaceous papules that coalesce to produce lichenoid or psoriasiform
plaques over the allografted limb, affecting eventually the nails. These (chronic) changes occur
several months postgraft (between months 16
and 28).
253
Pathologic changes of allograft rejection in the
skin vary greatly according to severity of rejection
and affect the dermis, epidermis and, in most
severe episodes, hypodermis. Considering the
spectrum of these changes, we recently proposed a
scoring system of five degrees of severity of allograft rejection that can be used to monitor development of rejection and its regression upon
adjustment of immunosuppressive treatment [34].
Changes seen in each grade are the following:
Grade 0: no rejection. The skin shows normal
histological structure, as described above.
Occasionally, a small number of lymphocytes may
be present around blood dermal vessels, but the
density of this infiltrate is not sufficient to raise
suspicion of rejection (Fig. 10). This grade corresponds clinically to normal-looking skin.
Grade I: mild rejection. This is characterised
by a mild dermal lymphocytic infiltrate forming
small perivascular cuffs in the upper and occasionally mid dermis (Fig. 11). Lymphoid cells
consist of both CD4+ and CD8+ T cells and are
of recipient origin, as shown by their expression
Fig. 10. Biopsy from normal-looking skin of a human hand
allograft shows no signs of rejection (grade 0). Note the presence of a minute number of perivascular lymphocytes
(haematoxylin-eosin)
254
J. Kanitakis
Fig. 11. Mild allograft rejection (grade I) in a human hand
allograft: a mild perivascular lymphocytic infiltrate is seen in
the dermis (haematoxylin-eosin)
of recipient-specific HLA antigens (Fig. 12). The
epidermis is as a rule unaffected. This grade corresponds macroscopically to pink noninfiltrated
macules developing within weeks posttransplantation; they may also be noted in clinically normal-looking skin, suggesting that starting (mild)
rejection may not be visible clinically.
Grade II: moderate rejection. This is characterised by a moderately dense dermal infiltrate,
forming perivascular aggregates and diffusing
somewhat between collagen bundles. The infiltrate is predominantly lymphocytic but may
contain occasional monocytic/histiocytic cells
(Fig. 13). The epidermis may be unaffected or
may show a mild degree of infiltration with
inflammatory cells (exocytosis) and/or intercellular oedema (spongiosis), predominating within the lowermost cell layers. These changes are
found in erythematous, noninfiltrated macular
skin lesions.
Fig. 12. The dermal lymphocytic infiltrate is of recipient origin, as shown by the expression of the recipient’s specific
human leukocyte antigen (HLA)-A24 antigen. The (donor)
epidermis is HLA-A24-negative (rejection grade III)
(immunoperoxidase revealed with aminoethyl carbazole)
Grade III: severe rejection. This is characterised by both epidermal and dermal changes.
The most regular ones are seen in the dermis
and consist of a dense, mainly lymphocytic,
infiltrate forming nodules around capillaries of
the upper dermis, larger blood vessels of the mid
and lower dermis, and eccrine sweat glands (Fig.
14). The epidermis contains scattered necrotic
KCs and shows focal vacuolar degeneration of
the basal cell layer, which is invaded by lymphocytes (interface dermatitis). Occasionally,
changes indistinguishable from those seen in
cutaneous graft-versus-host disease (GVHD) are
seen, such as epidermal hyperplasia (orthokeratotic hyperkeratosis, hypergranulosis, acanthosis
and papillomatosis), with a dense subepidermal
band-like lichenoid lymphocytic dermal infiltrate (Fig. 15). Scattered apoptotic/necrotic KCs
may be seen in epidermal adnexae also (hair follicles, eccrine excretory ducts). This grade corre-
Skin Rejection in Human Hand Allografts: Histological Findings and Grading System
255
Fig. 15. Severe rejection (grade III) of the skin in a human
hand allograft showing histologically an aspect of graft-versus-host disease (orthokeratotic hyperkeratosis, hypergranulosis, acanthosis, papillomatosis, dense dermal infiltrate forming a horizontal band in the papillary dermis) (haematoxylineosin)
Fig. 13. Moderate allograft rejection (grade II) of the skin in
a human hand allograft: a moderately dense lymphocytic
infiltrate forming perivascular cuffs is seen in the dermis
(haematoxylin-eosin)
Fig. 14. Severe rejection (grade III) of the skin in a human
hand allograft: a dense lymphocytic infiltrate is seen in the
dermis. The overlying epidermis contains foci of spongiosis
and lymphocytic exocytosis and shows some degree of basalcell vacuolisation (haematoxylin-eosin)
sponds to papular erythematous, infiltrated,
more or less scaly papules that are either isolated or coalescing in plaques, developing several
months posttransplantation.
Grade IV: very severe rejection. This is characterised by an epidermis of variable thickness
comprising both highly hyperplastic, lichenoid
areas and zones of epidermal thinning and
necrosis resulting from the confluence of necrotic KCs (Fig. 16). Intraepidermal lymphocytic
exocytosis is seen, especially within areas of epidermal hyperplasia. Subepidermal clefts may
Fig. 16. Very severe rejection (grade IV) of the skin in a
human hand allograft: the epidermis appears still hyperplastic on the right, but is thinned on the left where a subepidermal cleavage has developed.A dermal perivascular infiltrate is
present (haematoxylin-eosin)
256
J. Kanitakis
form as a result of KC necrosis and basal-celllayer vacuolisation. The dermis contains an
inflammatory infiltrate forming large aggregates
around blood vessels, hair follicles and eccrine
glands, and smaller ones around tactile corpuscles and nerves (Fig. 17); this extends focally to
the hypodermis in the form of perivascular nodules. Eccrine secretory ducts show basal cell vacuolisation and infiltration by lymphocytes; they
also often display malpighian metaplasia and
contain apoptotic KCs (Fig. 18). The wall of
some large vessels (venules) of the deep dermis
may show heavy lymphocytic infiltration. The
inflammatory infiltrate is polymorphous, made
Fig. 17. Very severe rejection (grade IV) of the skin in a
human hand allograft: the dermis contains a heavy lymphocytic infiltrate forming perivascular and perifollicular nodules
(haematoxylin-eosin)
Fig. 18. Very severe rejection (grade IV) of the skin in a
human hand allograft: the dermis contains a dense infiltrate
made of lymphocytes and eosinophils.An eccrine sweat gland
duct contains necrotic keratinocytes (haematoxylin-eosin)
mainly of activated (HLA class II+) CD45RO+
memory T cells, with abundant eosinophils and
lower numbers of CD20+ B cells, CD79a+ plasma
cells, tryptase+ mast cells and histiocytic cells.
Up until now, this grade has been found in the
amputation specimen of the first HHA recipient
(obtained during the 28th month postgraft) that
showed macroscopically, along with changes
observed in previous grades, superficial erosive
and necrotic areas.
Almost identical cutaneous clinicopathologic
findings have been reported during graft rejection in other patients with HHA [35, 36] and
abdominal-wall and intestine allotransplantation [13], and pathological grading systems very
similar to the one described above have been
proposed [37, 38]. Since follow-up of the patients
with CTA is relatively short, these grading systems will probably have to be refined in the
future. Indeed, the possibility exists that additional pathologic changes (such as dermal fibrosis resulting in a sclerodermoid state) could
develop in the long term. Furthermore, the role
of lymphoid cells infiltrating the skin needs further evaluation. Indeed, we have recently
observed that a small subset (usually around
10%) of skin-infiltrating lymphocytes both in
normal-looking skin and during episodes of
rejection expresses the FoxP3+ phenotype of
CD4+/CD25+ T-regulator cells (Fig. 19). These
cells could induce tolerance rather than rejection
[39]. Therefore, the functional properties of the
Fig. 19. FoxP3+ T-regulatory cells are present in the skin of
a human hand allograft during the fifth year postgraft
(immunoperoxidase revealed with aminoethyl carbazole)
Skin Rejection in Human Hand Allografts: Histological Findings and Grading System
lymphocytic infiltrate will probably need to be
considered in the assessment of the severity of
rejection.
Pathological data concerning underlying tissues (such as muscles or bones) during episodes
of rejection of skin-containing CTA are sparse
since these tissues are usually not subjected to
pathological study as long as the allograft has
not been removed. Such tissues were studied in
the amputation specimen of the first HHA; they
showed considerably less-severe changes compared with cutaneous ones, highlighting the
higher degree of antigenicity of the skin. The
main changes consisted in mild to moderate
perivascular lymphoid cell infiltrate present
within muscle fibres and tendons (Fig. 20).
Some muscle fibres looked atrophic, probably
reflecting lack of adequate re-education (rather
than graft rejection). The cartilage and bones
(including bone marrow) of small joints did not
257
show obvious changes [23]. These results are
similar to those observed during rejection of rat
limb allografts, showing pathological changes
mostly confined to the skin [31]. A preliminary
study of an HHA from China reported stronger
rejective pathologic changes in muscle and
nerve compared with the skin [40]. The reasons
for this discrepancy remain unclear.
In conclusion, pathological monitoring of the
skin appears at this time to be the most reliable
test allowing early detection of allograft rejection in the setting of HHA (and also of other
CTAs containing skin, such as abdominal wall
and intestine). Existing pathological grading
systems of rejection allow assessment of the
severity of allograft rejection and the effect of
antirejection treatments. Future studies should
aim at defining more precisely the functional
role of skin-infiltrating host lymphocytes and
the possible development of long-term changes.
Fig. 20. Amputation specimen of the first human hand allograft showing in the skin very severe rejection (grade IV):
a mild perivascular lymphocytic infiltrate is seen within a striated muscle (haematoxylin-eosin)
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