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In a recent study, the authors analyzed the gene expression
profile of different Banff grades of skin and showed that an￾tigen presenting cell (APC) and T-cell related genes were
upregulated in higher grades of rejection; these included
genes related to T-cell infiltration, Th1 polarization, and an￾tigen processing and presentation.5 Costimulatory pathways
were upregulated in the most severe cases of rejection. In
transplant medicine, the CD28-CD80/86 and CD40-CD40 L
costimulatory pathways are well characterized, and the tar￾geting of these pathways is a clinical reality. For example,
belatacept (a selective costimulation blocker used in cases of
kidney injury) blocks the interaction of the T-cell receptor
CD28 with the APC surface antigens CD80 and CD86, in turn
reducing effective T-cell activation and promoting the “toler￾ance” of T-cells to the allograft.6
The severity and frequency of skin rejection in VCA is at
least partially attributed to the transfer of donor-derived im￾mune cells (including T-cells and APCs). It has been hypoth￾esized that a hostile interaction between 2 immune systems
contributes to the high frequency of skin rejection episodes.5
Lian et al.
7 found that donor-derived tissue-resident memory
(predominantly CD8þ) T-cells (CD69þ/CD103þ/CLAþ) are
spatially associated with the sites of injury during facial
allograft rejection. Thus, a graft versus host type reaction was
hypothesized to contribute to allograft cell injury as a result of
collateral damage.
There is an ongoing debate about whether skin is the pri￾mary site of rejection. Recently published data indicate that
mucosa may be more antigenic compared with skin and point
to the importance of mucosal assessment during evaluation of
pleomorphic allograft rejection.8 In a recent publication, we
identified the mucosa of the oral and nasal cavities as one of
the main targets of rejection in facial VCA; in comparison to
skin, the mucosa consistently exhibits more prominent
microscopic changes indicative of an acute rejection event.8,9
There is a paucity of studies that investigate differences be￾tween the rejection processes in deeper tissues such as
vasculature and the skin. Investigating the differential effect
of the immune system on different tissue types is important
as chronic changes (see below) are often mediated by repeated
insults to target tissues such as vasculature. Ongoing sub￾clinical rejection in these tissues, which is not reliably pre￾dicted by skin biopsies alone, could limit the longevity of VCAs
and thus present an important question moving forward.
Antibody-mediated rejection
Another form of rejection of allografts is mediated by circu￾lating donor-specific antibodies (DSA) and primarily involves
the endothelium of graft vessels.2,10,11 Diagnostic criteria for
antibody-mediated rejection (AMR) in VCA have not yet been
formally established; however, based on experience with SOT,
the diagnosis of AMR typically requires evidence of acute graft
dysfunction with histological signs of graft injury (e.g., capil￾laritis with capillary dilation and leukocyte margination,
endothelialitis), presence of DSAs (targeted at human leuko￾cyte antigen [HLA] antigen class I/II/non-HLA antibodies), and
evidence of their action by presence of C4d deposits in target tissues.12,13 Evidence to date points to a lower incidence of AMR
in VCA when compared with SOT. In these few cases of AMR in
VCA, no clear correlation between C4d deposition and DSA
formation was observed. Landin et al.
14 reported on 2 bilateral
hand graft recipients with positive C4d staining in the allograft
during the rejection event but without the presence of DSA. In a
case series, Kaufmann et al. confirmed the lack of specificity
and informativeness of C4d staining in 5 hand recipients; in a
sixth case, she described C4d staining specific to the allograft
but in the absence of any DSA.15 Vice versa, Petruzzo et al.
detected circulating DSA in a recipient of hand transplant
without concomitantly observing C4d deposition.16,17 Of note,
such C4d deposits can also be seen in cutaneous amyloidosis
and inflammatory dermatoses unrelated to rejection events.18
Therefore, in an evolving field, these criteria have since been
revised for SOT, with C4d deposition no longer required for the
diagnosis of AMR, while gene expression profiling (“thoroughly
validated gene transcripts strongly associated with AMR”) was
added as a diagnostic criterion.13 These gene transcripts have
shown that endothelial activation is a hallmark of AMR. In a
recent study, confirming the findings in SOT, gene expression
analysis comparing T-cell mediated rejection to AMR in facial
skin VCA samples suggested that genes involved in the inter￾action between leukocytes and endothelium are upregulated
(e.g., intercellular adhesion molecule, vascular cell adhesion
molecule-1, selectin E), while histology confirmed a quantita￾tive increase in