In extremities, as well as in face transplantations , AR reactions manifest clinically as erythematous macules, diffuse redness, or asymptomatic papules over the allografted skin [7] . Microscopically, they show characteristic, although nonspecific, changes involving mainly the dermis and the epidermis that may even extend to the hypodermis in cases of severe rejection. These changes consist of a perivascular lymphocytic infiltrate in the superficial and mid-dermis predominantly made of CD3 ⁺ /CD4 ⁺  T cells, with smaller proportions of CD8 ⁺  and TIA-1 ⁺  cytotoxic T cells, FoxP3 ⁺  T regulatory cells, and occasional CD68 ⁺  histiomonocytic cells of recipient’s origin. The epidermis can show exocytosis and keratinocyte necrosis or apoptosis associated with basal keratinocyte vacuolization. More rarely, the epidermis shows spongiosis (intercellular edema) or lichenoid changes (orthokeratotic hyperkeratosis, hypergranulosis, acanthosis, band-like subepidermal infiltrate) similar to those observed in (lichenoid) graft-versus-host disease (GvHD). In the case of very severe rejection, the epidermis (and its appendages, hair follicles, and sweat glands) may show extensive necrosis. In those severe cases, the infiltrate may extend to the hypodermis and also contain eosinophils [5]. A specific score (Banff score 2007) consisting of five severity grades has been established in order to assess AR in hand and face transplantations [8, 9] .

In the case of facial allotransplantation, biopsies obtained from the allografted oral mucosa show qualitatively similar changes, which are as a rule more pronounced than those found concomitantly on the skin [10–12]. The explanations for this discrepancy are unclear; however, one possible explanation could be the existence of a higher density of vessels and antigen-presenting cells (dendritic and endothelial cells) in mucosa versus skin .

The presence of C4d deposits in the skin and their significance is somewhat controversial. In our experience, such deposits are rarely (if ever) detected in the allografted hand and face skin and mucosae [13]. In some studies, such deposits have been reported in the skin of hand transplants with and without signs of AR, albeit in the absence of concomitant donor-specific antibodies [14, 15]. The role of humoral rejection in VCA is not clear. It has yet to be demonstrated [16] in experimental limb transplantation, although in clinical hand and face transplantations alloantibody production against donor human leukocyte antigen (HLA) has been reported. In the unique case of lower extremity transplantation [17], the patient presented two AR episodes that were graded on the basis of Banff score; C4d deposits were detected without donor-specific HLA antibodies, but they were considered to be “artifacts” by the authors. It is interesting to note that in the first posttransplant year the patient presented two episodes of AR, grade II and III, respectively . These findings showed that the number and severity of AR episodes are not correlated to the mass of the transplanted tissues, which primarily consists of muscle. Indeed, several studies [18, 19] suggested that muscles are the most sensible tissue to the ischemia/reperfusion injury and, consequently, to rejection.

The immune response in hand and face transplantations is essentially T-cell mediated, and the cytotoxic activity of these T cells is donor specific, as shown in the first face transplantation recipient [20]. It has also been shown that the rejection of a VCA in sensitized recipients is mainly cell mediated and differs mechanistically from that of solid organ transplantation [21]. The predominance of the T-cell response during VCA rejection probably explains the efficacy of the traditional triple therapy approach used in the majority of VCAs (steroid, tacrolimus, mycophenolate mofetil (MMF), which primarily targets the T-cell response .