An allograft is transplanted from an unrelated member of the same species (e.g., a cadaveric split-thickness skin graft or donor kidney transplant). An isograft is tissue that is transferred from one individual to another who is genetically identical. An autograft is tissue that is transplanted within the same individual (e.g., a split-thickness skin graft or free deep inferior epigastric artery perforator [DIEP] flap). A xenograft is tissue that is transplanted from one species to another, such as a porcine heart valve when implanted in a human. Grafts can be vascularized such as a hand transplant or nonvascularized such as a split-thickness graft and can be transferred between individuals or within the same individual depending on the graft in question.1
The MHC antigens are part of the cell-mediated immune response and in humans they are referred to as human leukocyte antigen (HLA) molecules. They are relevant to allograft rejection and provide an immunological fingerprint. The HLA complex is a group of genes that encode proteins responsible for identifying foreign antigens to the immune system. They present antigen fragments to T-cells and bind T-cell receptors. There are two classes of molecules (not three) and they differ in a number of ways. Class I (HLA-A, HLA-B, and HLA-C) molecules are present on all nucleated cells, whereas class II (HLA-DP, HLA-DQ, and HLA-DR) are only found on antigen- presenting cells such as monocytes, macrophages, and B-cells. Class I molecules present target peptides generated from within the cell, whereas class II molecules target peptides acquired from outside the cell following processes such as phagocytosis.1–3
3. Kaufman CL, Marvin MR, Chilton PM, et al. Immunobiology in VCA. Transpl Int 2016;29(6):644–654 The adaptive or acquired immune system plays an important role in rejection of transplanted tissue. Activation of this pathway results in an antigen targeted immune response which is capable of memory. Furthermore, there is an enhanced secondary response that is more vigorous and has a faster onset. The primary cells involved in the adaptive response are the T- and B-cell lymphocytes with antigen-specific surface receptors. The T-cell activation requires three signals: (1) Foreign antigen recognition, (2) costimulatory signal, and (3) cytokine release. This process involves CD4 and CD8 cell types. In contrast, the innate immune system is a nonspecific, rapid-acting response (within minutes to hours) driven by neutrophils, macrophages, and monocytes. Its role within transplant rejection is less well defined and understood (see Table 7.1).1,2 Table 7.1 Innate versus Adaptive (Acquired) Immunity Innate Adaptive Components Neutrophils, monocytes, macrophages, dendritic cells, natural killer cells, complement Lymphocytes (T- and B-cells) Characteristics Occur rapidly (minutes to hours) Nonspecific Develops over long periods Capable of memory (faster and more vigorous) Antigen-specific
immunology. Types of allograft rejection may be categorized as hyperacute, accelerated, acute, or chronic. Chronic rejection occurs over months to years via the indirect pathway of donor organ recognition. Treatment is very challenging, with no successful treatment available. Chronic rejection was initially thought to have no significant role in VCA transplants compared with solid organ transplants. However, as duration of ongoing VCA transplants has increased, longer term analysis has shown chronic rejection to occur in both hand and face transplants. Hyperacute rejection occurs within minutes to hours and is mediated by donor-specific antibodies that circulate before transplantation. These antibodies are acquired by prior exposure to an alloantigen after pregnancy, blood transfusion, or previous transplants. Accelerated rejection occurs within the first few days after a transplant. It represents a secondary immune response that is mediated by sensitized T-cells. Treatment involves steroids and lymphocyte-depleting agents. Acute rejection occurs in the weeks or months following a transplant and may be cell mediated (T-cell–mediated response) or humoral (B-cell/antibody–mediated response). However, the only type of acute rejection reported in VCAs is cell mediated. Treatment for cell-mediated acute rejection involves pulse steroids, optimization of maintenance therapy, and lymphocyte-depleting agents.1,2
Vascularized composite allografts (VCAs) contain numerous tissue types within a single graft such as skin, bone, muscle, and nerve. Of these tissue components, skin is the most antigenic, and as a result, direct inspection is important to identify acute rejection. This may manifest as erythematous macules, diffuse redness, or asymptomatic papules.1–3
criteria? The Banff 2007 grading system (Box 7.1) for acute rejection has five categories ranging from 0 to IV.1 Grade 0 represents no rejection. Grade IV is the most severe rejection, and these patients present with frank necrosis of the epidermis or other skin structures. In face allografts, the transplanted mucosal surfaces may be similarly affected. BOX 7.1 BANFF 2007 GRADING SYSTEM FOR ACUTE REJECTION1 Grade 0 (no rejection) • No or rare inflammatory infiltrates Grade I (mild rejection) • Mild perivascular infiltration • No involvement of the overlying epidermis Grade II (moderate rejection) • Moderate to severe perivascular inflammation with or without mild epidermal and/or adnexal involvement (limited to spongiosis and exocytosis) • No epidermal dyskeratosis or apoptosis Grade III (severe rejection) • Dense inflammation and epidermal involvement, with epithelial apoptosis, dyskeratosis, and/or keratinolysis Grade IV (necrotizing acute rejection) • Frank necrosis of the epidermis or other skin structures
Following VCA transplant, a standard maintenance therapy involves three key drugs: A calcineurin inhibitor such as tacrolimus, an antimetabolite such as mycophenolate mofetil, and corticosteroids. In contrast, induction therapy, which is given at the time of transplantation, to prepare the recipient to receive foreign tissue, includes polyclonal antithymocyte globulin (ATGs), monoclonal anti-IL receptor antibodies (e.g., daclizub or basiliximab), and monoclonal anti-CD3 antibodies (OKT3) as in option B. Rescue therapy involves an increase in maintenance immunosuppression combined with steroid boluses, clobetasol, and sirolimus, as in option C.1
Tacrolimus is a calcineurin inhibitor and is one of the key components in maintenance antirejection therapy following transplant surgery. It blocks intracellular signaling pathways that lead to IL-2 release and amplification of the immune response. The main problems with tacrolimus are twofold: It has a narrow therapeutic index and hence requires regular monitoring of drug levels, and it can cause nephrotoxicity. It has also been found to cause neurotoxicity at higher levels but has conversely been found to enhance nerve recovery after coaptation at lower doses, which may have additional benefits in VCA patients.1 Corticosteroids are also important in transplant antirejection medications and can cause hypertension, hyperlipidemia, and hyperglycemia as well as weight gain and osteoporosis. Antiproliferative agents such as mycophenolate mofetil are also part of maintenance therapy and inhibit purine metabolism and DNA synthesis. They can cause bone marrow suppression. Cell cycle inhibitors such as sirolimus prevent T-cell proliferation and can cause lung toxicity. Biological agents such as OKT3, antithymocyte globulin (ATG), basiliximab, and daclizimab are monoclonal antibodies targeting CD3 or IL-2 receptors and are associated with cytokine release syndrome (see Table 7.4, Essentials of Plastic Surgery, third edition).2
This patient displays signs of acute rejection. This is managed with rescue therapy and involves systemic corticosteroids often alongside topical immunosuppressants such as clobetasol and protopic. It is important to confirm that calcineurin inhibitors such as tacrolimus are at therapeutic levels and if not, this must be addressed. Second-line agents include induction therapy agents, sirolimus and high-dose tacrolimus. Monoclonal antibodies and polyclonal antithymocyte globulin are part of a standard induction therapy regimen.1,2
The most common malignancy after transplant surgery is skin cancer. The most likely subtype is squamous cell carcinoma (SCC) and this would first present as a keratotic skin lesion. The reason for the increased risk is immune suppression therapy. This is one of a number of reasons why close follow-up by a plastic surgery team is required. Hemoptysis is a sign of lung cancer, pathologic fractures are signs of bone metastases, and lymphadenopathy may represent metastatic spread of an SCC or other tumor. Alternatively, post-transplant lymphoproliferative disease may occur. This is a B-cell proliferation due to neutropenic immune suppression. Symptoms range from infectious mononucleosis-like lesions to frank lymphoma. Change in bowel habit is associated with benign and malignant processes in the gastrointestinal (GI) tract but not specifically to immune suppression therapy.1