Composite tissue allotransplantation: opportunities and challenges

Abstract

Vascularized composite allotransplants (VCAs) have unique properties because of diverse tissue components transplanted en mass as a single unit. In addition to surgery, this type of transplant also faces enormous immunological challenges that demand a detailed analysis of all aspects of alloimmune responses, organ preservation, and injury, as well as the immunogenicity of various tissues within the VCA grafts to further improve graft and patient outcomes. Moreover, the side effects of long-term immunosuppression for VCA patients need to be carefully balanced with the potential benefit of a non-life-saving procedure. In this review article, we provide a comprehensive update on limb and face transplantation, with a specific emphasis on the alloimmune responses to VCA, established and novel immunosuppressive treatments, and patient outcomes.

Fig. 1

Unique immunological properties of the skin affecting the rejection process. a Skin-resident antigen-presenting cells can directly activate tissue resident memory T cells (TRM) without the need for lymph node homing. b Recipient allogeneic T cells migrating to the transplanted allograft are the main driver of graft rejection in vascularized composite allotransplant (VCA). c) Dendritic epidermal T cells are recruited early from the blood upon tissue damage. d Memory Th9 T cells are skin trophic and produce copious amounts of tumor necrosis factor-alpha and granzyme B. e Injury-induced inflammation occurs in VCA grafts. TRM invasion at the border between allograft and recipient tissues is shown along with high levels of interleukin-1b, interferon-gamma, transforming growth factor-beta, and CCL2-5. f TRM, especially CD8+ T cells, are abundant in the skin. Donor-derived passenger TRM can migrate to surrounding recipient tissue, causing graft versus host disease that may, in turn, contribute to the rejection process. g Endothelial cells can activate lymphocytes through the upregulation of human leukocyte antigen-II and adhesion molecules. h Endothelial cells secrete vasoactive molecules, including NO, bradykinin, and prostacyclin, affecting the inflammatory process. i The width of capillaries within the skin is narrower than the diameter of T cells, leading to contact with molecules upregulated by endothelial cells. j Skin-specific antigens such as Epa-1 and Skn-1 and 2 contribute to the augmented immunogenicity of the skin. k Bone marrow in VCA grafts may ameliorate/modulate rejections. l Size and mass of VCA grafts may interfere with alloimmune responses. m Skin alarmins, released by keratinocytes upon cell death, have chemoattractive abilities. Thus, both adaptive and innate immune cells are recruited to the site of tissue damage

Fig. 2

Novel approaches in improving vascularized composite allotransplant outcomes. a Tolerance protocols involving regulatory T cells or mesenchymal stromal cells. b Immunosuppression minimization protocols, including topical intragraft application of immunosuppressive drugs (e.g., tacrolimus/mycophenolate mofetil). c Minimally invasive microsurgical techniques. d Novel preservation approaches involving ex vivo hypo- or norm preservation. e Refined rejection criteria and guidelines to assess outcomes