Immunosuppression for composite tissue transplantations

Composite tissue transplantation refers to the grafting of skin, subcutaneous
tissue, muscle tendons, nerves, vascular tissues and bone generally to replace
injuries. On the one hand, these grafts do not provide or extend life as is the case for organ transplants. Thus, the threshold for adverse sequelae of immunosuppressive therapy is far lower than that for vital transplantations. In particular susceptibility to end organ toxicity, opportunistic infections and
increased risk of neoplasms represents appreciable risk to quality of life and
possibly survival. On the other hand, the composite mass represents a large
antigenic load with skin being the most immunogenic tissue. However, bone
marrow is a source of hematolymphopoietic stem cells which in experimental animals serve as vectors of alloacceptance or of chimerism. As low as 1%  donor chimerism of the hybrid immune system might produce bidirectional donor: host tolerance. In the report by Granger, peripheral microchimerism
occurred only transiently in hand transplantation. Furthermore, the risk of graft versus host disease must be balanced against the emergence of CD8+/ TCR facilitating cells as described by Ilstad to induce tolerogenic regulatory T cells which have the CD4+/CD25+ high/Fox P3/CCR4/CLA/CCR6 phenotype as described by Hirahara. The latter state is more likely to emerge following nonmyeloablative recipient conditioning with 2000cGyTBI combined with fludarabine and immunosuppression. Whereas triple immunosuppression has been widely employed for this purpose, induction with alemtuzumab has been followed by dual maintenance therapy with tacrolimus plus mycophenolate mofetil or tacrolimus plus prednisone in recent cases. The roles of agents blocking adhesion molecules or of adjunctive cutaneous drug application remain under active investigation.

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