Therapeutic application of T regulatory cells in composite tissue allotransplantation

Journal of Translational Medicine, Oct 2017

With growing number of cases in recent years, composite tissue allotransplantation (CTA) has been improving the quality of life of patient who seeks reconstruction and repair of damaged tissues. Composite tissue allografts are heterogeneous. They are composed of a variety of tissue types, including skin, muscle, vessel, bone, bone marrow, lymph nodes, nerve, and tendon. As a primary target of CTA, skin has high antigenicity with a rich repertoire of resident cells that play pivotal roles in immune surveillance. In this regard, understanding the molecular mechanisms involved in immune rejection in the skin would be essential to achieve successful CTA. Although scientific evidence has proved the necessity of immunosuppressive drugs to prevent rejection of allotransplanted tissues, there remains a lingering dilemma due to the lack of specificity of targeted immunosuppression and risks of side effects. A cumulative body of evidence has demonstrated T regulatory (Treg) cells have critical roles in induction of immune tolerance and immune homeostasis in preclinical and clinical studies. Presently, controlling immune susceptible characteristics of CTA with adoptive transfer of Treg cells is being considered promising and it has drawn great interests. This updated review will focus on a dominant form of Treg cells expressing CD4+CD25+ surface molecules and a forkhead box P3 transcription factor with immune tolerant and immune homeostasis activities. For future application of Treg cells as therapeutics in CTA, molecular and cellular characteristics of CTA and immune rejection, Treg cell development and phenotypes, Treg cell plasticity and stability, immune tolerant functions of Treg cells in CTA in preclinical studies, and protocols for therapeutic application of Treg cells in clinical settings are addressed in this review. Collectively, Treg cell therapy in CTA seems feasible with promising perspectives. However, the extreme high immunogenicity of CTA warrants caution.

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Therapeutic application of T regulatory cells in composite tissue allotransplantation

Yang and Eun J Transl Med Therapeutic application of T regulatory cells in composite tissue allotransplantation Jeong‑Hee Yang 0 Seok‑Chan Eun 0 0 Department of Plastic and Reconstructive Surgery, Composite Tissue Allotransplantation Immunology Laboratory, Seoul National University College of Medicine, Seoul National University Bundang Hospital , Seongnam , South Korea With growing number of cases in recent years, composite tissue allotransplantation (CTA) has been improving the quality of life of patient who seeks reconstruction and repair of damaged tissues. Composite tissue allografts are heterogeneous. They are composed of a variety of tissue types, including skin, muscle, vessel, bone, bone marrow, lymph nodes, nerve, and tendon. As a primary target of CTA, skin has high antigenicity with a rich repertoire of resident cells that play pivotal roles in immune surveillance. In this regard, understanding the molecular mechanisms involved in immune rejection in the skin would be essential to achieve successful CTA. Although scientific evidence has proved the necessity of immunosuppressive drugs to prevent rejection of allotransplanted tissues, there remains a lingering dilemma due to the lack of specificity of targeted immunosuppression and risks of side effects. A cumulative body of evidence has demonstrated T regulatory (Treg) cells have critical roles in induction of immune tolerance and immune homeostasis in preclinical and clinical studies. Presently, controlling immune susceptible characteristics of CTA with adoptive transfer of Treg cells is being considered promising and it has drawn great interests. This updated review will focus on a dominant form of Treg cells expressing CD4+CD25+ surface molecules and a forkhead box P3 transcription factor with immune tolerant and immune homeostasis activities. For future application of Treg cells as therapeutics in CTA, molecular and cellular characteristics of CTA and immune rejection, Treg cell development and phenotypes, Treg cell plasticity and stability, immune tolerant functions of Treg cells in CTA in preclinical studies, and protocols for therapeutic application of Treg cells in clinical settings are addressed in this review. Collectively, Treg cell therapy in CTA seems feasible with promising perspectives. However, the extreme high immunogenicity of CTA warrants caution. Composite tissue allotransplantation; Immune rejection; Skin antigenicity; T regulatory cell; Immune tolerance; Immunosuppressive drug; Cell therapy Background Since the first successful human hand transplantation performed in 1998 [ 1 ] and human face transplantation performed in 2005 [ 2 ], composite tissue allotransplantation (CTA) for reconstruction of damaged or defected tissues has been rapidly emerging in the last two decades. Up to date, over 100 cases of hand transplantation and more than 30 cases of partial or full facial transplantation have been conducted worldwide [ 3, 4 ]. Advancements in CTA have been improving the quality of life of patient who has damaged tissues such as massive burns, cancer resections, congenital malformations, and accident-related traumas. Composite tissue allografts are heterogeneous. They are composed of various tissue types, including skin, muscle, vessel, bone, bone marrow, lymph nodes, nerve, tendon, and different transplanted elements with different immunogenic characteristics [ 5– 7 ]. Skin, the primary target of CTA, has a rich repertoire of resident cells that play pivotal roles in immune surveillance. In this regard, understanding the molecular mechanism involved in immune rejection in the skin would be essential to successful CTA. Although there is scientific evidence demonstrating that the necessity of immunosuppressive drugs to prevent rejection of the transplanted tissues, 85–90% of hand transplant patients have experienced at least one episode of acute skin rejection with conventional immunosuppressive protocol, contrasts to the rejection rate of less than 10% in organ transplantation [ 8, 9 ]. There is a lingering dilemma in CTA because of limited responsiveness due to the lack of specificity and efficacy of targeted immunosuppressive drugs, which also have side effects such as risks of infection, cancer development, metabolic toxicity, and hypertension [ 10 ]. Maintaining immunosuppressive drugs on CTA would be challenging. Thus, there have been efforts to develop Treg cells with donor antigen-specificity to avoid harm to the body’s immune system. Treg cells expressing CD4+CD25+Foxp3+ are a dominant form of T regulatory cell. The immune tolerant role of naturally arising Treg cells in autoimmune diseases and their effects on prolonged allograft survival in CTA with transplant rejection prevention function have been well documented in preclinical model studies [ 11, 12 ]. Moreover, several studies have demonstrated that Treg cells participate in allotransplantation tolerance across major histocompatibility comple (...truncated)


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Jeong-Hee Yang, Seok-Chan Eun. Therapeutic application of T regulatory cells in composite tissue allotransplantation, Journal of Translational Medicine, 2017, pp. 218, DOI: 10.1186/s12967-017-1322-5