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)