Immunology of Vascularized Composite Allotransplantation: A Primer for Hand Surgeons

Duke University, Durham, North Carolina, United States
The Journal of hand surgery (Impact Factor: 1.67). 04/2012; 37(4):842-50. DOI: 10.1016/j.jhsa.2012.01.042
Source: PubMed


Vascularized composite allotransplantation is a recent innovation in the fields of transplantation surgery, plastic and reconstructive surgery, and orthopedic surgery. The success of hand and face transplantation has been based on extensive experience in solid organ transplantation. Advances in understanding the immunology of transplantation have had a major role in achieving excellent results in this new field. The purpose of this article is to introduce the basics of human immunology (innate and adaptive systems) and the immunological basis of human transplantation (the importance of human leukocyte antigen, direct and indirect pathways of antigen recognition, the 3 signals for T-cell activation, and mechanisms and types of allograft rejection) and focus on the mode of action of immunosuppressive drugs that have evolved as the mechanisms and pathways for rejection have been defined through research. This includes recent studies involving the use of costimulatory blockade, regulatory T cells, and tolerance induction that have resulted from research in understanding the mechanisms of immune recognition and function.

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    • "This immune response is dependent on three signals: alloantigen recognition, activation of T-cells, and signal for T-cell proliferation (30). Alloantigen recognition (the first signal) can occur by three different mechanisms: (a) Direct pathway: alloreactive T-cells directly recognize intact allogeneic MHC molecules expressed on donor cells (namely APCs) (31). (b) Indirect pathway: alloreactive T-cells recognize processed allogeneic MHC molecules expressed on recipient APCs (32). "
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    ABSTRACT: Advances in microsurgical techniques and immunomodulatory protocols have contributed to the expansion of vascularized composite allotransplantation (VCA) with very encouraging immunological, functional, and cosmetic results. Rejection remains however a major hurdle that portends serious threats to recipients. Rejection features in VCA have been described in a number of studies, and an international consensus on the classification of rejection was established. Unfortunately, current available diagnostic methods carry many shortcomings that, in certain cases, pose a great diagnostic challenge to physicians especially in borderline rejection cases. In this review, we revisit the features of acute skin rejection in hand and face transplantation at the clinical, cellular, and molecular levels. The multiple challenges in diagnosing rejection and in defining chronic and antibody-mediated rejection in VCA are then presented, and we finish by analyzing current research directions and novel concepts aiming at improving available diagnostic measures.
    Frontiers in Immunology 11/2013; 4:406. DOI:10.3389/fimmu.2013.00406
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    • "However, VCA is not routinely performed for tissue repair and reconstruction because lifelong administration of immunosuppressive agents, which have potentially harmful side effects, is necessary to avoid rejection of the highly antigenic skin tissue [7] [8] [9]. Furthermore, even if patient compliance is excellent, conventional immunosuppressive protocols may not be sufficient to prevent chronic rejection [4] [10] [11]. Consequently, researchers have been eagerly seeking alternative methods of establishing lifelong tolerance while minimizing toxicity. "
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    ABSTRACT: Vascularized composite allotransplantations (VCAs) are not routinely performed for tissue reconstruction because of the potentially harmful adverse effects associated with lifelong administration of immunosuppressive agents. Researchers have been eagerly seeking alternative methods that circumvent the long-term use of immunosuppressants. Mesenchymal stem cells (MSCs) show promise as an immunomodulatory therapeutic agent and are currently being tested in preclinical and clinical settings as therapies for autoimmune disorders or transplant rejection. The mechanisms by which MSCs modulate the immune response are still under thorough investigation, but these most likely involve expression of local factors influencing T-cell regulation, modulation of cytokine expression (e.g., IL-10, TGF-β, TNF-α, INF-γ, etc.), and interactions with dendritic or antigen presenting cells. In this paper, we summarize the current understanding of immunomodulation achieved by MSC therapies and introduce a possible outline for future clinical applications in VCA.
    Clinical and Developmental Immunology 11/2012; 2012:854846. DOI:10.1155/2012/854846 · 2.93 Impact Factor
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    ABSTRACT: Chronic rejection remains a potential long-term consequence of hand composite tissue allotransplantation (CTA). Scleroderma has already been proposed as a model for chronic facial allograft rejection based on potential parallels of observed progression of disease and pathophysiology course. This study proposes a similar model for how chronic rejection may manifest itself in the context of hand CTA through the functional and psychological assessment of patients with scleroderma, should it occur. 100 consecutive patients with a clinical diagnosis of scleroderma were recruited into the study. Subjective assessment of static hand disfigurement was carried out through the use of standardised digital photographs. Hand function was assessed through the measurement of active range of motion (AROM) and using the activities of daily living (ADL) and Disabilities of the Arm, Shoulder & Hand (DASH) questionnaire. Psychological and quality of life evaluation comprised the Hospital Anxiety Depression Scale (HADS) and the SF36 health survey. Examination of standardised digital photographs of subjects revealed a variety of hand changes characteristic of scleroderma, ranging from mild to moderate through to severe. Objective assessment of hand disfigurement did not correlate with duration of disease, nor psychological distress. However, individuals with worsening disfigurement demonstrated poorer AROM. Longitudinally no deterioration in terms of function was seen over time in terms of the DASH and ADL results. Nevertheless deterioration of function did have a significant impact on quality of life. Overall HADS showed 22% of individuals as suffering from clinical levels of anxiety and 10% from clinical depression. Chronic rejection has not yet occurred in any of the hand transplants performed to date. Scleroderma results in a spectrum of chronic functional and psychological disability that provides a model for the potential outcome of chronic hand allograft rejection. Findings from this study provide insight into the impact of this progressive disease for patients and contribute to the information and consent process for patients considering hand composite tissue transplantation.
    SpringerPlus 10/2013; 2(1):577. DOI:10.1186/2193-1801-2-577
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