Immunology and Research in Reconstructive Transplantation

Introduction

More than 89 upper extremities and 30 face transplants have been performed worldwide since 1998, proving that vascularized composite allotransplantation (VCA) is technically feasible and guarantees long-term survival under currently available immunosuppressive regimens.

VCA is not a lifesaving procedure, thus minimization or withdrawal of the systemic immunosuppression is imperative to avoid the long-term deleterious complications related to the chronic use of the immunosuppressive treatment. When compared with solid organ transplants, vascularized composite allografts contain a histologically heterogeneous array of different tissue types (skin, muscle, bone, bone marrow, lymph nodes, nerve, and tendon) that present different immunogenicity. Experimental models of limb transplantation showed that skin is one of the most antigenic tissues, and when combined with muscle, subcutaneous tissues, and bone (including bone marrow), can generate a high immunologic response. The vascularized muscle component of the limb allografts was shown to be less antigenic than skin ; whereas bone presents lower immunogenicity; and cartilage, tendon, and vessels are the least antigenic tissues.

In this chapter the authors discuss the basics of transplantation immunology, the mechanisms of allograft acceptance, and rejection as pertinent to vascularized composite allografts. An overview of the tolerance mechanisms and strategies developed to achieve tolerance is presented, as well as a short summary of the novel cell-based therapies, and their role in induction of transplantation tolerance. Considering the increasing number of vascularized composite allografts performed worldwide, as well as their applicability to the complicated cases of reconstructive surgery, it seems imperative that plastic surgeons should become familiar with these techniques and the related immunologic concepts, in order to select the most appropriate candidates and to properly inform and consent patients for these novel procedures of reconstructive transplantation.

Basics of Transplantation Immunology

The Role of the MHC/HLA Antigens

The major histocompatibility complex (MHC) genes code the strongest transplant antigens. Human MHC molecules called human leukocyte antigens (HLAs) are codified by a group of genes located on the short arm of chromosome 6. Each parent provides a haplotype (a linked set of MHC genes) to each offspring in the co-dominant inheritance. There are two classes of the MHC or HLA molecules. MHC class I molecules (HLA-A, HLA-B, and HLA-C) are expressed on all nucleated cells and generally present endogenous antigens, such as viruses and self-protein fragments to CD8 ⁺ T cells. Class II molecules (HLA-DP, HLA-DQ, and HLA-DR) are constitutively expressed only on professional antigen-presenting cells (APCs), including dendritic cells, macrophages, and B-cells. Their expression may be upregulated on epithelial and vascular endothelial cells after exposure to proinflammatory cytokines. Class II molecules present antigens derived from the extracellular proteins to the CD4 ⁺ T-cells. The degree of HLA mismatch between the donor and the recipient plays a role in determining the risk of chronic rejection and graft loss in solid organ transplantation. HLA-A, -B, and -DR (three pairs, six antigens) are traditionally used for typing and matching before kidney or pancreas transplantation. The HLA-Cw, -DP, and -DQ typing is currently used by many transplant centers. For kidney transplants, the long-term graft survival is best in HLA-identical living related kidney transplants. The major effect is attributed to the match of the DR antigen, and the order of importance for HLA match in kidney transplants is HLA-DR > HLA-B > HLA-A, respectively.

Data from the International Hand and Composite Tissue Transplantation Registry reveal that high mismatch rates for the hand transplantation cases were recorded in 50% of the recipients (for all or five out of six antigens) and in 57% of face transplant recipients.

Non-HLA Antigens

Acute and chronic graft rejection can occur in HLA-identical sibling transplants, indicating presence of the immune response to non-HLA antigens. Several non-HLA related antigens and antibodies derived from either the alloimmune or autoimmune responses have been reported.

ABO Blood Group Antigens

ABO blood group antigens are expressed on the red blood cells, on vascular endothelial cells, and other cells. ABO incompatibility triggers hyperacute rejection of the organ due to the presence of the preformed hemagglutinin A and/or B antibodies. Desensitization protocols to remove the preformed hemagglutinins from the recipient's circulation have been used for the ABO incompatible transplants. The rhesus factor (Rh) and other red cell antigens are not relevant to the organ transplants, since they are not expressed on the vascular endothelium.

Minor Histocompatibility Antigens

Minor histocompatibility antigens (MiHAs) are small endogenous peptides that occupy the antigen-binding site of the donor MHC molecules. They are generally recognized by CD8 ⁺ cytotoxic T-cells, leading to graft rejection. MiHA play an important role in pathogenesis of the graft-versus-host disease in patients who have received an HLA-matched bone marrow transplants. H-Y MiHA is encoded by the Y chromosome in males and can induce alloimmune response when a male organ is transplanted into a female recipient. MHC class I related chain A and B (MICA and MICB) are also expressed on the endothelial cells. Antibodies against MICA and/or MICB can cause antibody-mediated rejection (AMR) and graft loss. Some minor transplant antigens may be derived from the mitochondrial proteins and enzymes.

Allorecognition Pathways

Allorecognition can occur by one of the three pathways: direct, indirect, and semi-direct. In the direct pathway , recipient's T-cells recognize the intact allogeneic HLAs expressed by the donor cells. In the indirect pathway , T-cells recognize peptides derived from the donor HLAs presented by the recipient APC. In the semi-direct pathway, the recipient dendritic cells or other APCs, acquire the intact HLAs from the donor cells and present them to the recipient T cells. The direct and indirect pathways are well recognized in organ transplantation, whereas the semi-direct pathway is not of the clinical importance.

The direct pathway is very important in the immediate post-transplant period. Without appropriate immunosuppression, a strong and effective alloresponse would be initiated, primarily due to the high number of the recipient T-cells that will recognize the graft antigens and will cause the acute cellular rejection. While the indirect pathway of allorecognition may also participate in the acute rejection, it is predominantly observed in the late onset of rejection, as well as in the chronic rejection. As long as the allograft is present within the host, the recipient's APCs can pick up the alloantigens, shed them from the graft, and start the alloimmune response. Therefore, lifelong maintenance immunosuppression is required in order to prevent both the acute as well as chronic allograft rejection.

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