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For over 40 years, cardiac and lung transplantation have achieved remarkable one-year patient survivals beyond 90% and conditional half-lives of 13 and 7.9 years, respectively.1 While surgeons must acquire the technical expertise to perform these often demanding surgeries, long-term graft outcomes and the recipients’ well-being benefit from a multidisciplinary team well versed in the basics of the immunology of transplantation. Comfort with treating patients who receive immunosuppressive therapies, both conventional and innovative, requires familiarity with the nonsurgical language of transplantation. The goal of this enhanced chapter is to squeeze the essentials into an understandable short text. The core features of the alloresponse are presented with some specific references unique to heart and lung allografts. These include (1) histocompatibility; (2) activation of alloresponse T lymphocytes; (3) T-cell–mediated rejection (TMR); (4) antibody-mediated rejection (AMR); (5) immunosuppressive therapy; (6) surveillance for rejection; (7) immune monitoring; and (8) emerging regulators of immunity.


Major histocompatibility complex (MHC) molecules are a family of proteins that vary quite a lot between individuals (genetic polymorphism) and represent the molecular basis for how people’s immune systems distinguish “self” from “nonself” with respect to infections and transplants. Human MHC molecules are known as human leukocyte antigens (HLA) because they are expressed at high levels on leukocytes and were first measured on peripheral blood lymphocytes. HLA are heterodimeric glycoproteins expressed on the surface of almost every cell in the human body. If recognized by an organ recipient, these proteins can trigger rejection. This is known as allorecognition.

HLA molecules on donor cells or HLA fragments, shed from thoracic organ transplants, are determined to be foreign by the immune system of the host. Intact HLA molecules expressed on the surface of cells serve two key functions in the context of transplantation. Fragments of foreign proteins, including fragments of HLA molecules, are presented in the binding groove of HLA and are recognized by T-cell receptors (TCRs) of the recipient that happen to have high affinity for that protein fragment in the context of self HLA (indirect donor antigen presentation). In addition, recipient T-cells directly recognize donor HLA as “foreign” (direct donor antigen presentation).

The genes coding for these antigens are located on the short arm of chromosome 6. This region spans over 4 million base pairs in length and encodes for over 200 genes in three regions: Class I, Class II, and Class III (Fig. 59-1). HLA owns the most polymorphic title in man as more than 5000 types have been recognized.


The major histocompatibility complex is divided into three regions or classes: Class I, Class II, and Class III.

Classic Class I HLA proteins/antigens are HLA-A, HLA-B, and more recently HLA-C. The α-light chain is encoded in the MHC; however, the β-chain is β-2-microglobulin that ...

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