Page 1131 - Clinical Immunology_ Principles and Practice ( PDFDrive )

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Concepts and Challenges in Organ

Transplantation: Rejection,

Immunosuppression, and Tolerance

Kathryn J. Wood, Sushma Shankar, Joanna Hester, Fadi Issa

The clinical era of transplantation began on December 23, 1954, rejection, whereas allografts (transplantation of tissues from
when Dr. Joseph Murray and colleagues performed the first genetically different individuals) usually evoke an aggressive
successful renal transplant on the genetically identical Herrick immune response as a result of the antigenic differences between
1
twins. Solid organ transplantation (SOT) has since transformed the donor and the recipient. Tissue transplanted between species,
the landscape of modern medicine, offering dramatic improve- or xenografts, are also possible but not yet in clinical use in cell
ments in patient survival and quality of life in many end-stage and organ transplantations because these usually trigger a more
diseases. The development of powerful immunosuppressive rapid and aggressive immune response compared with an allograft.
regimens and cutting-edge biological agents represents an elegant This section considers the processes involved in allorecognition
proof of concept, translating seminal work from the laboratory and graft destruction.
bench to the patient’s bedside. However, this ground-breaking
field within clinical immunology is not free of setbacks. Rejection Innate Immunity and Ischemia-Reperfusion Injury
of transplanted organs and tissues can result in devastating Trauma to the graft is initiated during, or even before, retrieval
problems for the patient, and potent immunosuppression is because death of the donor brainstem induces hemodynamic
associated with substantial comorbidity, including exposure to and neuroendocrine responses; in addition, organs obtained from
infection, malignancy, and cardiovascular risks that may be fatal. donors after their cardiac death suffer a period of warm ischemia.
Theoretically, immunosuppression withdrawal and allograft- During cold storage, loss of intracellular potassium and cell injury
specific protection against host responses is the ultimate treatment continues. This leads to graft damage through cell swelling
to offer a transplant recipient. Although this is undoubtedly a and a buildup of toxic metabolites, leaving the graft susceptible
challenging goal, it is being realized in defined subgroups of to further ischemia–reperfusion injury on rapid warming fol-
recipients. This chapter examines the rejection response, outlines lowing revascularization. Efforts are made during storage
the mainstay of current immunosuppressive therapy, and discusses and organ implantation surgery to reduce the metabolic rate
the latest advances in the search for transplantation tolerance. through storage on ice and perfusion with specialized fluids.
This approach aims to minimize the accumulation of toxic
REJECTION metabolites and the resultant pH changes to reduce the effect
of cold ischemic time on posttransplantation outcomes, such as
The immune system is complex and has evolved to protect the delayed graft function. 2
individual from harm. This harm may be either in the form of Tissue injury leads to the expression of damage-associated
foreign pathogenic microorganisms or premalignant mutations molecular patterns (DAMPs), such as heparin sulfate, heat shock
in the individual’s own cells. To achieve this safely, the immune proteins (HSPs), nucleic acids, and high-mobility group box-1
system must have the ability to distinguish “self” from “non-self” (HMGB1) protein. These are identified by invariant pattern-
or “altered-self” to avoid damaging the host itself. Any immune recognition receptors (PRRs) of the innate immune system, for
response that is generated must also be proportional to the threat, example, Toll-like receptors (TLRs) (Chapter 3). This process
and thus antigens encountered in the context of inflammation results in the local production of inflammatory mediators, such
will prime T cells and evoke a more aggressive immune response. as interleukin (IL)-1 and -6, chemokines, and the expression of
Although an effective immune response is essential to survival adhesion molecules within the graft. These early innate responses
in the context of infection or malignancy, it can represent sig- are seen in autografts as well as isografts and are generally not
nificant management challenges in the transplantation setting. alloantigen specific, although a subcategory of innate cells does
Some elements of the immune system respond to the general display a limited degree of alloantigen reactivity. In turn, this
trauma associated with organ retrieval, perfusion, and surgery, triggers activation of macrophages and dendritic cells (DCs) via
3
whereas others respond after specific recognition of antigenic cell-surface and internal PRRs, causing both cell types to show
differences between the donor and the recipient. If this process greater antigen-presenting capacity and to enter a cytocidal state.
continues in an uncontrolled manner, it inevitably leads to Endogenous signals, such as stress, can also activate the comple-
destruction of the graft. Thus isografts or syngeneic grafts (grafting ment cascade to generate several products, including complement
of tissue between two genetically identical individuals such that component C3 in the graft, which promotes DC maturation and
there are no antigenic differences) do not typically result in subsequently their ability to activate T cells. DCs are also activated

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