Page 1142 - Clinical Immunology_ Principles and Practice ( PDFDrive )

1108 Part NiNe Transplantation

proliferation and the generation of an effective immune response,
Glucocorticoids including the cytokines IL-2, IL-4, TNF-α, and IFN-γ, and
Corticosteroids have complex immunosuppressive as well as costimulatory molecules, such as CD154. However, CNIs are
antiinflammatory effects (Chapter 86). They act principally by well known for their nephrotoxic properties and are thought to
binding to cytoplasmic glucocorticoid receptors, although at be major contributors to chronic allograft dysfunction in renal
higher doses they can exhibit receptor-independent effects as transplantation. Thus in modern immunosuppressive regimens,
well. The steroid–receptor complex translocates to the nucleus, an attempt is made to minimize or even replace this drug class
where it is able to alter the expression of multiple cytokines with less harmful yet equally effective agents.
through DNA-binding and by targeting transcription factors,
such as AP-1 and NF-κB. Corticosteroids reduce the expression Mechanistic Target of Rapamycin Inhibitors
of many molecules important in the immune response, including Sirolimus (rapamycin) and everolimus bind to the same immu-
IL-1, -2, -3, and -6; TNF-α; IFN-γ; and a number of chemokines. nophilin as tacrolimus (FKBP12), although the complexes they
By inhibiting cyclooxygenase, corticosteroids are also able to form are unable to interact with calcineurin. Instead they bind
reduce the production of inflammatory mediators, such as to the regulatory kinase mTOR, which has a critical role in
leukotrienes and prostaglandins. cytokine receptor signal transduction. The usual actions of mTOR
Corticosteroids have been the mainstay of maintenance are to activate the ribosomal enzyme p70 S6 kinase and block
immunosuppression regimens for several decades. However, an inhibitory protein 4E-BP1, both of which are required for
because of the agents’ wide-ranging effects, not only involving translation of proteins necessary for progression from the G 1
the immune response but also a multitude of organ systems, (growth) phase to the S (DNA synthesis) phase of the cell cycle.
and its direct nephrotoxicity and diabetogenic properties, in Therefore inhibition of this pathway in T cells blocks the action
modern immunosuppressive regimens, an attempt is made to of cytokines, such as IL-2, -4, and -15, preventing cell cycle
avoid or withdraw corticosteroids at the earliest possible time progression and clonal expansion.
after transplantation (Table 81.1). In addition to inhibiting clonal expansion of effector T cells,
there is growing evidence supporting the role of rapamycin in
Antiproliferative Agents promoting the generation and survival of Tregs, which have
Azathioprine and MMF interfere with DNA synthesis and prevent been shown in several animal models to be capable of preventing
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cell cycle progression. In the context of allograft rejection, this allograft rejection. For instance, rapamycin promotes the de
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impairs the clonal expansion of alloreactive T cells. novo conversion of alloantigen-specific Tregs. This is in contrast
Azathioprine is metabolized in the liver to the purine analogue to CNIs, which inhibit such conversion. This property makes
6-mercaptopurine and incorporated into DNA. By inhibiting rapamycin an attractive agent to potentially promote tolerance,
purine nucleotide synthesis (and therefore DNA and RNA as discussed further in the following section.
synthesis), it reduces gene transcription and prevents cell cycle
progression. The effects of azathioprine are not lymphocyte TOLERANCE
specific, and patients must be monitored closely for bone marrow
suppression. Billingham et al. first introduced the term transplantation tolerance
MMF is metabolized in the liver to mycophenolic acid, which in 1953, with the report that inoculation of fetal mice with
is a noncompetitive, reversible inhibitor of inosine monophos- lymphoid cells from an allogeneic adult donor mouse of a different
phate dehydrogenase (IMPDH). Cells are able to generate purines strain led to later acceptance of skin grafts from the original
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either de novo by converting inosine monophosphate to guanosine skin graft donors, and for their seminal work Medawar received
monophosphate (catalyzed by IMPDH) or from guanine via the the Nobel Prize for Medicine in 1960.
salvage pathway. The salvage pathway is less active in lymphocytes The condition in which an SOT recipient exhibits a well-
and therefore are relatively dependent on the de novo pathway functioning graft and lacks histological signs of rejection after
of purine synthesis compared with other cell types. As a result, receiving no immunosuppression for at least 1 year is referred to
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the effects of MMF are more lymphocyte specific than azathio- as clinical operational tolerance (COT). Importantly, patients
prine, and it is less myelosuppressive. Both agents are commonly demonstrating COT must also be capable of responding to other
used in modern maintenance immunosuppression regimens. non–transplantation-related immune challenges, including infec-
tions. Over recent years, experimental models have shown that it
Calcineurin Inhibitors is possible to exploit the processes by which immune homeostasis
The introduction of cyclosporine in the early 1980s presented and tolerance to self antigens are maintained to induce tolerance
a great step forward in transplant-related immunosuppression to alloantigen (Chapter 12). The optimal outcome for patients
because this was the first drug able to selectively block T-cell after transplantation would be harnessing of these mechanisms
activation. Subsequently a second CNI, the macrolide antibiotic to induce specific immunological unresponsiveness or tolerance
tacrolimus, replaced cyclosporine in most immunosuppressive to the graft, thus avoiding the adverse side effects associated with
regimens. Almost 99% of renal transplant recipients currently current immunosuppressive regimens (see Table 81.1).
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receive CNIs. Both cyclosporine and tacrolimus bind cytoplasmic Unfortunately, more than 5 decades of clinical experience in
immunophilins (cyclophilin in the case of cyclosporine and SOT have demonstrated that COT in humans is extremely difficult
FK506-binding protein 12 [FKBP12] in the case of tacrolimus) to induce intentionally and may only be possible in a subset of
to form complexes that can inhibit the calcium-dependent transplant recipients. Many successful experimental techniques
phosphatase calcineurin, a rate-limiting enzyme in the TCR can produce durable hyporesponsiveness to mismatched allografts
signal–transduction pathway. By preventing translocation of the in rodent models, but scarcely any have been successfully trans-
transcription factor NFAT to the nucleus, calcineurin inhibition lated into large animal models or clinical trials. Progress in the
impairs upregulation of many molecules important for T-cell field of transplantation tolerance has also been hampered by the