Page 1137 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPter 81 Concepts and Challenges in Organ Transplantation 1103

APC

Rituximab
MHC:peptide
Signal 1 Basiliximab
Belatacept
IL-2

Signal 2
CD28 TCR:CD3 Anti-CD3 IL-2 receptor
mAB
Ca 2+
Cyclosporine Signal 3
Tacrolimus Rapamycin
rATG Calcineurin mTOR

CD52 Cyclin/CDK
NF-AT
Steriods Cell Mycophenolate
IL-2 transcription cycle Azathioprine
Alemtuzumab

Immunodepletion
FiG 81.5 Immunosuppressive Drugs and Their Targets. Signal 1 results from major histocompat-
ibility complex (MHC): antigen recognition through the T-cell receptor (TCR)–CD3 complex, a
process blocked by anti-CD3 mAbs and indirectly by rituximab. Signal 2 results in costimulation,
a process which can be blocked by belatacept. Costimulation results in full activation of the
TCR–CD3 complex, initiating signal transduction, Signal 3: Downstream signaling pathways result
in calcineurin activation, a stage which can be inhibited by tacrolimus and cyclosporine. Activated
calcineurin dephosphorylates nuclear factor of activated T cells (NFAT), allowing interleukin-2
(IL-2) transcription, a process that can be inhibited by steroids. IL-2 receptor stimulation, a step
which can be blocked by basiliximab, activates the mechanistic target of rapamycin (mTOR) signaling
cascade, which can be inhibited by sirolimus. This pathway induces the T cell to enter cell cycle
and proliferate, which, in turn, can be blocked by mycophenolate and azathioprine. Rabbit anti-
thymocyte globulin (rATG) exerts polyclonal effects, and alemtuzumab binds to CD52, both
resulting in immunodepletion,

I polypeptide-related sequence A (MICA) being seen to affect Clinical regimens implemented today are focused on target-
allograft survival. ing the steps involved in the T cell–mediated immune response
The correlation among late acute rejection, chronic allograft to alloantigen. As outlined earlier, there are three main stages
dysfunction, and graft loss has been consistently reported, and in this pathway: recognition of alloantigen or self antigen;
there is increasing evidence that subclinical rejection may represent costimulation; and proliferation/differentiation of effector T
22
an important factor in predicting graft loss. Establishing a clear cells. The current clinical paradigm is based on blockade of
link between subclinical rejection and development of chronic at least one of these stages and/or by total immunodepletion
allograft dysfunction may be difficult, however, because of the therapy as well as by alterations in lymphocyte trafficking (see
interplay of other factors, including CNI toxicity. 21 Fig. 81.5).
The risk of acute graft rejection is greatest during the initial
IMMUNOSUPPRESSION three months following transplantation; therefore current
immunosuppression strategies are primarily based on a potent
In recent years, substantial advances in immunosuppressive induction regimen using a monoclonal antibody (mAb) or poly-
strategies and their translation to routine clinical practice have clonal antibody, followed by “maintenance immunosuppression”
revolutionized management and outcomes in solid organ often consisting of calcineurin inhibitors (CNIs, cyclosporine or
transplantation (SOT)—an option that has become the therapy tacrolimus), an antiproliferative agent (mycophenolate mofetil,
of choice for many end-stage organ diseases. Short-term outcomes, MMF), and low-dose corticosteroids (prednisolone). Provided
such as patient and allograft survival at 1 year, acute rejection there are no episodes of acute rejection, the doses of these agents
rates, and time-course of disease progression and symptom are gradually reduced, and then maintenance immunosuppres-
control have steadily improved since the first successful trans- sion is continued indefinitely (Fig. 81.6). This dose reduction is
plantations performed over 50 years ago. based on the concept that as graft inflammation subsides and