Page 1141 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPter 81 Concepts and Challenges in Organ Transplantation 1107

days and so may be difficult to appropriately titrate in transplant
CD28:B7 (CD80/CD86) Blockade recipients suffering from infections.
CTLA-4 (CD152) is an inducible, T-cell surface antigen that
when bound to CD80/86 receptor:ligand (B7 molecules) on APCs, Signal 3: Blockade of Proliferation/Differentiation
delivers inhibitory signals to the activated T cell. Belatacept Activated T cells produce IL-2, which, in turn, binds to IL-2Rs,
(LEA29Y) is a fusion protein that combines a mutated version which are expressed only on the surface of activated cells and
of the extracellular binding domain of CTLA-4 with the Fc portion are not present on resting T cells. IL-2R is composed of three
of IgG1, with specificity for CD80/86 expressed on APCs. Ligation high-affinity transmembrane protein subunits: α (CD25), β
of CD80/86 by CD28 (a surface antigen constitutively expressed (CD122), and γ (CD132) subunits, which are covalently linked.
on T cells) usually lowers the activation threshold of T cells. The α subunit is specific to IL-2R only, and it is the binding of
Belatacept has a higher affinity and slower dissociation rate from α and β subunits that is crucial to the IL-2 signal transduction
human B7 molecules (i.e., CD80/86) compared with CD28, and T-cell activation that subsequently leads to proliferation
resulting in inhibition of the costimulation required for effective and clonal expansion of T and B cells specific to alloantigen or
T-cell activation. 43 self antigen. These cells are also stimulated to release more IL-2,
The complexities of the human immune system present sig- further magnifying the immune response.
nificant challenges to the translation of such agents into clinical
+
practice: In vivo work indicates memory and cytotoxic CD8 T cells Anti-IL-2R Monoclonal Antibody
have different costimulation requirements for complete activation (Basiliximab and Daclizumab)
+
compared with CD4 naïve T cells and may therefore be more Anti-IL-2R (anti-CD25) mAbs specifically target activated T cells
resistant to some tolerance induction strategies. Such blockade but do not cause significant lymphocyte depletion and are not
may also affect the function of Tregs as the CD28:B7 pathway associated with major adverse effects compared with lymphocyte-
has been shown to be important for their expansion and survival. depleting agents. However, other T-cell subtypes, including Tregs,
However, reassuringly, data from clinical trials of belatacept in also express CD25, and therefore the use of these agents may
renal transplantation, albeit with small patient numbers, suggest impact some of the natural mechanisms of immunoregulation.
that costimulation blockade does not interfere with Treg homeo- Basiliximab (chimeric form) and daclizumab (humanized form)
stasis. 45,46 In non-human primate models, CTLA-4 Ig prolongs have been used in renal transplantation in low-risk recipients,
pancreatic islet survival and, in combination with CD154:CD40 as defined as first allografts with living-related donors. 50,51
pathway blockade, induces indefinite acceptance of renal and heart Basiliximab is currently the agent of choice and binds to IL-2R
allografts. with similar affinity as IL-2, thereby effectively competing with
BENEFIT (Belatacept Evaluation of Nephroprotection and IL-2 and subsequently inhibiting IL-2–driven T-cell proliferation.
Efficacy as First-line Immunosuppression Trial), a 3-year, phase Basiliximab has a high volume of distribution, almost completely
III clinical trial, randomized patients to three groups: cyclosporine, saturating IL-2R on the peripheral lymphocytes within 24 hours
less-intensive belatacept, and more-intensive belatacept. Patients of a single dose of 2.5–25 mg in renal transplant recipients. The
received induction with basiliximab and were maintained on half-life in adults is approximately 13.4 days, and IL-2R saturation
mycophenolate mofetil (MMF) and corticosteroids. Patient and and suppression can last for 4–6 weeks.
graft survival rates were similar across the three groups at both Two meta-analyses evaluating the efficacy and safety of
1 and 2 years after transplantation. At the end of 1 year, although basiliximab in renal transplant recipients have been published. 51,52
the incidence of acute rejection was greater for more-intensive Both studies showed that basiliximab was more effective than
and less-intensive belatacept compared with cyclosporine, no placebo in reducing acute cellular rejection 6 months after
apparent impact on graft survival was demonstrated. At the end transplantation. However, both meta-analyses illustrated no
of 2 years, however, glomerular filtration rates (GFRs) continued significant differences in patient or graft survival rates between
to be significantly higher (15–17 mL/min) in the belatacept- basiliximab and placebo groups at 1 year after transplantation.
treated patients. Encouragingly, belatacept-treated patients also However, in studies involving high-risk transplant recipients (i.e.,
had sustained benefits in their cardiovascular and metabolic risk high HLA-mismatch) the risk of rejection may be higher with
profiles compared with those treated with cyclosporine, supporting IL-2R mAb in comparison with rATG. 53
the potential role of belatacept as a nonnephrotoxic alternative The highly selective and short-term immunosuppressive effects
to CNIs. 47,48 Patients enrolled in this trial have now been followed of basiliximab, which are confined to the highly immunogenic
up for 7 years, and the long-term data show that patient and period immediately after transplantation, make this class of drug
graft survival and the mean eGFR are significantly higher with a useful substitute to steroids in early steroid-withdrawal or
belatacept (both the more-intensive regimen and the less-intensive steroid-free regimens, as illustrated in studies with liver trans-
regimen) than with cyclosporine. 49 plantation. Several prospective clinical trials using basiliximab
Because of concerns about an increased post-transplant induction to facilitate early steroid withdrawal or complete steroid
lymphoproliferative disease (PTLD) risk in Epstein-Barr virus avoidance after kidney transplantation were tried and proven
(EBV)–seronegative patients, current belatacept trial protocols safe. However, similar to alemtuzumab, the use of complete CNI
have now been modified to enroll EBV-seropositive patients only. avoidance protocols should be practiced with extreme caution;
Unfortunately, this exclusion will complicate the introduction in several studies that withheld CNIs for any more than a very
of this drug in young patients, who might derive the maximum short period, despite adequate immunosuppression with IL-2R
long-term benefit from nonnephrotoxic regimens. A significant mAbs, MMF, and steroids, the acute cellular rejection rates after
54
limitation to note is that administration of belatacept requires renal transplantation were much higher than with CNI use.
intravenous infusion; this is not an ideal characteristic for a Thus as with ATG and alemtuzumab, patients receiving basilix-
maintenance immunosuppressant and raises issues of patient imab are still exposed to chronic administration of maintenance
compliance. Furthermore, the agent has a long half-life of 8–10 immunosuppression and its associated comorbidities.