Transcript A Novel Approach in Kidney Transplantation: Costimulation

A Novel Approach in Kidney
Transplantation: Costimulation Blockade
Reference: Snanoudj R, Zuber J, Legendre
C. Costimulation blockade as a new
strategy in kidney transplantation. Drugs.
2010;70(16):2121–2131.
• Over the past 5 decades, immunosuppressive regimens for
kidney transplantation have significantly improved;
however, these agents have had little impact on long-term
graft survival.
• The reason being in part, to the broad nonimmune effects
of the current immunosuppressive drugs, which are
involved in the death of patients and in chronic allograft
dysfunction mostly due to their nephrotoxicity.
• However, recent progress in the development of biologicals
like antibodies and fusion proteins, allows the precise
targeting of the immune system, preventing the
nonimmune side-effects encountered with current
protocols.
• Apart from immunological factors, current immunosuppressive
protocols are involved in several mechanisms in the development of
chronic graft dysfunction (see Table 1).
• As a result, recent immunosuppressive protocols tend to minimize
or even avoid the use of calcineurin inhibitors (CNIs). Presently, it is
obvious that complete withdrawal of CNIs from the gold standard
triple therapy (with corticosteroids and mycophenolate mofetil)
results in a significant increase in the rate of late acute rejection.
• Therefore, the complete avoidance of CNIs is a challenge, as
preventing their toxic effects should not be associated with an
increased risk of triggering an alloimmune response.
• An attractive alternative is the use of costimulation blockade that
allow the precise and efficient immune targeting with a favorable
safety profile.
Costimulation Blockade:
Immunological Basis
Three Signals Engaged in T-Cell Activation
• T-lymphocyte activation requires three signals, which are shown in
Figure 1. The first involves T-cell receptor triggering by donor
antigen on the surface of dendritic cells (DCs) or other antigenpresenting cells.
• The second, or costimulation signal, which is not nantigendependent is delivered when B7-1/CD80 and B7-2/CD86 on the
surface of DCs engage CD28 on T cells.
• These two signals are necessary to activate three transduction
pathways that result in interleukin-2 binding to its receptor, which is
the third signal, and the downstream mammalian target of
rapamycin pathway activation, leading to T-cell clonal proliferation
and the generation of effector T cells.
The Intricacy of the B7/CD28/CTLA4 Conduit
• The B7/CD28/CTLA4 pathway is characterized by the dual
affinity of B7-1 and B7-2 for both the stimulatory receptor
CD28 and the inhibitory receptor (cytotoxic Tlymphocyteassociated antigen 4 (CTLA4) or CD152).
• The CD28 molecule, which is constitutively expressed on T
cells, provides a T-cell activation signal.
• Contrarily, the expression CTLA4 is rapidly upregulated
following T-cell activation, and delivers a T-cell inhibition
signal due to its higher receptor affinity for both B7-1 and
B7-2.
• CTLA4 plays a critical role in downregulating the T-cell
response, primarily by interrupting T cell–DC interactions.
From Experimental Models of ‘Classical’ Costimulation Blockade
with CTLA4-Ig to Clinical Studies with Belatacept
• One of the foremost tools used to target the B7/CD28 pathway
was the CTLA4 immunoglobulin (Ig) (abatacept) molecule.
• However, insufficient blockade of the CD28/ B7 interaction
could partly account for the limited results obtained in nonhuman primate (NHP) models.
• Recently, two amino acid substitutions in the CTLA4 binding
domain were identified as potentially useful, leading to the
development of a new molecule, belatacept (LEA29Y).
• With this, inhibition of T-cell activation was increased 10- fold
over that of CTLA4-Ig. Moreover, NHP studies showed a
prolongation of kidney allograft survival and an inhibition of
antidonor humoral response when belatacept was used alone
or in combination with corticosteroids and MMF.
• A large-scale 12-month phase II multicenter study was conducted with
belatacept in renal transplantation.
• Here, the primary noninferiority objective was reached, with very low and
similar incidences of acute rejection at 6 months.
• The glomerular filtration rate at 12 months was significantly higher in
patients receiving belatacept than in those treated with ciclosporin.
• In addition, the incidence of chronic allograft nephropathy (scarring
lesions) was lower in patients receiving belatacept by month 12.
• As for the adverse effects, the frequency of infections was found to be
similar.
• Many other preliminary results have also suggested that the use of
belatacept in CNI and corticosteroid avoiding regimens, in combination
with rabbit antithymocyte globulin (ATG) induction, might be a promising
avenue for future trials.
• Importantly, no case of post-transplantation lymphoproliferative disorder
(PTLD) was observed at 6 months in these patients.
Aiming Other Costimulatory Pathways
The CD40/CD40L Pathway
• The second major costimulatory pathway of interest in transplantation
immunology is the CD40/CD40L pathway.
• The CD40 is constitutively expressed on B cells, DCs, and macrophages.
• Several studies have suggested that the inhibition of CD40-mediated
signaling events is an important mechanism of action for both anti-CD40
and anti-CD40L antibodies.
Other Members of the CD28/B7 and Tumor Necrosis
Factor (TNF)/TNF Receptor Super-families
• Several other members of the CD28/B7 and TNF/TNF receptor superfamilies deliver positive or negative costimulatory signals, either early or
delayed after encountering an antigen.
Aiming Other Costimulatory Pathways
The Leukocyte Function-Associated Antigen (LFA)1/Intercellular Adhesion Molecule (ICAM) Pathway:
• Leukocyte function-associated antigen-1 is a β2-integrin
expressed on T cells, chiefly memory T cells.
• The introduction of efalizumab, a humanized anti-CD11a mAb
that blocks the binding of LFA-1 to ICAM-1 has received US
FDA approval for treatment of severe plaque psoriasis.
• However, owing to the occurrence of progressive multifocal
leukoencephalopathy, a potentially fatal JC
polyomavirusassociated disease in four patients treated for
psoriasis, it has been decided to initiate the progressive
withdrawal of efalizumab.
Aiming Other Costimulatory Pathways
• The CD2/LFA-3 Pathway: Alefacept (LFA-3-Ig) is a fusion
protein consisting of the CD2-binding portion of human LFA-3
linked to the Fc portion of human IgG1.
• The FDA approved alefacept for use in severe plaque
psoriasis.
• Alefacept has been shown to increase allograft cardiac
survival and, more interestingly, to prevent kidney allograft
rejection and alloantibody formation in combination with
CTLA4-Ig.
• Presently, two phase II multicenter studies are being
conducted to assess the efficacy and safety of alefacept in
renal transplant recipients.
Conclusion
• Belatacept is reportedly believed to become a first-line
immunosuppressive molecule given its short-term favorable
efficacy/safety ratio.
• This drug along with other costimulatory blocking agents in development
are foreseen as components of a combination therapy applied with other
biologicals or with lower doses of classical immunosuppressive drugs.
• Apart from the clear benefits in terms of cardiovascular risks and
nephrotoxicity afforded by these biologicals, concerns about infectious
and neoplastic complications call for a closely explored study in future
research.
• Nevertheless, this family of immunosuppressants could be a powerful tool
in the road to transplantation tolerance.
• Additional studies are required to find the adequate combinations of
molecules and the monitoring tools to identify the appropriate moment
and candidates for reduction and even weaning of immunosuppression.