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Transplantation
emphasises the requirement for the use of CNIs in human trans- immunological tolerance in allogeneic transplantation. Therefore, the
plantation, whereas these drugs constitute an additional barrier to effect of the IS drugs on the physiology of these cells is a critical concern.
tolerance. Finally, homeostatic proliferation renders the few naïve, Several studies have addressed this issue, particularly with the CNIs,
residual T cells resistant to tolerance induction.
10
mammalian target of rapamycin (mTOR) inhibitors and anti-interleukin-2
The problem raised by memory T cells regarding immunological tolerance
The Foxp3-expressing regulatory
concerns mostly outbred species such as humans and non-human
primates, but also, to a much lesser extent, inbred species such as mice. T cells involved in the control of
The main reason for this is that the latter species develop in specific
diverse immune responses have been
pathogen-free conditions that limit the presence of alloreactive memory
T cells. Indeed, alloreactive memory T cells are found in individuals who
the focus of increasing attention from
have never before been exposed to foreign tissues.
11,12
It is thought that
the immunological community over
alloreactive memory T cells correspond to cross-reactive pathogen-
specific clones, given that humans are extensively exposured to viral and
the last few years.
bacterial antigens.
13
The presence of these cells might explain why the
tolerogen protocols that easily induce tolerance to allogeneic grafts in (anti-IL-2) receptor antibody treatments. It is noteworthy that Foxp3
mice fail in humans. expression is suppressed by cyclosporin A.
20
In addition, cyclosporin A
inhibits the expansion and function of regulatory T cells.
21,22
Patients
Immunosuppressive Drugs and Activation-induced Cell treated with cyclosporin A have a significantly lower number of blood
Death of Alloreactive T Cells regulatory T cells compared with those treated with rapamycin.
23
In
Apoptosis of alloreactive T cells, also called activation-induced cell contrast, rapamycin promotes selective enrichment of Foxp3-expressing
death (AICD), seems crucial for the induction of stable peripheral regulatory T cells
24
and might even induce de novo-generated regulatory
allograft tolerance.
2
This physiological phenomenon is exacerbated T cells.
25
Furthermore, Foxp3+ regulatory T cells retain their suppressive
during tolerance induction, leading to a reduction of the effector cells, ability upon rapamycin treatment.
22,24
Altogether, these data explain why
which is a prerequisite step for tipping over the allogeneic response the regulatory T cells contribute to hyporesponsiveness against donor
towards tolerance. However, it has long been known that cyclosporin antigens in kidney recipients receiving rapamycin but not in recipients
A inhibits AICD of T cells.
14
In addition, a seminal and troubling receiving cyclosporin A.
26
observation was that CNIs blocked the allogeneic tolerance induced by
The negative effect of CNIs on regulatory T-cell development was first
attributed to the blockade of IL-2 secretion, which is a crucial cytokine for
In human transplantation, the
regulatory T cells.
27
However, treatments with mTOR inhibitor
28
or anti-IL-
long-term acceptance of a functional
2R antibody,
28,29
both of which interfere with IL-2 signalling, failed to
reduce the number or function of regulatory T cells. These discrepancies
graft requires continuous suppression
could be explained by recent data. First, it was shown recently that the
of the immune system by
transcriptional activity of Foxp3 protein depends on co-operative DNA
binding of the nuclear factor of activated T cells (NFAT) and Foxp3.
30
This
immunosuppressive drugs.
study provides evidence that NFAT/Foxp3 complexes bind to regulatory
elements of genes and modulate their expression.
30
On the other hand,
co-stimulation blockade in mice,
15
as well as in non-human primates.
16
the transcriptional activity of NFAT depends strongly on the calcineurin
Altogether, these data led Yi et al.
15
to demonstrate that CNIs inhibit phosphatase, which is directly targeted by CNIs. Therefore, the CNI-
the AICD of alloreactive T cells, precluding the tolerance induction. induced inhibition of NFAT may negatively impact the Foxp3-expressing
Importantly, the CNIs blocked the proliferation of alloreactive T cells but T cells independently of IL-2 signalling pathways.
inhibited their deletion as corollary.
15
In striking contrast, sirolimus did
not inhibit proliferation of alloreactive T cells but increased the number Second, the selective effect of rapamycin, favouring expansion of
of cells entering into apoptosis at each cycle of division.
15
Therefore, regulatory T cells over differentiation of effector T cells, might be explained
sirolimus reinforces the tolerising effect of co-stimulation blockade. by the requirement of a different IL-2 signalling pathway. Indeed, full T-cell
These in vivo experiments in mice were recently confirmed with human activation requires a functional mTOR-dependent signalling pathway.
31
In
lymphocytes in vitro.
17
The effect of the other IS drugs on AICD has contrast, the development, maintenance and function of regulatory T cells
been poorly studied. require IL-2R signalling through janus kinase 3 (JAK3)/signal transducer and
activator of transcription 5 (STAT5).
32,33
Immunosuppressive Drugs and Regulatory T-cell Expansion
The Foxp3-expressing regulatory T cells involved in the control of diverse There are very few data available regarding the effect of the other IS
immune responses have been the focus of increasing attention from the treatments on regulatory T cells. In agreement with the lesser sensitivity
immunological community over the last few years. Stable expression of of CD4+CD25+ regulatory T cells to steroid-induced cell death,
34
an
the Foxp3 gene is tightly linked to the regulatory T-cell lineage. The gene increased number of regulatory T cells have been reported in asthmatic
encodes for a transcription factor, which is required for the ontogeny, patients treated with glucocorticoid.
35
In addition, it was shown recently
phenotype and suppressive function of canonical regulatory T cells.
18,19
that ATG could induce Foxp3+ regulatory T cells.
36
However, the
These cells play a major role in inducing and maintaining a dominant substantial caveat of this study is that the conclusions are based on in
62 EUROPEAN RENAL DISEASE 2007