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Influence of Various Immunosuppressive Regimens on Tolerance Induction in Transplant Recipients
vitro experiments using low concentrations of ATG,
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whereas the higher memory T cells while allowing the generation of regulatory T cells.
40
dosages used in vivo lead to a profound depletion of regulatory T cells.
4
Perspectives and Conclusions
New Drugs Most of the available IS drugs impair the mechanisms involved in the
The availability of new therapeutic tools in clinical transplantation is always induction of dominant tolerance. It is important to emphasise the
very exciting, particularly given the challenging aim of achieving requirements for future IS regimens in order to reach this elusive goal.
operational tolerance. Unfortunately, the development of new drugs by First, IS induction would have to dramatically reduce the pool size of
pharmacological companies may not be driven by this ultimate goal. alloreactive T cells, especially the memory ones. Second, IS regimens
Therefore, few of the new molecules are promising in these settings. For would have to promote donor-specific regulatory T-cell expansion by
instance, given the ten-fold decrease of regulatory T cells in protein kinase avoiding drugs that interfere with their physiology. Third, these
Cθ (PKCθ)-deficient mice,
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one might expect that the recently developed regimens would have to respect as much as possible the development
PKCθ inhibitor AEB071 would affect this population with high specificity. and peripheral homeostasis of other T cells, especially the naïve ones.
Similarly, given the crucial role of the JAK3/STAT5 IL-2R pathway for This would ensure that the recipients remain capable of mounting an
the regulatory population, one would expect that the JAK3 inhibitor efficient immune response against pathogens.
CP-690,550 has a specific role in the depletion of this lymphocyte
subset.
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The belatacept CTLA-4-Ig might be more promising for tolerance Interestingly, a recently described IS protocol seems to be a strong
induction, but its impact on the regulatory compartment is uncertain, attempt to meet these requirements.
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With this protocol, an agonist
given the role of the CD28/B7 pathway in maintaining this population on anti-IL-2R antibody, boosting regulatory T-cell expansion, is associated
the periphery.
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with an antagonist anti-IL-15R antibody, blocking the antiapoptotic
signal in cytopathic memory T cells, and rapamycin, which inhibits the
Lastly, the properties of the non-mitogenic anti-CD3 antibody seem very rapid expansion of alloreactive T cells.
41
This protocol allows tolerance in
encouraging.
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Indeed, the antibody has been shown to be efficient in very stringent allotransplant models by skewing the alloimmune
reverting ongoing autoimmune disease, which suggests the control of response towards regulation. ■
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