zuber.qxp 9/7/07 10:49 am Page 63
Influence of Various Immunosuppressive Regimens on Tolerance Induction in Transplant Recipients
vitro experiments using low concentrations of ATG,
whereas the higher memory T cells while allowing the generation of regulatory T cells.
dosages used in vivo lead to a profound depletion of regulatory T cells.
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,
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
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.
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
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.
This protocol allows tolerance in
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. ■
1. Ashton-Chess J, Brouard S, Soulillou JP, Is clinical tolerance and induction of peripheral allograft tolerance, Nat Med, vitro, Am J Transplant, 2005;5(3):454–64.
realistic in the next decade?, Transpl Int, 2006;19(7):539–48. 1999;5(11):1298–302. 29. Kreijveld E, Koenen HJ, Klasen IS, et al., Following anti-CD25
2. Chiffoleau E, Walsh PT, Turka L, Apoptosis and transplantation 16. Kirk AD, Burkly LC, Batty DS, et al., Treatment with humanized treatment, a functional CD4+CD25+ regulatory T-cell pool is
tolerance, Immunol Rev, 2003;193:124–45. monoclonal antibody against CD154 prevents acute renal present in renal transplant recipients, Am J Transplant,
3. Wood KJ, Sakaguchi S, Regulatory T cells in transplantation allograft rejection in nonhuman primates, Nat Med, 2007;7(1):249–55.
tolerance, Nat Rev Immunol, 2003;3(3):199–210. 1999;5(6):686–93. 30. Wu Y, Borde M, Heissmeyer V, et al., FOXP3 controls regulatory
4. Pearl JP, Parris J, Hale DA, et al., Immunocompetent T-cells 17. Woodside KJ, Hu M, Liu Y, et al., Apoptosis of allospecifically T cell function through cooperation with NFAT, Cell,
with a memory-like phenotype are the dominant cell type activated human helper T cells is blocked by calcineurin 2006;126(2):375–87.
following antibody-mediated T-cell depletion, Am J Transplant, inhibition, Transpl Immunol, 2006;15(3):229–34. 31. Zheng Y, Collins SL, Lutz MA, et al., A role for mammalian
2005;5(3):465–74. 18. Gavin MA, Torgerson TR, Houston E, et al., Single-cell analysis target of rapamycin in regulating T cell activation versus anergy,
5. Heeger PS, Greenspan NS, Kuhlenschmidt S, et al., of normal and FOXP3-mutant human T cells: FOXP3 expression J Immunol, 2007;178(4):2163–70.
Pretransplant frequency of donor-specific, IFN-gamma- without regulatory T cell development, Proc Natl Acad Sci U S A, 32. Bensinger SJ, Walsh PT, Zhang J, et al., Distinct IL-2 receptor
producing lymphocytes is a manifestation of immunologic 2006;103(17):6659–64. signaling pattern in CD4+CD25+ regulatory T cells, J Immunol,
memory and correlates with the risk of posttransplant rejection 19. Hori S, Nomura T, Sakaguchi S, Control of regulatory T cell 2004;172(9):5287–96.
episodes, J Immunol, 1999;163(4):2267–75. development by the transcription factor Foxp3, Science, 33. Zorn E, Nelson EA, Mohseni M, et al., IL-2 regulates FOXP3
6. Neujahr DC, Chen C, Huang X, et al., Accelerated memory cell 2003;299(5609):1057–61. expression in human CD4+CD25+ regulatory T cells through a
homeostasis during T cell depletion and approaches to 20. Mantel PY, Ouaked N, Ruckert B, et al., Molecular mechanisms STAT-dependent mechanism and induces the expansion of
overcome it, J Immunol, 2006;176(8):4632–9. underlying FOXP3 induction in human T cells, J Immunol, these cells in vivo, Blood, 2006;108(5):1571–9.
7. Tough DF, Sprent J, Turnover of naive- and memory-phenotype 2006;176(6):3593–602. 34. Chen X, Murakami T, Oppenheim JJ, Howard OM, Differential
T cells, J Exp Med, 1994;179(4):1127–35. 21. Coenen JJ, Koenen HJ, van Rijssen E, et al., Rapamycin, and not response of murine CD4+CD25+ and CD4+CD25- T cells to
8. Chen Y, Heeger PS, Valujskikh A, In vivo helper functions of cyclosporin A, preserves the highly suppressive CD27+ subset dexamethasone-induced cell death, Eur J Immunol, 2004;34(3):
alloreactive memory CD4+ T cells remain intact despite donor- of human CD4+CD25+ regulatory T cells, Blood, 2006;107(3): 859–69.
specific transfusion and anti-CD40 ligand therapy, J Immunol, 1018–23. 35. Karagiannidis C, Akdis M, Holopainen P, et al., Glucocorticoids
2004;172(9):5456–66. 22. Zeiser R, Nguyen VH, Beilhack A, et al., Inhibition of upregulate FOXP3 expression and regulatory T cells in asthma,
9. Cobbold SP, Castejon R, Adams E, et al., Induction of foxP3+ CD4+CD25+ regulatory T-cell function by calcineurin-dependent J Allergy Clin Immunol, 2004;114(6):1425–33.
regulatory T cells in the periphery of T cell receptor transgenic interleukin-2 production, Blood, 2006;108(1):390–99. 36. Lopez M, Clarkson MR, Albin M, et al., A novel mechanism of
mice tolerized to transplants, J Immunol, 2004;172(10): 23. Segundo DS, Ruiz JC, Izquierdo M, et al., Calcineurin inhibitors, action for anti-thymocyte globulin: induction of
6003–10. but not rapamycin, reduce percentages of CD4+CD25+FOXP3+ CD4+CD25+Foxp3+ regulatory T cells, J Am Soc Nephrol,
10. Wu Z, Bensinger SJ, Zhang J, et al., Homeostatic proliferation is regulatory T cells in renal transplant recipients, Transplantation, 2006;17(10):2844–53.
a barrier to transplantation tolerance, Nat Med, 2004;10(1): 2006;82(4):550–57. 37. Schmidt-Supprian M, Tian J, Grant EP, et al., Differential
87–92. 24. Battaglia M, Stabilini A, Roncarolo MG, Rapamycin selectively dependence of CD4+CD25+ regulatory and natural killer-like T
11. Andree H, Nickel P, Nasiadko C, et al., Identification of dialysis expands CD4+CD25+FoxP3+ regulatory T cells, Blood, cells on signals leading to NF-kappaB activation. Proc Natl Acad
patients with panel-reactive memory T cells before kidney 2005;105(12):4743–8. Sci U S A, 2004;101(13):4566–71.
transplantation using an allogeneic cell bank, J Am Soc Nephrol, 25. Valmori D, Tosello V, Souleimanian NE, et al., Rapamycin- 38. Borie DC, Larson MJ, Flores MG, et al., Combined use of the
2006;17(2):573–80. mediated enrichment of T cells with regulatory activity in JAK3 inhibitor CP-690,550 with mycophenolate mofetil to
12. Poggio ED, Clemente M, Hricik DE, Heeger PS, Panel of reactive stimulated CD4+ T cell cultures is not due to the selective prevent kidney allograft rejection in nonhuman primates,
T cells as a measurement of primed cellular alloimmunity in expansion of naturally occurring regulatory T cells but to the Transplantation, 2005;80(12):1756–64.
kidney transplant candidates, J Am Soc Nephrol, 2006;17(2): induction of regulatory functions in conventional CD4+ T cells, 39. Lohr J, Knoechel B, Jiang S, et al., The inhibitory function of B7
564–72. J Immunol, 2006;177(2):944–9. costimulators in T cell responses to foreign and self-antigens,
13. Lakkis FG, Sayegh MH, Memory T cells: a hurdle to 26. Noris M, Casiraghi F, Todeschini M, et al., Regulatory T cells Nat Immunol, 2003;4(7):664–9.
immunologic tolerance, J Am Soc Nephrol, 2003;14(9): and T cell depletion: role of immunosuppressive drugs, J Am Soc 40. Belghith M, Bluestone JA, Barriot S, et al., TGF-beta-dependent
2402–10. Nephrol, 2007;18(3):1007–18. mechanisms mediate restoration of self-tolerance induced by
14. Shi YF, Sahai BM, Green DR, Cyclosporin A inhibits activation- 27. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY, antibodies to CD3 in overt autoimmune diabetes, Nat Med,
induced cell death in T-cell hybridomas and thymocytes, Nature, A function for interleukin 2 in Foxp3-expressing regulatory T 2003;9(9):1202–8.
1989;339(6226):625–6. cells, Nat Immunol, 2005;6(11):1142–51. 41. Zheng XX, Sanchez-Fueyo A, Sho M, et al., Favorably tipping
15. Li Y, Li XC, Zheng XX, et al., Blocking both signal 1 and signal 28. Game DS, Hernandez-Fuentes MP, Lechler RI, Everolimus and the balance between cytopathic and regulatory T cells to create
2 of T-cell activation prevents apoptosis of alloreactive T cells basiliximab permit suppression by human CD4+CD25+ cells in transplantation tolerance, Immunity, 2003;19(4):503–14.
EUROPEAN RENAL DISEASE 2007 63
| Page 2
| Page 3
| Page 4
| Page 5
| Page 6
| Page 7
| Page 8
| Page 9
| Page 10
| Page 11
| Page 12
| Page 13
| Page 14
| Page 15
| Page 16
| Page 17
| Page 18
| Page 19
| Page 20
| Page 21
| Page 22
| Page 23
| Page 24
| Page 25
| Page 26
| Page 27
| Page 28
| Page 29
| Page 30
| Page 31
| Page 32
| Page 33
| Page 34
| Page 35
| Page 36
| Page 37
| Page 38
| Page 39
| Page 40
| Page 41
| Page 42
| Page 43
| Page 44
| Page 45
| Page 46
| Page 47
| Page 48
| Page 49
| Page 50
| Page 51
| Page 52
| Page 53
| Page 54
| Page 55
| Page 56
| Page 57
| Page 58
| Page 59
| Page 60
| Page 61
| Page 62
| Page 63
| Page 64
| Page 65
| Page 66
| Page 67
| Page 68
| Page 69
| Page 70
| Page 71
| Page 72
| Page 73
| Page 74