Skip to main content
SpringerLink
Log in

STEALTH in transplantation tolerance

  • Published:
Immunologic Research Aims and scope Submit manuscript

An Erratum to this article was published on 28 September 2007

Abstract

Although contemporary immunosuppressive regimens are responsible for major improvements in allograft acceptance, there are indications that long-term survival may be compromised through drug toxicity and/or chronic immune deficiency. The ultimate goal for transplantation is tolerance, defined as durable, donor-specific allograft acceptance in the absence of long-term immunosuppression. This article reviews the non human primante STEALTH model of tolerance recently developed by the transplant immunobiology group at University of Alabama at Birmingham. The STEALTH model was designed for future application to human transplantation and comprises a concise peritransplant treatment strategy of only 2 wk. Tolerance is induced by depletion of T cells, with concomitant inhibition of nuclear factor-KB/RelB-dependent proinflammatory signaling. This treatment has resulted in an unprecedented frequency of kidney allograft survival (62.5% at 3 yr), with some primate recipients remaining in good health more than 6 yr posttransplant, in the complete absence of chronic pharmacologic immunosuppression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Cecka JM: The UNOS Scientific Renal Transplant Regixtry—2000. Clin Transpl 2000;14:1–18.

    Article  Google Scholar 

  2. Li XC, Wells AD, Strom TB, Turka LA: The role of T cell apoptosis in transplantation tolerance. Curr Opin Immunol 2000;12:522–527.

    Article  PubMed  CAS  Google Scholar 

  3. Waldmann PH, Cobbold S: T-cell regulation and transplatation tolerance. Curr Opin Organ Transplant 2000;5:83–89.

    Article  Google Scholar 

  4. Salama AD, Remuzzi G, Harmon WE, Sayegh MH: Challenges to achieving clinical transplantation tolerance. J Clin Invest 2001;108:943–948.

    Article  PubMed  CAS  Google Scholar 

  5. Thomas JM, Contreras JL, Jiang XL, Eckhoff DE, Wang PX, Hubbard WJ, et al. Peritransplant tolerance induction in macaques: early events reflecting the unique synergy between immunotox in and deoxyspergualin. Transplantation 1999;68:1660–1673.

    Article  PubMed  CAS  Google Scholar 

  6. Thomas JM, Hubbare WJ, Sooudi SK, Thomas FT: STEALTH maters: a novel paradigm of durable primate allograft tolerance. Immunol Rev 2001;183:223–233.

    Article  PubMed  CAS  Google Scholar 

  7. Thomas JM, Thomas FT: A preclinical view of transplant tolerance and chimerism: tolerance induction by posttransplant lymphoid irradiation and doner bone marrow; in Hstad S. (ed.): Chimerism and Tolerance. Heidelberg, Germany, Springer Verlag, 1996, pp. 143–158.

    Google Scholar 

  8. Kirk AD: Transplantation tolerance: a look at the nonhuman primate literature in the light of modern tolerance theories. Crit Rev Immunol 1999;19:349–388.

    PubMed  CAS  Google Scholar 

  9. Sachs DH: Immunologic tolerance to organ transplants. J Gastrointest Surg 1999;3:105–110.

    Article  PubMed  CAS  Google Scholar 

  10. Knechtle SJ: Knowledge about trasnplantation tolerance gainedin primaters. Curr Opin Immunol 2000;12:552–556.

    Article  PubMed  CAS  Google Scholar 

  11. Wekerle T: Transplantation tolerance induced by mixed chimerism. J Heart Lung Transplant 2001;20: 816–823.

    Article  PubMed  CAS  Google Scholar 

  12. Matzinger P: Tolerance, danger, and the extenden family. Annu Rev Immunol 1994;12:991–1045.

    PubMed  CAS  Google Scholar 

  13. Matzinger P: The immune system's role in graft loss theoretic considerations. Transplant Proc 1997;29: 11S-12S.

    Article  PubMed  CAS  Google Scholar 

  14. Thomas JM, Eckhoff DE, Contreras JL, et al: Durable donorspecific T and B cell tolerance in rhesus macaques induced with peritransplantation anti-CD3 immunotoxin and deoxyspergualin: absence of chronic allograft nephropathy. Transplantation 2000;69:2495–2503.

    Google Scholar 

  15. Contreras JL, Wang PX, Eckhoff DE, et al: Peritransplant tolerance induction withanti-CD 3-immunotoxin: a matter of proinflammatory cytokine control. Transplantation 1998;65:1159–1169.

    Article  PubMed  CAS  Google Scholar 

  16. Wu L, D'Amico A, Winkel KD, Suter M, Lo D, Shortman K: RelB is essential for the development of myeloid-related CD8 alpha-dendritic cells but not of lymphoid-related CD8alpha+dendritic cells. Immunity 1998;9:839–847.

    Article  PubMed  CAS  Google Scholar 

  17. Neville DM Jr, Scharff J, Hu HZ, et al: A new reagent for the induction of T-cell depletion, andti-CD3-CRM9. J Immunother Emphasis Tumor Immunol 1996;19:85–92.

    PubMed  CAS  Google Scholar 

  18. Hubbard WJ, Contreras JL, Eckhoff DE, Thomas FT, Neville DM, Thomas JM: Hummunotoxins and tolerance induction in primates. Curr Opin Organ Transplantation 2000;5:29–34.

    Article  Google Scholar 

  19. Nooij FJ, Borst JG, Van Meurs GJ, Jonker M, Balmer H: Differentiation antigens on rhesus monkey lymphocytes. I. Identification of T cels bearing CD3 and CD8, and of a subsewt of CD8-bearing cellsn. Eur J Immunol 1986;16:975–979.

    Article  PubMed  CAS  Google Scholar 

  20. Thomas JM, Neville DM, Contreras JL, et al: Preclinical studies of allograft tolerance in rhesus monkeys: a novel anti-CD3-monkeys: a novel anti-CD3-immunotoxin given peritrasplant with donor bone marrow induces operational tolerance to kidney allografts. Transplantation 1997; 64:124–135.

    Article  PubMed  CAS  Google Scholar 

  21. Contreras JL, Eckhoff DE, Cartner S, et al: Tolera bility and side effects of anti-CD3-immunotoxin in preclinical testing in kidney and pancreatic islet transplant recipients. Transplantation 1999;68:215–219.

    Article  PubMed  CAS  Google Scholar 

  22. Steinman RM, Inaba K, Turkey S, Pierre P, Mellman I: Antigen capture, processing, and presentation by dendritic cells: recent cell biological studies. Hum Immunol 1999;60:562–567.

    Article  PubMed  CAS  Google Scholar 

  23. Wu J, He J, Sooudi S, et al: Pretreatment of HL60 cells with Deoxyspergualin enhances trail-induced apoptosis independent of caspase 3 activation. Transplant Proc 2001;33:278.

    Article  PubMed  CAS  Google Scholar 

  24. Nadler SG, Eversole AC, Tepper MA, Cleaveland JS: Elucidating the mechanism of action of the immunosuppressant 15-deoxyspergualin. The Drug Monit 1995;17: 700–703.

    Article  CAS  Google Scholar 

  25. Snapper CM, Zelazowski P, Rosas FR, et al: B cells from p50/NF-kappa B knockout mice have selective defects in proliferation differentiation, germ-line CH transcription, and Ig class witching. J Immunol 1996;156:183–191.

    PubMed  CAS  Google Scholar 

  26. Thomas JM, Contreras JL, Smyth CA, et al: Successfurl reversal of streptozotocin-induced diabetes with stable allogeneic islet function in a preclinical model of typel diabetes. Diabetes 2001;50: 1227–1236.

    Article  PubMed  CAS  Google Scholar 

  27. Shapiro AM, Ryan EA, Lakey JR: Clinical islet transplant-state of the art. Transplant Proc 2001;33: 3502–3503

    Article  PubMed  CAS  Google Scholar 

  28. Murray J, Sheil AG, Mosley R, Knight P, Dickinson J, Dammin J: Analysis of mechanism of immunosuppressive drugs in renal homotransplantation. Ann Surg 1964;160:449–473.

    Article  PubMed  CAS  Google Scholar 

  29. Hubbard WJ, Moore JK, Contreras JL, et al: Phenotypic and functional analysis of T-cell recovery after anti-CD3 immunotoxin treatment for tolerance inductionn in rhesus macaques. Hum Immunol 2001 62:479–487.

    Article  PubMed  CAS  Google Scholar 

  30. Donnenberg AD, Margolick JB, Donnenberg VS: Lymphopoiesis, apoptosis, and immune ammesia. Ann NY Acad Sci 1995;770; 213–226.

    Article  PubMed  CAS  Google Scholar 

  31. Cho BK, Rao VP, Ge Q, Eisen HN, Chen J: Homeostasis-stimulated proliferation drives mive T cells to differentiate directly into memory T cells. J Exp Med 2000;193:549–556.

    Article  Google Scholar 

  32. Goldrath AW, Boglzki LY, Bevan MJ: Naive T cells transiently acquire a memory-like phenotype during homeostasis-driven prolife ration. J Exp Med 2000;192: 557–64.

    Article  PubMed  CAS  Google Scholar 

  33. Clarke SR, Rudensky AY: Survival and homeostatic proliferation of naive peripheral CD4+T cells in the absence of self peptide: MHC complexes. J Immunol 2000;165: 2458–2464.

    PubMed  CAS  Google Scholar 

  34. Murali-Krishna K, Ahmed R: Gutting edge naive T cells masquerading as memory cells. J Immunol 2000;165:1733–1737.

    PubMed  CAS  Google Scholar 

  35. McKenna RM, Takemoto SK, Terasaki PJ: Anti-HLA antibodies after solid organ transplantation. Transplantation 2000;69:319–326.

    Article  PubMed  CAS  Google Scholar 

  36. Tepper MA, Nadler SG, Esselstyn JM, Sterbenz KG: Deoxyspergualin inhibits kappu light chain expression in 70Z/3 pre-B cells by blocking lipopolysaccharide-induced NF-kappa B activation. J Immunol 1995;155:2427–2436.

    PubMed  CAS  Google Scholar 

  37. Banchereau J, Steinman RM: Dendritic cells and the control of immunity. Nature 1998;392:245–252.

    Article  PubMed  CAS  Google Scholar 

  38. Bretscher PA: A two-step, two-signal model for the primary activation of precursor helper T cells. Proc Natl Acad Sci USA 1999; 96:185–190.

    Article  PubMed  CAS  Google Scholar 

  39. Ridge JP, Fuchs EJ, Matzinger P: Neonatal tolerance revisited: tuming on newborn T cells with dendritic cells. Science 1996;271: 1723–1726.

    Article  PubMed  CAS  Google Scholar 

  40. Rengarajan J, Szabo SJ, Glimcher LH: Transcriptional regulation of Th1/Th2 polarization. Immunol Doday 2000;21:479–483.

    Article  CAS  Google Scholar 

  41. Godfrey DI, Hammond KJ, Poulton LD, Smyth MJ, Baxter AG: NKT cells: facts, functions and falacies. Immunol Today 2000;21: 573–583.

    Article  PubMed  CAS  Google Scholar 

  42. Burdin N, Brossay L, Kronenberg M: Immunization with lapha-galactosy lceramide polarizes CD1-reactive NK T cells towards Th2 cytokine synthesis. Eur J Immunol 1999;29:2014–2025.

    Article  PubMed  CAS  Google Scholar 

  43. Carnaud C, Lee D, Donnars O, et al: Cutting edge: cross-talk between cells of the imate immune system: NKT cells rapidly activate NK cells. J Immunol 1999;163: 4647–4650.

    PubMed  CAS  Google Scholar 

  44. Zhai Y, Kupiec-Weglinski JW: What is the role of regulatory T cells in transplantation tolerance? Curr Opin Immunol 1999;11:497–503.

    Article  PubMed  CAS  Google Scholar 

  45. Hara M, Kinglsy CI, Niimi M, et al: IL-10 is required for regulatory T cells to mediate tolerance to alloartigens in vivo. J Immunol 2001;166:3789–379.

    PubMed  CAS  Google Scholar 

  46. Levings MK, Ronacarolo MG: T-regulatory 1 cells: a novel subset of CD4 T cells with immunoregulatory properties. J Allergy Clin Immunol 2000;106:S109-S112.

    Article  PubMed  CAS  Google Scholar 

  47. Taams LS, Smith J, Rustin MH, Salmon M, Poulter LW, Akbar AN: Human anergic/supperssive CD4(+)CD25(+) Tcells: a highly differentiated andapoptosis-prone population. Eur J Immunol 2001; 31:1122–1131.

    Article  PubMed  CAS  Google Scholar 

  48. Levings MK, Sangegorio R, Galbiati F, Squadrone S, de Waal Malefyt R Roncarolo MG: IFN-alpha-andIL-10 induce the differentiation of human type 1 T regulatory cells. J Immunol 2001;166:5530–5539.

    PubMed  CAS  Google Scholar 

  49. Inaba K, Turley S, Yamaide F, et al. Efficient presentation of phagocytosed cellular fragments on the major histocompatibility complex class II products of dendritic cells. J exp Med 1998;188:2163–2173.

    Article  PubMed  CAS  Google Scholar 

  50. Weih DS, Yilmaz ZB, Weith F: Essential role of RelB in germinal center and marginal zone formation and proper expression of homing chemokines. J Immunol 2001;167:1909–1919.

    PubMed  CAS  Google Scholar 

  51. Dengler TJ, Pober JS: Human vascular endothelial cells stimulate memory but not naive CD8+T cells to differentiate into CTL retaining an early activation phenotype. J Immunol 2000;164: 5146–5155.

    PubMed  CAS  Google Scholar 

  52. Geginat J, Sallusto F, Lanzavecchia A: Cytokine-driven proliferation and differentiation of human naive, central memory and effector memory CD4(+) T cells. J Exp Med 2001;194: 1711–1719.

    Article  PubMed  CAS  Google Scholar 

  53. Womer KL, Lee RS, Madsen JC, Sayegh MH: Tolerance and chronic rejection. Philos Trans R Soc Lond B Biol Sci 2001;356:727–738.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Transplantation Immunobiology, Department of Surgery, University of Alabama at Birmingham, 35494-0012, Birmingham, AL

    Anne Hutchings, William J. Hubbard, Frank T. Thomas & Judith M. Thomas

Authors
  1. Anne Hutchings
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. William J. Hubbard
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Frank T. Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Judith M. Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anne Hutchings.

Additional information

An erratum to this article is available at http://dx.doi.org/10.1007/s12026-007-8007-8.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hutchings, A., Hubbard, W.J., Thomas, F.T. et al. STEALTH in transplantation tolerance. Immunol Res 26, 143–152 (2002). https://doi.org/10.1385/IR:26:1-3:143

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1385/IR:26:1-3:143

Key Words

Search

Navigation