Skip to main content
SpringerLink
Log in

Paradoxical early upregulation of intragraft Th1 cytokines is associated with graft acceptance following donor-specific blood transfusion

  • Original Article
  • Published:
Transplant International

Abstract

Donor-specific blood transfusion (DSBT) promotes graft acceptance in certain experimental and clinical situations. However, the exact nature of the operating mechanisms, and in particular the role of Th1/Th2 cytokines, remains controversial. We recently described a fully mismatched rat combination [RA rat (RT1p) to PVG rat (RT1c)] in which a single pre-transplant (Tx) DSBT induces donor-specific tolerance following heart transplantation (Htx). In order to delineate better the role of Th1 and Th2 cytokines in the development of tolerance versus rejection, we studied the intragraft mRNA for Th1 and Th2 cytokines at different time points post-Tx in rejecting and DSBT-tolerized heart grafts. We performed reverse transcriptase–polymerase chain reaction (RT–PCR) to examine intragraft Th1/Th2 cytokines profile. In contrast to findings from previous data, we detected an early (post-Tx day 2) Th1 cytokine upregulation. Th1 downregulation/Th2 immune deviation was observed only at a later period (post-Tx day 30). Consistent with this Th1 early upregulation, a dense mononuclear cellular infiltrate was seen in tolerized grafts, which was equivalent to that seen in rejecting grafts. Despite in vivo unresponsiveness, peripheral lymphocyte derived from tolerant animals proliferated against donor-matched antigens to the same degree as against those of a third party until post-Tx day 30. Altogether, these observations (dense graft cellular infiltrate, early post-Tx Th1 cytokine production, early preserved cellular proliferative responses), suggest that the development of tolerance is preceded by an active Th1 cytokine-mediated immune response. The mechanisms by which an early Th1 response promotes tolerance need to be further studied.

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

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.
Fig. 5.

Similar content being viewed by others

References

  1. Babcock GF, Alexander W (1996) The effect of blood transfusion on cytokine production by Th1 and Th2 lymphocytes in the mouse. Transplantation 61:465–468

    CAS  PubMed  Google Scholar 

  2. Bishop GA, McCaughan GW (2001) Immune activation is required for the induction of liver allograft tolerance: implications for immunosuppressive therapy. Liver Transpl 7:161–172

    CAS  PubMed  Google Scholar 

  3. Fabre JW, Morris PJ (1972) The mechanism of specific immunosuppression of renal allograft rejection by donor strain blood. Transplantation 14:634–640

    CAS  PubMed  Google Scholar 

  4. Ganschow R, Broering DC, Nolkemper D, Albani J, Kemper MJ, Rogiers X, Burdelski M (2001) Th2 cytokine profile in infants predisposes to improved graft acceptance after liver transplantation. Transplantation 72:929–934

    CAS  PubMed  Google Scholar 

  5. Hara M, Kingsley CI, Niimi M, Read S, Turvey SE, Bushell AR, Morris PJ, Powrie F, Wood KJ (2001) IL-10 is required for regulatory T cells to mediate tolerance to alloantigens in-vivo. J Immunol 166:3789–3796

    CAS  PubMed  Google Scholar 

  6. Josien R, Pannetier C, Douillard P, Cantarovich D, Menoret S, Bugeon L, Kourilsky P, Soulillou JP, Cuturi MC (1995) Graft-infiltrating T helper cells, CD45RC phenotype, and Th1/Th2-related cytokines in donor-specific transfusion-induced tolerance in adult rats. Transplantation 60:1131–1139

    CAS  PubMed  Google Scholar 

  7. Keown PA, Descamps B (1979) Improved renal allograft survival after blood transfusion: a nonspecific, erythrocyte-mediated immunoregulatory process. Lancet 1:20–22

    CAS  PubMed  Google Scholar 

  8. Koshiba T, Ji P, Waer M, Pirenne J (2001) The technical aspects of combined intestinal and heart transplantation in rats. Transplant Proc 33:532–534

    Article  CAS  PubMed  Google Scholar 

  9. Koshiba T, Van Damme B, Ji P, Lu Y, Sefrioui H, Overbergh L, Tanaka K, Mathieu C, Waer M, Pirenne J (2001) Addition of steroids blocks the tolerogenic potential of donor-specific blood transfusion (DSBT). Transplant Proc 33:375–376

    Article  CAS  PubMed  Google Scholar 

  10. Levy AE, Alexander JW (1996) The significance of timing of additional short-term immunosuppression in the donor-specific transfusion/cyclosporine-treated rat. Transplantation 62:262–266

    CAS  PubMed  Google Scholar 

  11. Ono K, Lindsey ES (1969) Improved technique of heart transplantation in rats. J Thorac Cardiovasc Surg 57:225–229

    CAS  PubMed  Google Scholar 

  12. Onodera K, Hancock WW, Graser E (1997) Type 2 helper T cell-type cytokines and the development of infectious tolerance in rat cardiac allograft recipients. J Immunol 158:1572–1581

    CAS  PubMed  Google Scholar 

  13. Overbergh L, Valckx D, Waer M, Mathieu C (1999) Quantification of murine cytokine mRNAs using real time quantitative reverse transcriptase PCR. Cytokine 11:305–312

    Article  CAS  PubMed  Google Scholar 

  14. Quigley RL, Wood KJ, Morris PJ (1988) Investigation of the mechanism of acute enhancement of renal allograft survival by blood transfusion. Immunology 63:373–381

    CAS  PubMed  Google Scholar 

  15. Salvatierra O, Vincenti F, Amend W, Potter D, Iwaki Y, Opelz G, Terasaki P, Duca R, Cochrum K, Hanes D, Stoney RJ, Feduska NJ (1980) Deliberate donor-specific blood transfusion prior to living related renal transplantation. A new approach. Ann Surg 192:543–552

    PubMed  Google Scholar 

  16. Sharland A, Shastry S, Wang C, Rokahr K, Sun J, Sheil AGR (1998) Kinetics of intragraft cytokine expression, cellular infiltration and cell death in rejection of renal allografts compared with acceptance of liver allografts in a rat model. Early activation and apoptosis is associated with liver graft acceptance. Transplantation 65:1370–1377

    CAS  PubMed  Google Scholar 

  17. Singal DP, Joseph S (1982) Role of blood transfusions on the induction of antibodies against recognition sites of T lymphocytes in renal transplant patients. Hum Immunol 4:93–108

    Article  CAS  PubMed  Google Scholar 

  18. Smith MD, Hardy G, William JD, Coles GA (1983) Suppressor cell numbers and activity in non-transfused renal dialysis patients. Clin Nephrol 20:130–135

    CAS  PubMed  Google Scholar 

  19. Yan Y, Shastry S, Richards C, Wang C, Bowen DG, Sharland AF, Painter DM, McCaughan GW, Bishop GA (2001) Posttransplant administration of donor leukocytes induces long-term acceptance of kidney or liver transplants by an activation-associated immune mechanism. J Immunol 166:5258–5264

    CAS  PubMed  Google Scholar 

  20. Zhai Y, Ghobrail RM, Busuttil RW, Kupiec-Weglinski JW (1999) Th1 and Th2 cytokines in organ transplantation: paradigm lost? Crit Rev Immunol 19:155–172

    CAS  PubMed  Google Scholar 

  21. Zhai Y, Kupiec-Weglinski JW (1999) What is the role of regulatory T cells in transplantation tolerance? Curr Opin Immunol 11:497–500

    CAS  PubMed  Google Scholar 

  22. Zhai Y, Li J, Hammer M, Busuttil RW, Volk HD, Kupiec-Weglinski JW (2001) Evidence of T cell clonality in the infectious tolerance pathway: implications toward identification of regulatory T cells. Transplantation 71:1701–1708

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Abdominal Transplant Department, University Hospital of Leuven, Herestraat 49, 3000, Leuven, Belgium

    Takaaki Koshiba, Hiroaki Kitade & Jacques Pirenne

  2. Laboratory for Experimental Transplantation, University Hospital of Leuven, Leuven, Belgium

    Takaaki Koshiba, Annapaula Giulietti, Lut Overbergh, Omer Rutgeerts, Hiroaki Kitade, Mark Waer, Chantal Mathieu & Jacques Pirenne

  3. Pathology Department, University Hospital of Leuven, Leuven, Belgium

    Boudewijn Van Damme

Authors
  1. Takaaki Koshiba
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Annapaula Giulietti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Boudewijn Van Damme
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lut Overbergh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Omer Rutgeerts
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hiroaki Kitade
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mark Waer
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chantal Mathieu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jacques Pirenne
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jacques Pirenne.

Additional information

Part of this work was presented at the 10th Congress of the European Society for Organ Transplantation, 6–8 October 2001, Lisbon, Portugal

About this article

Cite this article

Koshiba, T., Giulietti, A., Van Damme, B. et al. Paradoxical early upregulation of intragraft Th1 cytokines is associated with graft acceptance following donor-specific blood transfusion. Transpl Int 16, 179–185 (2003). https://doi.org/10.1007/s00147-002-0515-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00147-002-0515-9

Keywords

Search

Navigation