Skip to main content
SpringerLink
Log in

Donor-specific renal, but not cardiac, allograft tolerance promotes engraftment of the normally rejected rat skin graft

  • Original Article
  • Published:
Transplant International

Abstract

This study examined whether a heart or kidney graft could provide protection for the more resistant skin graft. Buffalo rat recipients were given a single dose of RIB 5/2 (non-depleting anti-CD4 mAb) plus i.v. Lewis splenocytes 21 days before being given Lewis heart or kidney grafts. Lewis skin was grafted either simultaneously with, or after, long-term (>50 days) Lewis heart or kidney allograft acceptance. Immune responsiveness was analyzed by in vitro mixed lymphocyte culture (MLC), cytotoxic T lymphocytes (CTLs), and limiting dilution analysis (LDA). While i.v. alloantigen plus RIB 5/2 resulted in long-term acceptance of heart and kidney, survival of skin grafts alone was not prolonged. However, simultaneous transplantation with kidney, but not heart, resulted in long-term skin graft acceptance, while skin grafts subsequently grafted to recipients tolerant to kidney or heart were not accepted. In vitro analysis revealed a down-regulation of proliferation, cytotoxicity, and precursor T-helper cells (pThs)/precursor cytotoxic T lymphocytes (pCTLs) in Buffalo recipients accepting Lewis kidney and skin allografts. While RIB 5/2 plus Lewis splenocytes do not prolong the survival of skin grafts, Lewis skin grafted simultaneously with a kidney, but not heart, is accepted indefinitely and provides donor-specific protection for a subsequent skin graft.

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. Arima T, Lehmann M, Flye MW (1997) Induction of donor-specific transplantation tolerance to cardiac allografts following treatment with non-depleting (RIB 5/2) or depleting (OX-38) anti-CD4 mAb plus intrathymic or intravenous donor alloantigen. Transplantation 63:284–288

    Google Scholar 

  2. Billingham R, Medawar P (1952) The technique of free skin grafting in mammals. Br J Exp Biol 28:385–402

    Google Scholar 

  3. Calhoun R, Mohanakumar T, Flye MW (1996) Tissue- and organ-specific immune responses: role in human disease and allograft immunity. Transplant Rev 10:34–39

    Google Scholar 

  4. Davis HS, Kamada N, Roser BJ (1983) Mechanisms of donor-specific unresponsiveness induced by liver grafting. Transplant Proc 15:831–832

    Google Scholar 

  5. Fabre J, Lim SH, Morris PJ (1971) Renal transplantation in the rat: details of a technique. Aust N Z J Surg 41:69–75

    CAS  PubMed  Google Scholar 

  6. Flye MW, Pennington L, Kirkman R, Weber B, Sindelar W, Sachs DH (1999) Spontaneous acceptance or rejection of orthotopic liver transplants in outbred and partially inbred miniature swine. Transplantation 68:599–607

    Google Scholar 

  7. Herbert J, Roser B (1988) Strategies of monoclonal antibody therapy that induce permanent tolerance of organ transplants. Transplantation 46 [2 Suppl]:128S–134S

  8. Horneff G, Emmrich F, Reiter C, Kalden JR, Burmester GR (1992) Persistent depletion of CD4+ T cells and inversion of the CD4/CD8 T cell ratio induced by anti-CD4 therapy. J Rheumatol 19:1845–1850

    CAS  PubMed  Google Scholar 

  9. Johnson LL, Bailey DW, Mobraaten LE (1981) Genetics of histocompatibility in mice. IV. Detection of certain minor (non-H-2) H antigens in selected organs by the popliteal lymph node test. Immunogenetics 14:63–71

    CAS  PubMed  Google Scholar 

  10. Lafferty KJ, Prowse SJ, Simeonovic CJ, Warren HS (1983) Immunobiology of tissue transplantation: a return to the passenger leukocyte concept. Annu Rev Immunol 1:143–173

    CAS  PubMed  Google Scholar 

  11. Lautenschlager I, Nyman N, Vaananen H, Lehto VP, Virtanen L, Häyry P (1983) Antigenic and immunogenic components in rat liver. Scand J Immunol 17:61–68

    CAS  PubMed  Google Scholar 

  12. Lehmann M, Sternkopf F, Metz F, Brock J, Docke WD, Plantikow A, Kuttler B, Hahn HJ, Ringel B, Volk HD (1992) Induction of long-term survival of rat skin allografts by a novel, highly efficient anti-CD4 monoclonal antibody. Transplantation 54:959–962

    Google Scholar 

  13. Madsen JC, Peugh WN, Wood KJ, Morris PJ (1987) The effect of anti-L3T4 monoclonal antibody treatment on first-set rejection of murine cardiac allografts. Transplantation 44:849–852

    Google Scholar 

  14. Manca F, Barocci S, Kunkl A, Gurreri G, Costantini M, Celada F (1983) Recognition of donor fibroblast antigens by lymphocytes homing in the human grafted kidney. Transplantation 36:670–674

    Google Scholar 

  15. Moreland LW, Pratt PW, Bucy RP, Jackson BS, Feldman JW, Koopman WJ (1994) Treatment of refractory rheumatoid arthritis with a chimeric anti-CD4 monoclonal antibody. Long-term follow-up of CD4+ T cell counts. Arthritis Rheum 37:834–838

    CAS  PubMed  Google Scholar 

  16. Motoyama K, Arima T, Lehmann M, Flye MW (1997) Tolerance to heart and kidney grafts induced by non-depleting anti-CD4 monoclonal antibody (RIB 5/2) versus depleting anti-CD4 monoclonal antibody (OX-38) with donor antigen administration. Surgery 122:213–219

    CAS  PubMed  Google Scholar 

  17. Motoyama K, Lehmann M, Flye MW (1999) Analysis of donor-specific unresponsiveness to rat allografts by non-depleting anti-CD4 monoclonal antibody (RIB 5/2) plus donor antigen. Transplant Proc 31:1237–1238

    Google Scholar 

  18. Motoyama K, Arima T, Yu S, Lehmann M, Flye MW (2000) The kinetics of tolerance induction by non-depleting anti-CD4 monoclonal antibody (RIB 5/2) plus intravenous donor alloantigen administration. Transplantation 69:285–293

    Google Scholar 

  19. Naji A, Barker CF, Silvers WK (1979) Relative vulnerability of isolated pancreatic islets, parathyroid, and skin allografts to cellular and humoral immunity. Transplant Proc 11:560–562

    Google Scholar 

  20. Nakafusa Y, Goss JA, Mohanakumar T, Flye MW (1993) Induction of donor-specific tolerance to cardiac but not skin or renal allografts by intrathymic injection of splenocyte alloantigen. Transplantation 55:877–882

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  22. Poindexter NJ, Naziruddin B, McCourt DW, Mohanakumar T (1995) Isolation of a kidney-specific peptide recognized by alloreactive HLA-A3-restricted human CTL. J Immunol 154:3880–3887

    CAS  PubMed  Google Scholar 

  23. Poindexter NJ, Steward NS, Shenoy S, Jendrisak MD, Flye MW, Howard TK, Mohanakumar T (1995) Cytolytic T lymphocytes from human renal allograft biopsies are tissue-specific. Hum Immunol 44:43–49

    Article  CAS  PubMed  Google Scholar 

  24. Reinherz EL, Schlossman, SF (1980) The differentiation and function of human T lymphocytes. Cell 19:821–827

    CAS  PubMed  Google Scholar 

  25. Savas CP, Nolan MS, Lindsey NJ, Boyle PF, Slater DN, Fox M (1985) Renal transplantation in the rat—a new simple, non-suture technique. Urol Res 13:91–93

    CAS  PubMed  Google Scholar 

  26. Shizuru JA, Gregory AK, Chao CT, Fathman CG (1987) Islet allograft survival after a single course of treatment of recipient with antibody to L3T4. Science 237:278–280

    CAS  PubMed  Google Scholar 

  27. Shizuru JA, Seydel KB, Flavin TF, Wu AP, Kong CC, Hoyt EG, Fujimoto N, Billingham ME, Starnes VA, Fathman CG (1990) Induction of donor-specific unresponsiveness to cardiac allografts in rats by pretransplant anti-CD4 monoclonal antibody therapy. Transplantation 50:366–373

    Google Scholar 

  28. Shizuru JA, Alters SE, Fathman CG (1992) Anti-CD4 monoclonal antibodies in therapy: creation of non-classical tolerance in adults. Immunol Rev 129:105–130

    CAS  PubMed  Google Scholar 

  29. Siegling A, Lehmann M, Riedel H, Platzer C, Brock J, Emmrich F, Volk HD (1994) A non-depleting anti-rat CD4 monoclonal antibody that suppresses T helper 1-like but not T helper 2-like intragraft lymphokine secretion induces long-term survival of renal allografts. Transplantation 57:464–467

    Google Scholar 

  30. Steinmuller D (1998) The enigma of skin allograft rejection. Transplant Rev 12:42–57

    Google Scholar 

  31. Steinmuller D, Wachtel SS (1980) Transplantation biology and immunogenetics of murine skin-specific (Sk) alloantigens (review). Transplant Proc 12:100–106

    Google Scholar 

  32. Steinmuller D, Wakely E, Landas SK (1991) Evidence that epidermal alloantigen Epa-I is an immunogen for murine heart as well as skin allograft rejection. Transplantation 51:459–463

    Google Scholar 

  33. Sun J, Sheil AG, Wang C, Wang L, Rokahr K, Sharland A, Jung SE, Li L, McCaughan GW, Bishop GA (1996) Tolerance to rat liver allografts. IV. Acceptance depends on the quantity of donor tissue and on donor leukocytes. Transplantation 62:1725–1730

    Google Scholar 

  34. Swain SL (1983) T cell subsets and the recognition of MHC class. Immunol Rev 74:129–142

    CAS  PubMed  Google Scholar 

  35. Tak PP, van der Lubbe PA, Cauli A, Daha MR, Smeets TJ, Kluin PM, Meinders AE, Yanni G, Panayi GS, Breedveld FC (1995) Reduction of synovial inflammation after anti-CD4 monoclonal antibody treatment in early rheumatoid arthritis. Arthritis Rheum 38:1457–1465

    CAS  PubMed  Google Scholar 

  36. Takeuchi E, Ishikura H, Ishizu A, Harada H, Kato H, Yasuda K, Yoshiki T (1997) Induced expression of Thy-1 molecules on dermal endothelial cells in skin allografts. Pathol Res Pract 193:623–627

    CAS  PubMed  Google Scholar 

  37. Teh HS, Garvin AM, Forbush KA (1991) Participation of CD4 coreceptor molecules in T cell repertoire selection. Nature 349:241–243

    CAS  PubMed  Google Scholar 

  38. van der Lubbe PA, Reiter C, Breedveld FC, Kruger K, Schattenkirchner M, Sanders ME, Riethmuller G (1993) Chimeric CD4 monoclonal antibody cM-T412 as a therapeutic approach to rheumatoid arthritis. Arthritis Rheum 36:1375–1379

    PubMed  Google Scholar 

  39. Wustrack KO, Gruber RP, Lucas ZJ (1975) Immunologic enhancement of skin allografts in the rat: role of vascular and lymphatic reconstitution. Transplantation 19:156–165

    CAS  PubMed  Google Scholar 

  40. Zuniga-Pflucker JC, McCarthy SA, Weston M, Longo DL, Singer A, Kruisbeek AM (1989) Role of CD4 in thymocyte selection and maturation. J Exp Med 169:2085–2096

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Surgery, Washington University School of Medicine, Suite 5103, One Barnes-Jewish Hospital Plaza, St. Louis, MO 63110, USA

    Julie A. Margenthaler, Samuel Yu, Naoki Otomo & M. Wayne Flye

  2. Institute of Medical Biochemistry, University of Rostock, Rostock, Germany

    Manfred Lehmann

Authors
  1. Julie A. Margenthaler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Samuel Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Naoki Otomo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Manfred Lehmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. Wayne Flye
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Wayne Flye.

About this article

Cite this article

Margenthaler, J.A., Yu, S., Otomo, N. et al. Donor-specific renal, but not cardiac, allograft tolerance promotes engraftment of the normally rejected rat skin graft. Transpl Int 16, 713–720 (2003). https://doi.org/10.1007/s00147-003-0599-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00147-003-0599-x

Keywords

Search

Navigation