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Ballistic CTLA4 and IL-4 gene transfer into the lower lid prolongs orthotopic corneal graft survival in mice

  • Laboratory Investigation
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Abstract

Purpose

To explore outflow from the eye and to determine and modulate the influence of lymphatic drainage on corneal graft survival in mice.

Methods

Tracer experiments were conducted in BALB/c mice using the 99mTc colloidal albumin Nanocoll. Count rates were determined in the eyes, submandibular lymph nodes, spleen, liver and blood 24 h after subconjunctival, intracorneal, intracameral (anterior chamber), intravenous and subcutaneous lower-lid or upper-lid injections (n=6 each). Four groups of BALB/c mice (n=8) received corneal transplants from C3H mice; two of them were treated ballistically with vector CTLA4+IL-4 onto the leg or the lower lid, one group was untreated and the other control group was treated with an empty minimalistic, immunologically defined, gene expression (MIDGE) vector.

Results

Radioactivity was detected in the liver, spleen and ipsilateral submandibular lymph node after intracameral injection as follows: 91.9%, 6.6% and 1.2% respectively. Radioactivity uptake of the ipsilateral submandibular lymph node was also low after intravenous injection (0.1%) but high after intracorneal (33.8%), lower-lid (62.0%) and subconjunctival (71.2%) injection. Vector CTLA4+IL-4 treatment of the lower lid but not of the leg prolonged graft survival (P=0.004).

Conclusion

These tracer studies confirmed for the first time identical lymphatic drainage from the cornea and the lower lid. Logically, lymphatic drainage could be manipulated and graft survival improved by gene transfer to the lower lid.

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References

  1. Ayliffe W, McLeod D, Hutchinson IV (1992) The effect of blood transfusions on rat corneal graft survival. Invest Ophthalmol Vis Sci 33:1974–1978

    CAS  Google Scholar 

  2. Bell D, Young JW, Banchereau J (1999) Dendritic cells. Adv Immunol 72:255–324

    CAS  PubMed  Google Scholar 

  3. Bill A (1965) Movement of albumin and dextran through the sclera. Arch Ophthalmol 74:248–252

    CAS  Google Scholar 

  4. Chargui J, Hase T, Wada S, Naganuma T, Yoshimura R (2001) NKT cells as nonspecific immune-regulator inducing tolerance in mouse model transplantation. Transplant Proc 33:3833–3834

    Article  CAS  Google Scholar 

  5. Comer RM, King WJ, Ardjomand N, Theoharis S, George AJ, Larkin DF (2002) Effect of administration of CTLA4-Ig as protein or cDNA on corneal allograft survival. Invest Ophthalmol Vis Sci 43:1095–1103

    PubMed  Google Scholar 

  6. Greenfield EA, Nguyen KA, Kuchroo VK (1998) CD28/B7 costimulation: a review. Crit Rev Immunol 18:389–418

    CAS  PubMed  Google Scholar 

  7. Hoffmann F, Zhang EP, Pohl T, Kunzendorf U, Wachtlin J, Bulfone-Paus S (1997) Inhibition of corneal allograft reaction by CTLA4-Ig. Graefes Arch Clin Exp Ophthalmol 235:535–540

    CAS  PubMed  Google Scholar 

  8. Hoffmann F, Zhang EP, Mueller A, Schulte F, Foss HD, Franke J, Coupland SE (2001) Contribution of lymphatic drainage system in corneal allograft rejection in mice. Graefes Arch Clin Exp Ophthalmol 239:850–858

    CAS  PubMed  Google Scholar 

  9. Ishii N, Aoki I, Ishii T, Mizuki N, Okuda K, Nakajima H (1988) Suppressor T cells in mice made unresponsive to skin allografts. J Invest Dermatol 91:333–335

    CAS  Google Scholar 

  10. Kagaya F, Hori J, Kamiya K, Kaji Y, Oshika T, Amano S, Yamagami S, Tsuru T, Tanaka S, Matsuda H, Yagita H, Okumura K (2002) Inhibition of murine corneal allograft rejection by treatment with antibodies to CD80 and CD86. Exp Eye Res 74:131–139

    Article  CAS  PubMed  Google Scholar 

  11. Konig Merediz SA, Zhang EP, Wittig B, Hoffmann F (2000) Ballistic transfer of minimalistic immunologically defined expression constructs for IL4 and CTLA4 into the corneal epithelium in mice after orthotopic corneal allograft transplantation. Graefes Arch Clin Exp Ophthalmol 238:701–707

    Article  PubMed  Google Scholar 

  12. Kuffova L, Lumsden L, Vesela V, Taylor JA, Filipec M, Holan V, Dick AD, Forrester JV (2001) Kinetics of leukocyte and myeloid cell traffic in the murine corneal allograft response. Transplantation 72:1292–1298

    CAS  PubMed  Google Scholar 

  13. Lechler R, Ng WF, Steinman RM (2001) Dendritic cells in transplantation—friend or foe? Immunity 14:357–368

    CAS  PubMed  Google Scholar 

  14. Lenschow DJ, Zeng Y, Thistlethwaite JR, Montag A, Brady W, Gibson MG, Linsley PS, Bluestone JA (1992) Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4lg. Science 257:789–792

    CAS  PubMed  Google Scholar 

  15. Lin H, Bolling SF, Linsley PS, Wei RQ, Gordon D, Thompson CB, Turka LA (1993) Long-term acceptance of major histocompatibility complex mismatched cardiac allografts induced by CTLA4Ig plus donor-specific transfusion. J Exp Med 178:1801–1806

    CAS  PubMed  Google Scholar 

  16. Matsumura Y, Zuo XJ, Prehn J, Linsley PS, Marchevsky A, Kass RM, Matloff JM, Jordan SC (1995) Soluble CTLA4Ig modifies parameters of acute inflammation in rat lung allograft rejection without altering lymphocytic infiltration or transcription of key cytokines. Transplantation 59:551–558

    CAS  Google Scholar 

  17. Plskova J, Duncan L, Holan V, Filipec M, Kraal G, Forrester JV (2002) The immune response to corneal allograft requires a site-specific draining lymph node. Transplantation 73:210–215

    PubMed  Google Scholar 

  18. Polack FM, Gonzales CE (1968) The response of lymphoid tissue to corneal heterografts. Arch Ophthalmol 80:321–324

    Google Scholar 

  19. Sayegh MH, Akalin E, Hancock WW, Russell ME, Carpenter CB, Linsley PS, Turka LA (1995) CD28-B7 blockade after alloantigenic challenge in vivo inhibits Th1 cytokines but spares Th2. J Exp Med 181:1869–1874

    CAS  PubMed  Google Scholar 

  20. Sonoda Y, Streilein JW (1992) Orthotopic corneal transplantation in mice—evidence that the immunogenic rules of rejection do not apply. Transplantation 54:694–704

    CAS  PubMed  Google Scholar 

  21. Steinman RM, Nussenzweig MC (2002) Inaugural Article: Avoiding horror autotoxicus: the importance of dendritic cells in peripheral T cell tolerance. Proc Natl Acad Sci U S A 99:351–358.

    Article  CAS  PubMed  Google Scholar 

  22. Strand SE, Bergqvist L (1989) Radiolabeled colloids and macromolecules in the lymphatic system. Crit Rev Ther Drug Carrier Syst 6:211–238

    PubMed  Google Scholar 

  23. Streilein JW (1995) Immunological non-responsiveness and acquisition of tolerance in relation to immune privilege in the eye. Eye 9:236–240

    PubMed  Google Scholar 

  24. Wilbanks GA, Streilein JW (1989) The differing patterns of antigen release and local retention following anterior chamber and intravenous inoculation of soluble antigen. Evidence that the eye acts as an antigen depot. Reg Immunol 2:390–398

    CAS  PubMed  Google Scholar 

  25. Wilhelm AJ, Mijnhout GS, Franssen EJ (1999) Radiopharmaceuticals in sentinel lymph-node detection—an overview. Eur J Nucl Med 26:36–42

    Article  Google Scholar 

  26. Yamagami S, Dana MR, Tsuru T (2002) Draining lymph nodes play an essential role in alloimmunity generated in response to high-risk corneal transplantation. Cornea 21:405–409

    Article  PubMed  Google Scholar 

  27. Zhang E-P, Schründer S, Hoffmann F (1996) Orthotopic corneal transplantation in the mouse—a new technique with minimal endothelial cell loss. Graefes Arch Clin Exp Ophthalmol 234:714–719

    CAS  PubMed  Google Scholar 

  28. Zhang EP, Bulfone-Paus S, Hoffmann F (2002) [Immunomodulation after keratoplasty by CTL4-Ig and anti-CD154 antibodies]. Ophthalmologe 99:183–187

    CAS  PubMed  Google Scholar 

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Acknowledgement

Supported by DFG grant Ho 674/9-3.

Author information

Authors and Affiliations

  1. Department of Ophthalmology, University Hospital Benjamin Franklin, Free University of Berlin, Hindenburgdamm 30, 12203 , Berlin, Germany

    Er-Ping Zhang & Friedrich Hoffmann

  2. Department of Nuclear Medicine, University Hospital Benjamin Franklin, Free University of Berlin, Berlin, Germany

    Jürgen Franke

  3. Mologen, Berlin, Germany

    Matthias Schroff & Claas Junghans

  4. Institute for Molecular Biology and Bioinformatics, Free University of Berlin, Berlin, Germany

    Burghardt Wittig

Authors
  1. Er-Ping Zhang
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  2. Jürgen Franke
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  3. Matthias Schroff
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  4. Claas Junghans
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  5. Burghardt Wittig
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  6. Friedrich Hoffmann
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Corresponding author

Correspondence to Friedrich Hoffmann.

Additional information

Presented in part at the 101st meeting of the German Ophthalmologic Society (DOG), Berlin, Germany, September 2003

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Zhang, EP., Franke, J., Schroff, M. et al. Ballistic CTLA4 and IL-4 gene transfer into the lower lid prolongs orthotopic corneal graft survival in mice. Graefe's Arch Clin Exp Ophthalmol 241, 921–926 (2003). https://doi.org/10.1007/s00417-003-0763-0

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  • DOI: https://doi.org/10.1007/s00417-003-0763-0

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