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Tolerance Induction in Composite Facial Allograft Transplantation in the Rat Model


Demir, Yavuz M.D.; Ozmen, Selahattin M.D.; Klimczak, Aleksandra M.D.; Siemionow, Maria M.D., Ph.D.

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Plastic and Reconstructive Surgery: March 2006 - Volume 117 - Issue 3 - p 1044-1045
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It was a pleasure to read Dr. Hettiaratchy and Dr. Butler's correspondence regarding our article, “Tolerance Induction in Composite Facial Allograft Transplantation in the Rat Model” (Plast. Reconstr. Surg. 114: 1790, 2004). In their letter, they discuss our results in the context of tolerance induction in our hemiface transplantation model. Over the years, the definition of tolerance has changed with the introduction of different therapeutic strategies.1–3Complete tolerance is defined as the state of indefinite allograft survival with stable function, without the requirement of immunosuppressive maintenance therapy.1–3 However, Monaco1 suggested that the tolerance induction protocol must take into consideration the relationship of time in any definition of operational tolerance. Therefore, “strategies directed at achieving a minimal immunosuppressive regimen (rather than complete immunosuppression withdrawal) might be more appropriate when the concept of time and tolerance are considered.”1 Calne2 introduced a new concept of “prope” (almost) tolerance, which is defined as donor-specific hyporesponsiveness under a lower dosage of cyclosporine A immunosuppressive therapy that will reduce immunosuppression-related side effects but will allow improved allograft survival without acute or chronic rejection episodes.2 This partial tolerance state with a minimal baseline nontoxic dose of maintenance therapy is suggested to be clinically more appropriate. Sachs introduced an updated definition, stating that “tolerance is not merely the absence of a response, but may involve an active down-regulatory response and may be induced through a variety of mechanisms.”3

In our study, down-regulatory response and functional immune deficit were attributed to the low maintenance dose of the cyclosporine A monotherapy allowing for indefinite survival of hemifacial skin allografts. Mixed lymphocyte reaction assays confirmed that hemiface transplant recipients were functionally tolerant to the recipient and donor antigens and were competent to respond to the third-party alloantigens. Colson et al.,4 in their rat experimental model, defined lymphocytes from mixed allogenic chimeras as functionally tolerant to the host when a stimulation index of 2.6 was present. In our study, a mixed lymphocyte reaction assay with a stimulation index of 2.7 confirmed down-regulation of the immunological responses. In addition, lower response to the third-party antigens, when compared with naïve controls, confirmed that the low dose of cyclosporine A therapy was sufficient not only to down-regulate immunological response but also to maintain immunological competence of hemiface transplant recipients.

Functional tolerance was achieved in different experimental models and was defined as successful organ acceptance and long-term survival.5 In our model, we achieved functional tolerance, as evidenced by graft acceptance up to 240 days after transplantation and the absence of an aggressive response in the mixed lymphocyte reaction assay. In our discussion section, we emphasized that functional tolerance was achieved in the hemiface transplant recipients under a low maintenance dose of cyclosporine A monotherapy. We have not claimed to achieve complete tolerance, neither in the abstract nor in the discussion.

Our protocol may be clinically applicable because of development of the prope (almost) tolerant state in facial allograft recipients under cyclosporine A monotherapy.

Yavuz Demir, M.D.

Selahattin Ozmen, M.D.

Aleksandra Klimczak, M.D.

Faculty of Medicine, Afyon Kocatepe University

Maria Siemionow, M.D., Ph.D.

The Cleveland Clinic Foundation


1.Monaco, A. P. Prospects and strategies for clinical tolerance. Transplant. Proc. 36: 227, 2004.
2.Calne, R. Y. Prope tolerance: The future of organ transplantation from the laboratory to the clinic. Int. Immunopharmacol. 5: 163, 2005.
3.Sachs, D. H. Mixed chimerism as an approach to transplantation tolerance. Clin. Immunol. 95: S63, 2000.
4.Colson, Y. L., Zadach, K., Nalesnik, M., and Ildstad, S. Mixed allogenic chimerism in the rat. Transplantation 60: 971, 1995.
5.Goggins, W. C., Fisher, R. A., Dattilo, J. B., et al. Analysis of functional renal allograft tolerance with single-dose rapamycin based induction immunosuppression. Transplantation 63: 310, 1997.

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