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T-Regulatory Cells May Mediate Tolerance Towards Both Vascularized and Non-Vascularized Skin Allograft Transplants
Jeff Chang, MD1, Tiffany Butts, BS2, Scott Graves, PhD2, Rainer F. Storb, MD2, David W. Mathes, MD1.
1University of Washington Seattle, SEATTLE, WA, USA, 2Fred Hutchinson Cancer Research Center, SEATTLE, WA, USA.

Purpose: The transplantation of a vascularized composite tissue allograft (VCA) such as hand or face is now a clinical reality. A significant problem facing VCA recipients is rejection of the VCA despite immunosuppression. It is believed that the skin component of the VCA triggers rejection due to its high antigencity.
Previous large animal studies in attempts to understand tolerance mechanisms towards VCA and non-vascularized skin allografts (NVSA) induce tolerance towards the VCA but fail to do so with a NVSA. This may suggest different tolerance mechanisms between a vascularized and a non-vascularized graft.
We have established a mixed chimera protocol to induce tolerance towards VCA in a matched large animal model. This experiment was to assess the mechanisms of tolerance towards VCA and NVSA transplants. Specifically we are investigating the role of donor cell chimerism and T-regulatory cells after tolerance induction.
Methods: Five dog transplants were performed across a matched DLA, minor mismatched barrier. All dogs received 200 cGy of radiation and donor bone marrow to induce tolerance. They then underwent a VCA transplant (Myocutaneous rectus flap). They were followed for donor cell chimerism in their peripheral blood. Allografts underwent routine biopsies and were followed clinically. After a year of stable VCA tolerance, full thickness donor skin grafts were placed on the recipients. Autologous skin grafts were performed as a control. Donor-specific tolerance was assessed using 3rd party skin grafts. T-regulatory cells were assayed by staining VCA and NVSA for FoxP3.
Results: All five dogs demonstrated tolerance towards both the VCA and NVSA.
Summary of transplanted VCA, NVSA, and donor cell chimerism
AnimalLong-Term Tolerance Towards VCA > 1 year?Chimerism Before Donor Skin Graft Placement (G/L%)Tolerance Towards Donor Skin Grafts >100 days?Tolerance Towards 3rd Party Skin Grafts?
G949Yes44/51%YesNo
H081Yes0/0%YesNo
H103Yes5/6%YesNo
H110Yes86/49%YesNo
H191Yes36/36%YesNo
Presentation of skin antigens may not be necessary to establish tolerance because G949 did not receive a VCA transplant during induction of mixed chimerism. For maintenance of these transplants, there may not be a requirement for donor cell chimerism, as one dog H081 demonstrated no chimerism yet did not reject its VCA or NVSA.
The overall percentage of T-regulatory cells was significantly higher in VCA and NVSA as compared to normal and rejecting tissues.
Because of these observations, maintenance of tolerance towards VCA and NVSA may not be centrally mediated. Peripheral mechanisms with local regulation by T-regulatory cells appear to allow for tolerance.
Conclusion: This study demonstrates that maintenance of tolerance towards a vascularized and non-vascularized graft is dependent on a peripheral mechanism rather than a central mechanism. T-regulatory cells infiltrate the transplanted graft and exert its local anti-inflammatory effects, thereby providing tolerance within the graft.


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