Mathes David W, Chang Jeff, Hwang Billanna, Graves Scott S, Storer Barry E, Butts-Miwongtum Tiffany, Sale George E, Storb Rainer
1 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA. 2 Department of Surgery, University of Washington, Seattle, WA. 3 Plastic Surgery Service, VA Puget Sound Health Care System, Seattle, WA. 4 Department of Medicine, University of Washington, Seattle, WA. 5 School of Public Health, University of Washington, Seattle, WA. 6 Department of Pathology, University of Washington, Seattle, WA. 7 Address correspondence to: David W. Mathes, M.D., Clinical Research Division, Fred Hutchinson Cancer Research Center, PO Box 19024; D1-100 1100 Fairview Ave, N, Seattle, WA 98109.
Transplantation. 2014 Jul 27;98(2):131-8. doi: 10.1097/TP.0000000000000204.
We have previously demonstrated that tolerance to a vascularized composite allograft (VCA) can be achieved after the establishment of mixed chimerism. We test the hypothesis that tolerance to a VCA in our dog leukocyte antigen-matched canine model is not dependent on the previous establishment of mixed chimerism and can be induced coincident with hematopoietic cell transplantation (HCT).
Eight dog leukocyte antigen-matched, minor antigen mismatched dogs received 200 cGy of radiation and a VCA transplant. Four dogs received donor bone marrow at the time of VCA transplantation (group 1), whereas a second group of four dogs did not (group 2). All recipients received a limited course of postgrafting immunosuppression. All dogs that received HCT and VCA were given donor, third-party, and autologous skin grafts.
All group 1 recipients were tolerant to their VCA (>62 weeks). Three of the four dogs in group 2 rejected their VCA transplants after the cessation of immunosuppression. Biopsies obtained from the muscle and skin of VCA from group 1 showed few infiltrating cells compared with extensive infiltrates in biopsies of VCA from group 2. Compared with autologous skin and muscle, elevated levels of CD3+ FoxP3+ T-regulatory cells were found in the skin and muscle obtained from the VCA of HCT recipients. All group 1 animals were tolerant to their donor skin graft and promptly rejected the third-party skin grafts.
These data demonstrated that donor-specific tolerance to all components of the VCA can be established through simultaneous nonmyeloablative allogeneic HCT and VCA transplantation protocol.
我们之前已经证明，在建立混合嵌合体后可实现对血管化复合异体移植（VCA）的耐受。我们检验了这样一个假设，即在我们的犬白细胞抗原匹配的犬类模型中，对VCA的耐受并不依赖于先前建立的混合嵌合体，并且可以在造血细胞移植（HCT）的同时被诱导产生。
八只犬白细胞抗原匹配、次要抗原不匹配的犬接受了200 cGy的辐射及VCA移植。四只犬在VCA移植时接受了供体骨髓（第1组），而另一组四只犬未接受（第2组）。所有受者均接受了有限疗程的移植后免疫抑制。所有接受HCT和VCA的犬均接受了供体、第三方和自体皮肤移植。
所有第1组受者均对其VCA耐受（>62周）。第2组的四只犬中有三只在免疫抑制停止后排斥了它们的VCA移植。与第2组VCA活检中大量浸润细胞相比，第1组VCA肌肉和皮肤活检显示浸润细胞较少。与自体皮肤和肌肉相比，在HCT受者VCA获取的皮肤和肌肉中发现CD3+ FoxP3+调节性T细胞水平升高。所有第1组动物均对其供体皮肤移植耐受，并迅速排斥第三方皮肤移植。
这些数据表明，通过同时进行非清髓性同种异体HCT和VCA移植方案，可以建立对VCA所有成分的供体特异性耐受。
