Hivelin Mikael, Klimczak Aleksandra, Cwykiel Joanna, Sonmez Erhan, Nasir Serdar, Gatherwright James, Siemionow Maria
Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH, USA.
L. Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland.
Arch Immunol Ther Exp (Warsz). 2016 Aug;64(4):299-310. doi: 10.1007/s00005-015-0380-8. Epub 2015 Dec 26.
Many more patients would benefit from vascularized composite allotransplantation if less toxic and safer immunosuppressive protocols will become available. Tolerance induction protocols with donor cells co-transplantation are one of the promising pathways to reduce maintenance immunosupressive regimens. We investigated the role of donor bone marrow cells (BMC), mesenchymal stromal cells (MSC) and in vivo created chimeric cells (CC) used as supportive therapies in a fully MHC-mismatched rat face transplantation model. Twenty-four fully MHC-mismatched hemiface transplantations were performed between ACI (RT1(a)) donors and Lewis (RT1(l)) recipients under combined seven-day immunosuppressive regimen of anti-αβ-T-cell receptor (TCR) monoclonal antibody and cyclosporin A. We studied four experimental groups-group 1: no cellular therapy; group 2: supportive therapy with BMC; group 3: supportive therapy with MSC; group 4: supportive therapy with CC generated in a primary chimera. We evaluated clinical and histological rejection grades, transplanted cells migration, donor-specific chimerism in the peripheral blood and bone marrow compartments, and CD4(+)/CD25(+) T-cell levels. Face allograft rejection was observed at 26.8 ± 0.6 days post-transplant (PT) in the absence of cellular therapy, at 34.5 ± 1.1 days for group 2, 29.3 ± 0.8 days for group 3, and 30.3 ± 1.38 PT for group 4. The longest survival was observed in allografts supported by co-transplantation of BMC. All support in cellular therapies delayed face allograft rejection by chimerism induction and/or immunomodulatory properties of co-transplanted cells. Survival time was comparable between groups, however, further studies, with different cell dosages, delivery routes and delivery times are required.
如果能有毒性更低、更安全的免疫抑制方案,将会有更多患者从血管化复合组织移植中获益。与供体细胞共移植的耐受诱导方案是减少维持性免疫抑制方案的有前景的途径之一。我们在完全主要组织相容性复合体(MHC)不匹配的大鼠面部移植模型中,研究了供体骨髓细胞(BMC)、间充质基质细胞(MSC)和体内生成的嵌合细胞(CC)作为支持性治疗的作用。在抗αβ - T细胞受体(TCR)单克隆抗体和环孢素A联合的7天免疫抑制方案下,对ACI(RT1(a))供体和Lewis(RT1(l))受体进行了24次完全MHC不匹配的半脸移植。我们研究了四个实验组:第1组:无细胞治疗;第2组:用BMC进行支持性治疗;第3组:用MSC进行支持性治疗;第4组:用在初级嵌合体中生成的CC进行支持性治疗。我们评估了临床和组织学排斥等级、移植细胞迁移、外周血和骨髓区室中的供体特异性嵌合现象以及CD4(+)/CD25(+) T细胞水平。在无细胞治疗的情况下,移植后(PT)26.8±0.6天观察到面部同种异体移植排斥,第2组为34.5±1.1天,第3组为29.3±0.8天,第4组为30.3±1.38 PT。在BMC共移植支持的同种异体移植中观察到最长存活时间。所有细胞治疗支持均通过嵌合诱导和/或共移植细胞免疫调节特性延迟了面部同种异体移植排斥。各实验组存活时间相近,然而,需要进一步研究不同的细胞剂量、给药途径和给药时间。