Department of Surgery, Experimental Surgery, Charité - Universitätsmedizin Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.
Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany.
Front Immunol. 2024 May 10;15:1395945. doi: 10.3389/fimmu.2024.1395945. eCollection 2024.
Acute cellular rejection remains a significant obstacle affecting successful outcomes of organ transplantation including vascularized composite tissue allografts (VCA). Donor antigen presenting cells (APCs), particularly dendritic cells (DCs), orchestrate early alloimmune responses by activating recipient effector T cells. Employing a targeted approach, we investigated the impact of donor-derived conventional DCs (cDCs) and APCs on the immunogenicity of skin and skin-containing VCA grafts, using mouse models of skin and hind limb transplantation. By post-transplantation day 6, skin grafts demonstrated severe rejections, characterized by predominance of recipient CD4 T cells. In contrast, hind limb grafts showed moderate rejection, primarily infiltrated by CD8 T cells. Notably, the skin component exhibited heightened immunogenicity when compared to the entire VCA, evidenced by increased frequencies of pan (CD11bCD11c), mature (CD11bCD11cMHCII) and active (CD11bCD11cCD40) DCs and cDC2 subset (CD11bCD11c MHCII) in the lymphoid tissues and the blood of skin transplant recipients. While donor depletion of cDC and APC reduced frequencies, maturation and activation of DCs in all analyzed tissues of skin transplant recipients, reduction in DC activities was only observed in the spleen of hind limb recipients. Donor cDC and APC depletion did not impact all lymphocyte compartments but significantly affected CD8 T cells and activated CD4 T in lymph nodes of skin recipients. Moreover, both donor APC and cDC depletion attenuated the Th17 immune response, evident by significantly reduced Th17 (CD4IL-17) cells in the spleen of skin recipients and reduced levels of IL-17E and lymphotoxin-α in the serum samples of both skin and hind limb recipients. In conclusion, our findings underscore the highly immunogenic nature of skin component in VCA. The depletion of donor APCs and cDCs mitigates the immunogenicity of skin grafts while exerting minimal impact on VCA.
急性细胞排斥仍然是影响器官移植（包括血管化复合组织同种异体移植物[VCA]）成功的重要障碍。供体抗原提呈细胞（APCs），特别是树突状细胞（DCs），通过激活受者效应 T 细胞来协调早期同种免疫反应。我们采用靶向方法，通过小鼠皮肤和下肢移植模型，研究了供体来源的常规 DC（cDC）和 APC 对皮肤和含皮肤的 VCA 移植物免疫原性的影响。在移植后第 6 天，皮肤移植物表现出严重的排斥反应，特征是受者 CD4 T 细胞占主导地位。相比之下，下肢移植物表现出中度排斥反应，主要由 CD8 T 细胞浸润。值得注意的是，与整个 VCA 相比，皮肤成分表现出更高的免疫原性，证据是皮肤移植物受者的淋巴组织和血液中 pan（CD11bCD11c）、成熟（CD11bCD11cMHCII）和活性（CD11bCD11cCD40）DC 以及 cDC2 亚群（CD11bCD11cMHCII）的频率增加。虽然供体耗尽 cDC 和 APC 会降低皮肤移植物受者所有分析组织中 DC 的频率、成熟度和激活度，但仅在下肢受者的脾脏中观察到 DC 活性降低。供体 cDC 和 APC 耗竭不会影响所有淋巴细胞区室，但会显著影响皮肤受者淋巴结中的 CD8 T 细胞和活化的 CD4 T 细胞。此外，供体 APC 和 cDC 耗竭均可减弱 Th17 免疫反应，表现为皮肤受者脾脏中 Th17（CD4IL-17）细胞显著减少，皮肤和下肢受者血清样本中 IL-17E 和淋巴毒素-α水平降低。总之，我们的研究结果强调了 VCA 中皮肤成分的高度免疫原性。供体 APC 和 cDC 的耗竭可减轻皮肤移植物的免疫原性，同时对 VCA 的影响最小。
