Decellularization of xenogeneic heart valves might lead to excellent regenerative implants, from which many patients could benefit. However, this material carries various xenogeneic epitopes and thus bears a considerable inherent immunological risk. Here, we investigated the regenerative and immunogenic potential of xenogeneic decellularized heart valve implants using pigs deficient for the galactosyltransferase gene (GGTA1-KO) as novel large animal model. Decellularized aortic and pulmonary heart valves obtained from sheep, wild-type pigs or GGTA1-KO pigs were implanted into GGTA1-KO pigs for 3, or 6 months, respectively. Explants were analyzed histologically, immunhistologically (CD3, CD21 and CD172a) and anti-αGal antibody serum titers were determined by ELISA. Xenogeneic sheep derived implants exhibited a strong immune reaction upon implantation into GGTA1-KO pigs, characterized by massive inflammatory cells infiltrates, presence of foreign body giant cells, a dramatic increase of anti-αGal antibody titers and ultimately destruction of the graft, whereas wild-type porcine grafts induced only a mild reaction in GGTA1-KO pigs. Allogeneic implants, wild-type/wild-type and GGTA1-KO/GGTA1-KO valves did not induce a measurable immune reaction. Thus, GGTA1-KO pigs developed a ‘human-like’ immune response toward decellularized xenogeneic implants showing that immunogenicity of xenogeneic implants is not sufficiently reduced by decellularization, which detracts from their regenerative potential.

中文翻译：

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去细胞异种心脏瓣膜移植到GGTA1-KO猪后的免疫学和功能特征

异种心脏瓣膜的去细胞化可能会导致出色的再生植入物，许多患者可以从中受益。然而，这种材料携带各种异种表位，因此具有相当大的固有免疫风险。在这里，我们使用半乳糖基转移酶基因 (GGTA1-KO) 缺陷的猪作为新型大型动物模型研究了异种脱细胞心脏瓣膜植入物的再生和免疫原性潜力。将从绵羊、野生型猪或 GGTA1-KO 猪获得的去细胞主动脉瓣和肺心瓣膜分别植入 GGTA1-KO 猪中 3 个月或 6 个月。外植体进行组织学、免疫组织学（CD3、CD21 和 CD172a）分析，并通过 ELISA 测定抗 αGal 抗体血清滴度。异种绵羊来源的植入物在植入 GGTA1-KO 猪后表现出强烈的免疫反应，其特征是大量炎性细胞浸润，存在异物巨细胞，抗 αGal 抗体滴度显着增加并最终破坏移植物，而野生-型猪移植物在 GGTA1-KO 猪中仅引起轻微反应。同种异体植入物、野生型/野生型和 GGTA1-KO/GGTA1-KO 瓣膜不会引起可测量的免疫反应。因此，GGTA1-KO 猪对脱细胞异种植入物产生了“类人”免疫反应，表明异种植入物的免疫原性并未通过脱细胞化充分降低，这削弱了它们的再生潜力。抗αGal抗体滴度显着增加并最终破坏了移植物，而野生型猪移植物在GGTA1-KO猪中仅引起轻微反应。同种异体植入物、野生型/野生型和 GGTA1-KO/GGTA1-KO 瓣膜不会引起可测量的免疫反应。因此，GGTA1-KO 猪对脱细胞异种植入物产生了“类人”免疫反应，表明异种植入物的免疫原性并未通过脱细胞化充分降低，这削弱了它们的再生潜力。抗αGal抗体滴度显着增加并最终破坏了移植物，而野生型猪移植物在GGTA1-KO猪中仅引起轻微反应。同种异体植入物、野生型/野生型和 GGTA1-KO/GGTA1-KO 瓣膜不会引起可测量的免疫反应。因此，GGTA1-KO 猪对脱细胞异种植入物产生了“类人”免疫反应，表明异种植入物的免疫原性并未通过脱细胞化充分降低，这削弱了它们的再生潜力。