Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Transpl Immunol. 2019 Oct;56:101225. doi: 10.1016/j.trim.2019.101225. Epub 2019 Jul 19.
Myeloid-derived suppressor cells (MDSC) are a heterogenous population of immunosuppressive myeloid cells now considered important immune regulatory cells in diverse clinical conditions, including cancer, chronic inflammatory disorders and transplantation. In rodents, MDSC administration can inhibit graft-versus-host disease lethality and enhance organ or pancreatic islet allograft survival. There is also evidence, however, that under systemic inflammatory conditions, adoptively-transferred MDSC can rapidly lose their suppressive function. To our knowledge, there are no reports of autologous MDSC administration to either human or clinically-relevant non-human primate (NHP) transplant recipients. Monocytic (m) MDSC have been shown to be more potent suppressors of T cell responses than other subsets of MDSC. Following their characterization in rhesus macaques, we have conducted a preliminary analysis of the feasibility and preliminary efficacy of purified mMDSC infusion into MHC-mismatched rhesus kidney allograft recipients. The graft recipients were treated with rapamycin and the high affinity variant of the T cell co-stimulation blocking agent cytotoxic T lymphocyte antigen 4 Ig (Belatacept) that targets the B7-CD28 pathway. Graft survival and histology were not affected by infusions of autologous, leukapheresis product-derived mMDSC on days 7 and 14 post-transplant (cumulative totals of 3.19 and 1.98 × 10 cells/kg in n = 2 recipients) compared with control monkeys that did not receive MDSC (n = 2). Sequential analyses of effector T cell populations revealed no differences between the groups. While these initial findings do not provide evidence of efficacy under the conditions adopted, further studies in NHP, designed to ascertain the appropriate mMDSC source and dose, timing and anti-inflammatory/immunosuppressive agent support are likely to prove instructive regarding the therapeutic potential of MDSC in organ transplantation.
髓系来源的抑制性细胞（MDSC）是一种异质性的免疫抑制性髓系细胞群体，现在被认为是多种临床情况下重要的免疫调节细胞，包括癌症、慢性炎症性疾病和移植。在啮齿动物中，MDSC 的给药可以抑制移植物抗宿主病的致死性，并增强器官或胰腺胰岛同种异体移植物的存活。然而，也有证据表明，在全身炎症状态下，过继转移的 MDSC 可能会迅速失去其抑制功能。据我们所知，目前还没有关于自体 MDSC 给药给人类或临床相关的非人类灵长类动物（NHP）移植受者的报道。单核细胞（m）MDSC 被证明比其他 MDSC 亚群更能抑制 T 细胞反应。在恒河猴中对其进行特征描述后，我们对纯化的 m MDSC 输注到 MHC 错配的恒河猴肾同种异体移植物受者中的可行性和初步疗效进行了初步分析。移植物受者接受雷帕霉素和高亲和力的 T 细胞共刺激阻断剂 CTLA-4 Ig（贝那普利塞）治疗，该阻断剂靶向 B7-CD28 途径。与未接受 MDSC 的对照猴子（n=2）相比，在移植后第 7 和 14 天输注自体、白细胞分离产物衍生的 m MDSC（n=2）并没有影响移植物的存活和组织学（累计总量分别为 3.19 和 1.98×10 个细胞/kg）。对效应 T 细胞群的连续分析显示两组之间没有差异。虽然这些初步发现并不能为所采用的条件下提供疗效的证据，但在 NHP 中进行进一步的研究，旨在确定适当的 m MDSC 来源和剂量、时间以及抗炎/免疫抑制药物支持，可能会证明对 MDSC 在器官移植中的治疗潜力具有指导意义。
