Graft versus neuroblastoma reaction is efficiently elicited by allogeneic bone marrow transplantation through cytolytic activity in the absence of GVHD
Graft versus neuroblastoma reaction is efficiently elicited by allogeneic bone marrow transplantation through cytolytic activity in the absence of GVHD
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DOI：
10.1007/s00262-009-0715-6
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发表时间：
2009-12-01
影响因子：
5.8
通讯作者：
Yaniv, Isaac
中科院分区：
文献类型：
--
作者：
Ash, Shifra;Gigi, Vered;Yaniv, Isaac
我们不断致力于开发神经母细胞瘤（NB）的免疫治疗方法，神经母细胞瘤是一种在高剂量常规细胞毒疗法和自体骨髓细胞（BMC）重建后复发率很高的肿瘤。本研究提出了一系列移植实验，旨在评估同种异体 BMC 移植的功效。 Neuro-2a 细胞被发现表达低水平的 I 类主要组织相容性复合体 (MHC) 抗原。虽然放射和同基因骨髓移植 (BMT) 减少了肿瘤生长 (P < 0.001)，但同种异体 BMT 进一步损害了 Neuro-2a 细胞的皮下发育 (P < 0.001)。同种异体供体来源的 T 细胞在体外表现出针对 Neuro-2a 的直接细胞毒活性，这是一种免疫介导的肿瘤生长抑制机制。携带皮下肿瘤的同系小鼠的淋巴细胞增殖受到肿瘤裂解物的抑制，表明可溶性因子抑制同系淋巴细胞的细胞毒活性。然而，当在同基因和同种异体 BMT 后的不同时间植入嵌合小鼠时，Neuro-2a 细胞的生长受到损害。 F1（供体-宿主）脾细胞被输注，试图促进免疫重建，但它们的移植是短暂的，对肿瘤生长没有影响。总而言之，这些数据表明：(1) Neuro-2a 细胞表达 MHC 抗原和免疫原性肿瘤相关抗原。 (2) 与同基因（自体）免疫造血重建相比，同种异体 BMT 是开发 NB 移植物抗肿瘤 (GVT) 免疫疗法的明显更好的平台。 (3) 荷瘤小鼠中有效的 GVT 反应由 MHC 差异引发并针对肿瘤相关抗原。
Continuous efforts are dedicated to develop immunotherapeutic approaches to neuroblastoma (NB), a tumor that relapses at high rates following high-dose conventional cytotoxic therapy and autologous bone marrow cell (BMC) reconstitution. This study presents a series of transplant experiments aiming to evaluate the efficacy of allogeneic BMC transplantation. Neuro-2a cells were found to express low levels of class I major histocompatibility complex (MHC) antigens. While radiation and syngeneic bone marrow transplantation (BMT) reduced tumor growth (P < 0.001), allogeneic BMT further impaired subcutaneous development of Neuro-2a cells (P < 0.001). Allogeneic donor-derived T cells displayed direct cytotoxic activity against Neuro-2a in vitro, a mechanism of immune-mediated suppression of tumor growth. The proliferation of lymphocytes from congenic mice bearing subcutaneous tumors was inhibited by tumor lysate, suggesting that a soluble factor suppresses cytotoxic activity of syngeneic lymphocytes. However, the growth of Neuro-2a cells was impaired when implanted into chimeric mice at various times after syngeneic and allogeneic BMT. F1 (donor-host) splenocytes were infused attempting to foster immune reconstitution, however they engrafted transiently and had no effect on tumor growth. Taken together, these data indicate: (1) Neuro-2a cells express MHC antigens and immunogenic tumor associated antigens. (2) Allogeneic BMT is a significantly better platform to develop graft versus tumor (GVT) immunotherapy to NB as compared to syngeneic (autologous) immuno-hematopoietic reconstitution. (3) An effective GVT reaction in tumor bearing mice is primed by MHC disparity and targets tumor associated antigens.