在使用逆转录病毒转导的小鼠自杀性淋巴细胞的小鼠同种异体移植模型中，通过维持移植物抗白血病效应来控制移植物抗宿主病。

Control of graft-versus-host disease with maintenance of the graft-versus-leukemia effect in a murine allogeneic transplant model using retrovirally transduced murine suicidal lymphocytes.

作者信息

Kornblau Steven M, Aycox Preston G, Stephens Clifton, McCue L David, Champlin Richard E, Marini Frank C

机构信息

Department of Blood and Marrow Transplantation, Unit 448, M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030-4009, USA.

出版信息

Exp Hematol. 2007 May;35(5):842-53. doi: 10.1016/j.exphem.2007.02.008.

DOI:10.1016/j.exphem.2007.02.008

PMID:17577932

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4075062/

Abstract

OBJECTIVE

Limited clinical trials have validated the hypothesis of controlling graft-versus-host disease (GVHD) arising from stem cell transplant utilizing suicidal T-lymphocytes that have been transduced to express the HSV-TK gene. However, clinical utility has been limited by diminished T-cell function arising from the production process. To evaluate strategies for harnessing the graft-versus-leukemia (GVL) effect while improving the safety and function of suicidal lymphocytes, we have developed techniques to produce fully functional, retrovirally transduced, HSV-TK-positive murine T cells (TK+TC).

METHODS

Utilizing a murine major histocompatibility complex-matched transplant model, we evaluated the ability of TK+TC to generate a GVL effect and the ability to control GVHD in experiments where we varied the dose of TK+TC, ganciclovir (GCV) dose, the start of GCV administration (day 4, 7, 10, 13, 15, or 19) posttransplantation, and the GCV administration route (osmotic pump versus intraperitoneal).

RESULTS

At TK+TC doses in excess of the standard lethal dose (SLD) of unmanipulated T-cells, GCV administration completely (2 x SLD) and partially (4 x SLD) controlled GVHD. Additionally, GVHD remained reversible despite delaying administration of GCV for a week after GVHD developed. Importantly, GVHD was controlled with a 1-log but not 2-log reduction in GCV dose, and this "partial suicide" preserved more circulating TK+TC compared with standard-dose GCV. Survival of leukemia-positive mice receiving TK+TC and GCV was significantly increased compared with control cohorts not receiving GCV or transplanted with unmanipulated T cells, thereby demonstrating a GVL effect.

CONCLUSION

Retrovirally transduced suicidal lymphocytes generate a potent GVL effect while simultaneously enabling control of GVHD, which results in improved leukemia and GVHD-free survival.

摘要

目的

有限的临床试验验证了利用经转导表达单纯疱疹病毒胸苷激酶（HSV-TK）基因的自杀性T淋巴细胞来控制干细胞移植引起的移植物抗宿主病（GVHD）这一假说。然而，临床应用受到生产过程中T细胞功能减弱的限制。为了评估在提高自杀性淋巴细胞安全性和功能的同时利用移植物抗白血病（GVL）效应的策略，我们开发了生产功能完全、经逆转录病毒转导的HSV-TK阳性小鼠T细胞（TK+TC）的技术。

方法

利用小鼠主要组织相容性复合体匹配的移植模型，我们在实验中改变TK+TC剂量、更昔洛韦（GCV）剂量、移植后GCV给药开始时间（第4、7、10、13、15或19天）以及GCV给药途径（渗透泵与腹腔内给药），评估TK+TC产生GVL效应的能力以及控制GVHD的能力。

结果

在TK+TC剂量超过未处理T细胞的标准致死剂量（SLD）时，给予GCV可完全（2×SLD）和部分（4×SLD）控制GVHD。此外，尽管在GVHD发生后将GCV给药延迟一周，GVHD仍保持可逆。重要的是，用降低1个对数而非2个对数的GCV剂量即可控制GVHD，与标准剂量GCV相比，这种“部分自杀”保留了更多循环中的TK+TC。与未接受GCV或移植未处理T细胞的对照队列相比，接受TK+TC和GCV的白血病阳性小鼠的存活率显著提高，从而证明了GVL效应。