COBLOCKADE OF THE LFA1-ICAM AND CD28/CTLA4-B7 PATHWAYS IS A HIGHLY EFFECTIVE MEANS OF PREVENTING ACUTE LETHAL GRAFT-VERSUS-HOST DISEASE INDUCED BY FULLY MAJOR HISTOCOMPATIBILITY COMPLEX-DISPARATE DONOR GRAFTS
COBLOCKADE OF THE LFA1-ICAM AND CD28/CTLA4-B7 PATHWAYS IS A HIGHLY EFFECTIVE MEANS OF PREVENTING ACUTE LETHAL GRAFT-VERSUS-HOST DISEASE INDUCED BY FULLY MAJOR HISTOCOMPATIBILITY COMPLEX-DISPARATE DONOR GRAFTS
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DOI：
10.1182/blood.v85.9.2607.bloodjournal8592607
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发表时间：
1995-05-01
期刊：
影响因子：
20.3
通讯作者：
VALLERA, DA
中科院分区：
文献类型：
--
作者：
BLAZAR, BR;TAYLOR, PA;VALLERA, DA
我们已经开发了一种体外系统，其中C57 BL/6供体脾细胞暴露于B10.BR宿主同种异体抗原的背景下，缺乏CD 28：B7信号传导作为一种手段，预防移植物抗宿主病（GVHD）。虽然54%至82%的MLR同种异体反应被细胞毒性T淋巴细胞抗原4（CTLA 4）-Ig处理的宿主刺激细胞抑制，但处理的脾细胞在体内输注时仍然能够引起GVHD。通过在体外将抗白细胞功能抗原1（anti-LFA 1）抗体添加到hCTLA 4-lg以共阻断LFA 1：细胞间粘附分子（ICAM）信号传导，脾同种异体反应被抑制大于或等于89%，而GVHD诱导能力被保留。由于抗原致敏的细胞可能对CD 28：B7阻断更敏感，我们研究了单独的hCTLA 4-Ig、单独的抗LFA 1抗体或两者的组合添加到供体-抗宿主体外致敏的细胞中是否可以减少GVHD。为了促进低反应性诱导和阻断在GVHD期间上调的B7和ICAM配体，这些试剂也被施用给BMT后的受体。我们已经表明，hCTLA 4-Ig加抗LFA 1抗体在预防GVHD诱导的致死性方面是高度有效的（88%至100%的治疗小鼠存活，而对照组存活为0%至28%）。为了最佳预防，hCTLA 4-Ig和抗LFA 1两者必须在供体-抗宿主致敏的脾细胞的背景下在体外使用并在体内继续使用。这种体外-体内结合的方法与供体移植相关，并且受体没有受到全面的免疫抑制。我们得出结论，阻断CD 28/B7和LFA 1：ICAM途径对于有效预防GVHD至关重要，并且可能为体外供体T细胞去除提供优势。(C)1995年，美国血液学会。
We have developed an in vitro system in which C57BL/6 donor splenocytes are exposed to B10.BR host alloantigens in the context of deficient CD28:B7 signaling as a means of preventing graft-versus-host disease (GVHD). Although 54% to 82% of MLR alloresponse was inhibited by cytotoxic T-lymphocyte antigen 4 (CTLA4)-lg treatment of host stimulator cells, treated splenocytes were still capable of causing GVHD when infused in vivo. By adding anti-leukocyte function antigen 1 (anti-LFA1) antibody to hCTLA4-lg in vitro to coblock the LFA1:intercellular adhesion molecule (ICAM) signaling, splenic alloresponse was inhibited by greater than or equal to 89%, yet GVHD induction capabilities were retained. Because antigen-primed cells might be more susceptible to CD28:B7 blockade, we investigated whether hCTLA4-lg alone, anti-LFA1 antibody alone, or the combination of both added to donor-antihost in vitro primed cells could reduce GVHD. To facilitate hyporesponsiveness induction and to block B7 and ICAM ligands that are upregulated during GVHD, these reagents were also administered to recipients post-BMT. We have shown that hCTLA4-lg plus anti-LFA1 antibody is highly effective in preventing GVHD-induced lethality (88% to 100% of treated mice surviving versus 0% to 28% of controls surviving), For optimal prevention, both hCTLA4-lg and anti-LFA1 must be used in vitro in the context of donor-antihost primed splenocytes and continued in vivo. This in vitro-in vivo combined approach was associated with donor engraftment, and recipients were not globally immunosuppressed, We conclude that blocking both the CD28/B7 and the LFA1:ICAM pathways are critical to effective GVHD prevention and may offer advantages to in vitro donor T-cell removal. (C) 1995 by The American Society of Hematology.