Nash R A, Burstein S A, Storb R, Yang W, Abrams K, Appelbaum F R, Boone T, Deeg H J, Durack L D, Schuening F G
Fred Hutchinson Cancer Research Center, Seattle, WA 98104, USA.
Blood. 1995 Sep 1;86(5):1765-75.
Administration of recombinant canine granulocyte-macrophage colony-stimulating factor (rcGM-CSF) to normal dogs in previous studies induced an increase in peripheral blood neutrophils and a dose-dependent decrease in platelet counts. In six dogs that received the highest tested dose of rcGM-CSF (50 micrograms/kg/d) for a minimum of 12 days, the mean nadir of the platelet count was 46,000/microL (range, 4,000 to 91,000/microL) on day 9 +/- 1.1 after starting therapy, compared with a mean baseline platelet count of 398,000/microL (range, 240,000 to 555,000/microL). In three dogs, survival of autologous 111In-labeled platelets was reduced from a mean of 4.9 days to 1.3 days during the administration of rcGM-CSF. Biodistribution studies with gamma camera imaging indicated that there was an increase in mean hepatic uptake during the administration of rcGM-CSF, from 15% to 44% of the total injected 111In-labeled platelets at 2 hours, whereas splenic uptake was not significantly changed. In contrast, in two evaluable dogs who were recipients of 111In-labeled platelets from matched allogeneic donors receiving rcGM-CSF, platelet survival was not reduced and no increased hepatic uptake was noted. A third dog became alloimmunized to the matched donor platelets and was not evaluable. Immunohistologic studies of liver and spleen were performed with monoclonal antibodies specific for canine gpIIb/IIIa and P-selectin in dogs treated with rcGM-CSF and compared with untreated controls. On treatment, a marked reduction of platelets in the red pulp of the spleen was evident, and in general, the presence of platelet antigen in the liver was unchanged. Therefore, platelets were not being sequestered, but destroyed in the liver and spleen. The platelet antigens, P-selectin and gpIIb/IIIa, were identified in association with Kupffer cells in the liver, but no difference in the number of distribution of these Kupffer cells was found between controls and rcGM-CSF-treated dogs. In the spleen during rcGM-CSF treatment, most platelet antigens were associated with large mononuclear cells in the marginal zone. During administration of rcGM-CSF, CD1c and CD11c expression was increased on Kupffer cells. Platelet P-selectin expression and binding of leukocytes to circulating platelets were unchanged from baseline studies with rcGM-CSF treatment. In conclusion, during the administration of rcGM-CSF to dogs, a local process in the liver and spleen is induced resulting in thrombocytopenia.(ABSTRACT TRUNCATED AT 400 WORDS)
在先前的研究中，给正常犬注射重组犬粒细胞-巨噬细胞集落刺激因子（rcGM-CSF）可导致外周血中性粒细胞增多以及血小板计数呈剂量依赖性下降。在6只接受rcGM-CSF最高测试剂量（50微克/千克/天）至少12天的犬中，开始治疗后第9±1.1天血小板计数的平均最低点为46,000/微升（范围为4,000至91,000/微升），而基线血小板计数的平均值为398,000/微升（范围为240,000至555,000/微升）。在3只犬中，自体111铟标记血小板的生存期在注射rcGM-CSF期间从平均4.9天缩短至1.3天。用γ相机成像进行的生物分布研究表明，在注射rcGM-CSF期间肝脏平均摄取量增加，2小时时从总注射111铟标记血小板的15%增至44%，而脾脏摄取量无明显变化。相比之下，在2只可评估的接受匹配同种异体供体111铟标记血小板并注射rcGM-CSF的犬中，血小板生存期未缩短，且未观察到肝脏摄取增加。第3只犬对匹配的供体血小板产生了同种免疫，无法进行评估。用针对犬gpIIb/IIIa和P-选择素的单克隆抗体对接受rcGM-CSF治疗的犬的肝脏和脾脏进行免疫组织学研究，并与未治疗的对照进行比较。治疗时，脾脏红髓中血小板明显减少，总体而言，肝脏中血小板抗原的存在未改变。因此，血小板不是被隔离，而是在肝脏和脾脏中被破坏。在肝脏中，血小板抗原P-选择素和gpIIb/IIIa与库普弗细胞相关，但在对照犬和接受rcGM-CSF治疗的犬之间，这些库普弗细胞的数量和分布没有差异。在rcGM-CSF治疗期间的脾脏中，大多数血小板抗原与边缘区的大单核细胞相关。在注射rcGM-CSF期间，库普弗细胞上的CD1c和CD11c表达增加。与rcGM-CSF治疗的基线研究相比，血小板P-选择素表达以及白细胞与循环血小板的结合未改变。总之，给犬注射rcGM-CSF期间，肝脏和脾脏中会引发局部过程，导致血小板减少。（摘要截断于400字）
