Granulocyte-macrophage colony-stimulating factor expression by human fibroblasts is both upregulated and subsequently downregulated by interleukin-1

Interleukin-1 (IL-1) treatment of human WI-38 lung fibroblasts results in granulocyte-macrophage colony-stimulating factor (GM-CSF) expression as well as a delayed increase in prostaglandin E2 (PGE2) production that closely correlates with the decline of GM-CSF mRNA levels. Pretreatment with PGE2 reduces the IL-1 induced GM-CSF mRNA and protein expression to 10% to 15% of control values at concentrations of PGE2 that are endogenously produced after IL-1 stimulation. Inhibition of PGE2 synthesis by indomethacin prolongs the IL-1 induced GM-CSF mRNA expression and increases the cumulative GM-CSF protein secretion. Exposure of WI-38 fibroblasts to PGE2 results in an increase in intracellular cyclic adenosine monophosphate (cAMP) levels. The inhibition of GM-CSF expression by PGE2 can be mimicked by stable cAMP analogs as well as cAMP elevating agents such as cholera toxin, forskolin, and isobutylmethylxanthine. Thus the inhibition exerted by PGE2 is mediated via cAMP. Taken together, these results suggest that IL-1 stimulation of human fibroblasts provides not only the upregulatory signal for GM-CSF expression but also a delayed and indirect downregulatory signal that serves to limit GM-CSF expression in the continued presence of IL-1.     

Bispecific-armed, interferon gamma-primed macrophage-mediated phagocytosis of malignant non-Hodgkin's lymphoma

To show that macrophages can be effectively targeted against malignant B cells, bispecific antibodies (BsAb) were constructed from two antibodies having specificity for the high-affinity Fc receptor for IgG (Fc gamma RI/CD64) and the B-cell differentiation antigens CD19 and CD37. Using a flow cytometry-based assay and confocal imaging, we show that these constructs mediated significant phagocytosis of B lymphocytes by macrophages that could be enhanced with interferon gamma (IFN gamma) and IFN gamma in combination with macrophage colony- stimulating factor. BsAb-dependent phagocytosis was triggered through Fc gamma RI and could be blocked only by using F(ab')2 fragments from the parent molecule or by cross-linking Fc gamma RI. BsAb-dependent phagocytosis was not blocked by antibodies to the other Fc receptors, Fc gamma RII and Fc gamma RIII. Because these antibody constructs bind to an epitope outside the Fc gamma RI ligand binding site, we show that autologous serum, polyclonal IgG, and monomeric IgG1 did not block BsAb- dependent phagocytosis, whereas autologous serum and the IgG fractions blocked parent molecule monoclonal antibody-dependent phagocytosis due to the avid binding of monomeric IgG to Fc gamma RI. Finally, BsAb- mediated phagocytosis was effective against the malignant B cells of patients with mantle cell lymphoma, prolymphocytic leukemia, and chronic lymphocytic leukemia. Based on these studies, we propose that BsAbs may provide an effective means of immunomodulation for patients with B-cell malignancies.     

Cutaneous lymphoblastic lymphoma with pre-B markers

Two children with cutaneous convoluted lymphoblastic lymphoma are reported. Malignant cells from both patients contained cytoplasmic Mu heavy chains characteristic of pre-B-cells and expressed CALLA and la antigens as well. Most cases of convoluted lymphoblastic lymphoma are T- cell-derived neoplasms. The non-T, non-B phenotype found in these two children demonstrates that histology does not necessarily predict immunophenotype. The association of the pre-B phenotype with cutaneous lymphoma has not been previously reported, but may represent a unique clinical-histopathologic-immunologic entity that occurs in young children.     

手术及经皮自体骨髓移植治疗骨延迟愈合和骨不连

观察手术及经皮自体骨髓移植治疗四肢骨折骨不连、骨延迟愈合的临床效果。选择1997-11/2004-02山东省聊城市第二人民医院应用经皮自体骨髓移植法治疗骨不连、骨延迟愈合的患者23例,患者均了解相关治疗目的、方法并同意治疗方案。①17例骨不连患者采用手术治疗。15例存在骨质缺损者在骨折端间隙及周围自体髂骨植骨10例,收集术中骨屑及骨髓原位植骨4例,异体植骨1例;2例单纯外固定架重新固定未植骨并行自体骨髓移植。术后2周抽取自体骨髓注入骨折部位,注射10～20mL/次,每2周1次,需注射2～4次。②6例骨延迟愈合患者仅行自体骨髓移植,未改变固定方式。术后定期随访,观察患者骨折愈合情况。骨折愈合标准:X射线片显示连续骨痂通过折线,骨折处无疼痛及压痛,能够全部负重。23例骨不连、骨延迟愈合患者全部进入结果分析,无脱落。23例患者术后平均随访12.5个月,其中随访7～9个月11例,10～12个月6例,13～15个月5例,16个月1例。23例患者均达到骨性愈合,愈合率100%,平均愈合时间为5.6个月。坚强固定加必要的植骨修复骨缺损是治疗骨折术后骨不连的基础和关键,自体骨髓具有成骨作用,可进一步促进骨折愈合。     

Approaches to preventing or reversing platelet alloimmunization using animal models

Animal transfusion models were established to assess treatment programs for preventing or reversing platelet alloimmunization. Five control baboons given weekly transfusions of radiolabeled platelets from a single unrelated donor became immunized after an average of 2.4 +/- 2.1 transfusions. Similarly, 18 of 21 (86%) dogs given up to eight platelet transfusions from a single unrelated donor became immunized after an average of 2.3 +/- 1.7 transfusions. In six of seven baboons, prednisone or antithymocyte globulin alone or in combination effectively delayed platelet alloimmunization. In contrast, only two of 12 (17%) dogs given prednisone or antithymocyte serum (ATS) resisted alloimmunization. Neither splenectomy nor cyclophosphamide prevented alloimmunization in the baboon. In addition, attempts to reduce the immunogenicity of transfused platelets by inactivating the contaminating leukocytes with gamma radiation or by giving leukocyte-poor platelets were of no benefit in dogs. Reversal of platelet alloimmunization was achieved in two of three dogs treated with ATS and procarbazine hydrochloride. However, neither splenectomy, cyclophosphamide, ATS plus prednisone, nor vincristine sulfate produced any improvement. These studies show that the highly immunogenic nature of platelet transfusions in animals makes feasible the study of the prevention and reversal of platelet alloimmunization.