比较脐血与成人外周血中T淋巴细胞亚群分布及其因子产生的差异

目的：探讨脐血与成人外周血中淋巴细胞亚群分布及细胞因子的差异及其与移物抗宿主病（GVHD）发生的关系,方法：采用流式细胞术,三色荧光单克隆抗体标记对脐血和成人外周血中淋巴细胞进行分类,并对其分泌的IL－2,TNF－α和IFN－r进行分析比较,结果：（1）脐血中T淋巴细胞以CD^4 ,CD45RA^ 细胞为主,而成人外周血以CD^ ,CD4R5RO^ 和CD^ 8CD450^ 两种表型为主,（2）脐血淋巴细胞产生IL－2,TNF－α和IFN－r的量明显低于成人外周血淋巴细胞,进一步分析表明,脐血中产生细胞因子的细胞大部分为CD^ 4CD45^ 细胞,而成人外周血中大部分为CD^ 4CD45RO^ 和CD^ 8CD^ 45RO细胞。结论：成人外周血与脐血淋巴细胞不仅存在亚群比例上的差异,而且亚群分泌细胞因子的量也明显减少,脐血干细胞移植的GVHD发生率较低可能与脐血中淋巴细胞亚群的比例不同及分泌细胞因子减少有关。     

异基因造血干细胞移植中供体CD4+CD25+T细胞与aGVHD的相关性研究

目的探讨供体CD4 CD25 免疫调控T细胞的表达水平与受者急性移植物抗宿主病(Agvhd)的相关性.方法 13例异基因造血干细胞移植中,采用流式细胞仪检测供体CD4 CD25 免疫调控T细胞的表达水平,并随访患者移植后Agvhd的发生情况及严重程度.结果 13例患者均获造血重建,Ⅰ (a)GVHD 5例, Ⅱ (a)GVHD 2例 ,ⅣaGVHD 1例.发生aGVHD组供体CD4 CD25 免疫调控T细胞水平为(1.52±1.25)%,未发生aGVHD组为(2.70±2.08)%,两组免疫调控T细胞水平差异有显著性(P<0.05).结论供体CD4 CD25 免疫调控T细胞的表达水平与受者aGVHD的发生有相关性,提高供体免疫调控T细胞水平有望减低移植后aGVHD发生率.     

造血干细胞移植治疗重型再生障碍性贫血

目的 评价异基因造血干细胞移植(Allo-HSCT)治疗重型再生障碍性贫血(SAA)的疗效.方法 2003年3月至2009年5月接受Allo-HSCT治疗SAA患者4例,其中HLA位点全相合同胞供者3例,HLA 5个位点相合同胞供者1例.回顾性分析从诊断到移植时间、HSCT方式、预处理方案、植入时间、HSCT并发症和疗效等.结果 诊断到移植时间平均70(19-180)d.HLA位点全相舍HSCT采用骨髓+外周血干细胞移植3例,HLA 5个位点相合HSCT采用骨髓+外周血+脐血干细胞移植1例,预处理方案均为环磷酰胺/抗人胸腺细胞球蛋白(CY/ATG).4例患者均植活,中性粒细胞绝对值(ANC)≥0.5×109/L和血小板(BPC)≥20 × 109/L中位时间分别为移植后14.5(9～28)d、16(9～28)d,其中2例患者发生Ⅰ度急性移植物抗宿主病(aGVHD),1例患者发生局限性慢性移植物抗宿主病(cGVHD).至随访截止日无死亡病例,中位生存40.6(2～63)个月.结论 Allo-HSCT是治愈SAA的有效方法,并且对于HLA位点不全相合同胞供者的Allo-HSCT,同样是安全有效的.     

外周血造血干细胞移植治疗恶性血液病16例临床总结

目的:观察外周血造血干细胞移植(peripheral blood stem cell transplantation,PBSCT)对恶性血液病的临床疗效.方法:对16例恶性血液病患者进行PBSCT,其中9例行异基因PBSCT(allo-PBSCT),7例行自体PBSCT(auto-PBSCT).allo-PBSCT采用粒细胞集落刺激因子(G-CSF),auto-PBSCT采用化疗联合G-CSF动员外周血造血干细胞.预处理方案采用改良的白消安/环磷酰胺或全身照射/环磷酰胺方案.allo-PBSCT患者接受CD34 细胞中位数为6.43×106/kg,auto-PBSCT患者接受CD34 细胞中位数为5.7×106/kg.allo-PBSCT患者移植物抗宿主病(GVHD)的预防采用环孢素A联合短疗程甲氨蝶呤,部分患者加用霉酚酸酯,2例人类白细胞抗原(HLA)不全相合患者加用抗胸腺细胞球蛋白.结果:全部患者均成功植入并快速重建造血,中性粒细胞恢复至≥0.5×109/L、血小板恢复至≥20×109/L的天数,在auto-PBSCT分别为12～18天和14～22天,在allo-PBSCT中分别为14～21天和16～26天.allo-PBSCT中Ⅰ～Ⅳ度急性GVHD的发生率为33.3%,慢性GVHD的发生率为77.8%.全组总死亡率18.8%.结论:auto-PBSCT和allo-PBSCT均能很快重建造血,是治疗恶性血液病最有效的手段之一.预防和治疗GVHD仍然是PBSCT中的重要问题.     

Reduced incidence of acute graft versus host disease (GVHD) of the gut in Chinese carriers of<Emphasis Type="Italic"> Helicobacter Pylori</Emphasis> during allogeneic bone marrow transplantation

Helicobacter pylori (H. Pylori) infection is associated with gastritis and peptic ulcer, but its relationship with gut graft versus host disease (GVHD) is unknown. We investigated the association between H. Pylori carriage and incidence and severity of mucosal toxicity and GVHD in 128 consecutive matched sibling stem cell transplantation (SCT) recipients. Using a verified enzyme linked immunosorbant assay (ELISA), 43.5% of patients had H. Pylori exposure before SCT. There was absolute concordance between serological and breath test data in 40 prospective cases. There was no increased risk in WHO grade 3 or 4 mucositis in H. Pylori carriers. Significant (grade II or above) overall GVHD was only predicted by preceding mucositis (p<0.001), while gut GVHD was associated with increased age (p=0.001) and mucositis (p=0.022). Despite increased incidence with age, H. Pylori carriage was associated with significantly reduced risk of gut GVHD (p=0.04) but not overall GVHD. The reduced risk of immune-mediated gut inflammation in H. Pylori carriers after SCT may be related to the known reduced incidence of inflammatory bowel disease in chronic H. Pylori carriers.     

Clinical relevance of a newly identified HLA-A24-restricted minor histocompatibility antigen epitope derived from BCL2A1, ACC-1, in patients receiving HLA genotypically matched unrelated bone marrow transplant

Minor histocompatibility antigens (mHAs) are major histocompatibility complex (MHC)-associated peptides, which trigger T-cell responses that mediate graft versus host disease (GVHD) and graft versus leukaemia effects. We recently identified a new mHA epitope, termed ACC-1, which is presented by HLA-A*2402 and encoded by BCL2A1, whose expression is restricted to haematopoietic cells including leukaemic cells. HLA-A24/ACC-1 tetramer detected the presence of ACC-1-specific CD8+ cells in the peripheral blood of a patient up to 7 months following transplantation, and these tetramer-positive cells were expandable in vitro by ACC-1 peptide stimulation. A retrospective analysis of 320 patients with HLA-A*2402 who had received a human leucocyte antigen (HLA) genotypically matched unrelated donor through the Japan Marrow Donor Programme was conducted to determine whether ACC-1 disparity is associated with adverse clinical outcomes such as GVHD. Among these patients, ACC-1 disparity was detected in 55 (17.2%) donor/recipient pairs. After adjusting for known risk factors, the hazard ratios or odds ratios of acute and chronic GVHD, relapse and disease-free survival were not statistically different between patients receiving ACC-1 compatible and incompatible transplantation. These data suggest that disparity of haematopoietic cell-specific mHA, ACC-1, is unlikely at least to augment GVHD, and that T cells specific for ACC-1 may also be used for immunotherapy of recurring leukaemia without GVHD.     

Combination of anti‐CD4 antibody treatment and donor lymphocyte infusion ameliorates graft‐versus‐host disease while preserving graft‐versus‐tumor effects in murine allogeneic hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is not only a well‐established immunotherapy for hematologic malignancies, but is potentially useful for treating solid tumors refractory to available therapies. However, application of allo‐HSCT to solid tumors is limited, despite the beneficial antitumor effects, by the risk of graft‐versus‐host disease (GVHD). CD4⁺ T cells have been implicated in several aspects of GVHD, and suppress antitumor CD8⁺ T‐cell responses. In the present study, we investigated clinically applicable allo‐HSCT protocols designed to maximize antitumor effects while reducing the risk of GVHD. We used a mouse model of allo‐HSCT with s.c. tumors. We found that myeloablative conditioning was associated with better inhibition of tumor growth but with severe acute GVHD. Early treatment with anti‐CD4 mAb substantially ameliorated GVHD while preserving antitumor effects, leading to improved survival in myeloablative allo‐HSCT. Late treatment with anti‐CD4 mAb also ameliorated GVHD to some extent. Donor lymphocyte infusion in GVHD mice treated with anti‐CD4 mAb further suppressed tumor growth without exacerbating GVHD. Collectively, our results suggest that myeloablative allo‐HSCT followed by anti‐CD4 mAb treatment and donor lymphocyte infusion could be a potent and safe immunotherapy for patients with cancers refractory to available therapies.     

Do incident and new subsequent cases of non-melanoma skin cancer registered in a Danish prospective cohort study have different 10-year mortality?

Background: The Danish Gerda Frentz Cohort (GFC) was created for registering all incident and new subsequent cases of non-melanoma skin cancer (NMSC) among patients seen by Danish dermatologists in 1995. We have recently found, in this cohort, a lower 10-year mortality than in the general population in patients with basal cell carcinoma (BCC). Differences in mortality between incident and new subsequent cases, incomplete registration or selection bias may be responsible for this finding. Methods: We aimed to quantify differences in mortality between incident and new subsequent cases of NMSC in the GFC and to compare mortality among incident cases recorded in the GFC and those recorded in the Danish Cancer Registry (DCR). We followed 10,830 skin cancer patients and 106,696 age-, gender- and residence-matched population controls through 2006 and computed their cumulative mortality and mortality rate ratio (MRR). Results: One-, 5-, and 10-year cumulative mortality of incident and new subsequent cases of BCC and SCC in the GFC were similar. Likewise, MRR for incident BCC (MRR = 0.91; 95% CI 0.84–0.98) and incident SCC (MRR = 1.29; 95% CI 1.05–1.56) among patients registered in the GFC were similar to their counterparts in the DCR (MRR = 0.96; 95% CI 0.91–1.00 and MRR = 1.36; 95% CI 1.22–1.52). Conclusion: Mortality of incident and new subsequent cases of NMSC was similar and thus did not explain the reduced mortality of BCC patients.     

Autograft mediated adoptive immunotherapy of cancer in the context of autologous stem cell transplantation

The infused stem cell autograft in autologous stem cell transplantation (ASCT) has been viewed mainly as hematologic rescue from the myelosuppressive side effect of conditioning regimens. However, recent reports have shown that the immune effector cells collected at the same time as the stem cells can produce an autologous graft-versus-tumor effect, similar to the graft-versus-tumor effect seen in allogeneic stem cell transplantation without the detrimental effects of graft-versus-host disease. In this article, we review the different immune effector cells collected and infused from the stem cell autograft and their association with clinical outcome post-ASCT, suggesting that ASCT can be viewed not only as a therapeutic maneuver to recover bone marrow function after deliver high-dose chemotherapy, but also as an adoptive immunotherapeutic intervention capable of eradicating residual tumor cells in patients with cancer.     

rhGM-CSF After Allogeneic Bone Marrow Transplantation From Unrelated Donors: A Pilot Study of Cyclosporine and Prednisone as Graft-Versus-Host Disease Prophylaxis

Cyclosporine and prednisone were administered as graft-versus-host disease (GVHD) prophylaxis to nine patients undergoing marrow transplant from HLA matched, unrelated donors. RhGM-CSF was administered at a dose of 250 μ;g/m² daily to all patients. The median day of neutrophil recovery to 500/mm³ was Day 16. Four patients developed Grade II acute GVHD and four developed Grade 111 acute GVHD. One patient, who survived only 25 days, did not develop GVHD at all. One patient developed systemic infection within the first 28 days after marrow infusion. Comparison of these data to a prior series of patients undergoing bone marrow transplant (BMT) from unrelated donors who were treated with rhGM-CSF along with methotrexate and cyclosporine for GVHD prophylaxis suggests that rhGM-CSF is well-tolerated, neutrophil recovery may be earlier but the severity of GVHD does not appear reduced. Selection of the GVHD prophylaxis regimen may affect the hematopoietic response to cytokine therapy. Further trials with rhGM-CSF in patients undergoing BMT from unrelated donors are required.