Serum levels of stem cell factor in patients during transplantation of bone marrow or peripheral blood stem cells

Stem cell factor (SCF) synergizes with other cytokines in vitro to stimulate the proliferation and differentiation of cells of the myeloid, megakaryocytic, erythroid, and lymphoid lineages. In vivo, it may play a role in engraftment after transplantation of bone marrow (BM) or peripheral blood stem cells (PBSC). Serum levels of SCF were closely monitored in 82 patients before and after allogeneic (n = 38), autologous (n = 6), or syngeneic (n = 1) BM transplantation (BMT) or autologous PBSC transplantation (PBSCT) (n = 37), respectively. SCF serum levels fluctuated around a mean in patients after allogeneic or autologous BMT or after PBSCT. In two patient subgroups (5 patients with acute myeloid leukemia [AML] and 6 patients with chronic myelogenous leukemia [CML]) with identical pretransplant conditioning regimen followed by allogeneic BMT, serum IL-6 levels significantly increased up to day +14 (p < 0.05). Correlation was not found between SCF serum levels and leukocyte or thrombocyte counts or the day of engraftment of these cell types. These data are a basis for further studies and constitute a further mosaic stone in understanding the changes in the complex cytokine network during engraftment.     

多位点VNTR用于异基因骨髓移植植入存活检定研究

目的：探讨多位点可变数串联重复序列（ Ｖ Ｎ Ｔ Ｒ）—— Ｄ１７ Ｓ３０、 Ｐ Ａ Ｈ、 Ｖ Ｓ１７、 Ｍ Ｌ Ｏ Ｗ １ 在异基因骨髓移植存活检定中的应用。方法：以聚合酶链反应（ Ｐ Ｃ Ｒ）扩增４ 个位点 Ｖ Ｎ Ｔ Ｒ, Ｐ Ｃ Ｒ 产物以聚丙烯酰胺凝胶电泳及银染法检测,对２ 名异基因骨髓移植（ Ａｌｌｏ Ｂ Ｍ Ｔ）患者作移植物成活检定研究。结果：受者获得了供者源性细胞植入存活的证据。结论：多位点 Ｖ Ｎ Ｔ Ｒ个体特异性强、识别力高,可作为 Ａｌｌｏ Ｂ Ｍ Ｔ 植活的可靠指标,尤其是用于血型、性别、 Ｈ Ｌ Ａ 表型全相合的 Ａｌｌｏ Ｂ Ｍ Ｔ,移植后 １５ 天便可获得植入证据。     

Therapeutic plasma exchange in patients suffering from thrombotic microangiopathy after allogeneic bone marrow transplantation.

Thrombotic microangiopathy (TM) is a potentially fatal complication of allogeneic bone marrow transplantation (BMT). The underlying pathophysiology is thought to be generalized endothelial cell damage caused by several factors including conditioning treatment, cyclosporin A (CsA), or graft versus host disease (GVHD). In the present retrospective study, 6 patients suffering from Grade 2 BMT-TM at a mean of 62 days post BMT were treated by 3-15 daily sessions of therapeutic plasma exchange (TPE). In most sessions, cryosupernatant (CSN) of plasma, in some fresh frozen plasma (FFP) was used as the substitution fluid. All patients suffered from acute graft versus host disease (aGVHD) of the skin, which was treated by CsA. CsA was withdrawn in all patients. TPE caused a response in 4 of 6 patients evidenced by a decrease to Grade 0 (n = 3) or 1 (n = 1) BMT-TM. Only 1 patient had mild renal insufficiency which did not improve during TPE. While all patients were dependent on platelet transfusions at baseline, the platelet counts improved in 2 of 6 patients after the TPE course. One patient did not show any response to TPE with FFP, and his disease improved only after CSN was introduced as substitution fluid (Grade 0). Four patients were still alive 175-495 days post BMT, and 2 patients died about 2-3 weeks after the end of the TPE course, 1 from cachexia and 1 from systemic aspergillosis. In summary, in this pilot study, TPE positively influenced BMT-TM, especially if CSN was used as the substitution fluid.     

Bone marrow transplantation as a strategy for treatment of non-insulin- dependent diabetes mellitus in KK-Ay mice

The effects of allogeneic bone marrow transplantation (BMT) on non-insulin-dependent diabetes mellitus (NIDDM) were examined using KK-Ay mice. KK-Ay mice reconstituted with KK-Ay bone marrow cells showed glycosuria, hyperinsulinemia, and hyperlipidemia. However, KK-Ay mice (H-2b) that had been lethally irradiated (9.0 Gy) and then reconstituted with T cell-depleted bone marrow cells from normal BALB/c mice (H-2d) showed negative urine sugar with decreases in serum insulin and lipid levels 4 mo after BMT. Morphological recovery of islets and glomeruli was also noted after allogeneic BMT. These findings suggest that BMT can be used to treat not only a certain type of NIDDM but also its complications such as hyperlipidemia and diabetic nephropathy.     

慢性粒细胞白血病异基因骨髓移植后残留白血病观察

目的：观察慢性粒细胞白血病（ＣＭＬ）异基因骨髓移植（ａｌｏ－ＢＭＴ）后残留白血病情况。方法：用逆转录－多聚酶链反应（ＲＴ－ＰＣＲ）技术测定４６例经ａｌｏ－ＢＭＴ植活的ＣＭＬ患者骨髓细胞Ｍ－ｂｃｒ／ａｂｌｍＲＮＡ表达。结果：ａｌｏ－ＢＭＴ能使约７０％ＣＭＬ患者在移植后３个月ｂｃｒ／ａｂｌｍＲＮＡ转阴。其中４例患者在移植后＋１．５～２．０个月时为ｂｃｒ／ａｂｌｍＲＮＡ（＋），于＋３个月转为阴性；１例于＋９个月转阴。１例无病存活６年以上患者，其ｂｃｒ／ａｂｌｍＲＮＡ为阳性；另１例无病存活４年以上患者ｂｃｒ／ａｂｌｍＲＮＡ为阴性。结论：ＲＴ－ＰＣＲ是当前检测残留白血病最灵敏的方法，但不能忽视其局限性。     

异基因造血干细胞移植治疗重型β地中海贫血

目的 研究异基因造血干细胞移植治疗重型β地中海贫血的临床效果。方法 确诊为重型β地中海贫血患儿15例，年龄1—10岁(中位年龄3．5岁)，其中男8例，女7例；Pesaro中心地中海贫血分度Ⅰ—Ⅱ度12例，Ⅲ度3例。对低体重供使用G-CSF动员后采集骨髓 外周血造血干细胞。HLA相合同胞骨髓移植10例，外周血造血干细胞移植2例，脐带血移植3例。随访时间为6—54个月。结果15例中9例长期无病生存，8例HLA人相合同胞骨髓移植Ⅰ—Ⅱ度患儿7例无病生存；2例母亲供髓HLA人不相合移植，1例无病生存，1例末植入。2例外周血造血干细胞移植，其中1例立即接受骨髓移植并获成功。2例无关供脐带血移植均末长期植入。15例患中发生Ⅰ度和Ⅲ度GVHD分别为3例和1例；4例并发间质性肺炎，所有长期无病生存无后期合并症。结论 Ⅰ—Ⅱ度β地中海贫血患儿骨髓移植成功率较高(87．5％)。对低体重供使用C—CSF动员后采集骨髓 外周血造血干细胞方法是确保植入的有效办法。但有增加急性和慢性GVHD和植入综合征的倾向。     

霉酚酸酯联合CsA和短程MTX预防非亲缘异基因骨髓移植的急性GVHD

目的　评价霉酚酸酯（MMF）联合环孢菌素A（CsA）和短程甲氨蝶呤(MTX)预防非亲缘异基因骨髓移植中急性移植物抗宿主病（aGVHD）的有效性和安全性。方法　12例患者非亲缘异基因骨髓移植当天始联合应用MMF（骁悉胶囊）1.0 g/d,CsA 3 mg     

Recipient‐derived HPA‐1a antibodies: a cause of prolonged thrombocytopenia after unrelated donor stem cell transplantation

BACKGROUND: Patients with human platelet antigen (HPA) specific antibodies in cases of neonatal alloimmune thrombocytopenia and platelet (PLT) refractoriness derive clinical benefit from the use of HPA‐selected PLTs. STUDY DESIGN AND METHODS: This study describes three patients with underlying diagnoses of acute myeloid leukemia, chronic lymphocytic leukemia, and myelodysplasia, respectively, who underwent allogeneic bone marrow transplantation (BMT) with unrelated donors matched at the HLA‐A, B, C, Dr, and DQ loci but who failed to achieve an adequate PLT count. Investigation using PLT immunofluorescence test, monoclonal antibody immobilization of PLT antigens assay, and genotyping revealed the presence of recipient‐derived HPA‐1a antibodies. RESULTS: In two patients, anti‐HPA‐1a was detected post‐BMT and in the third patient, anti‐HPA‐1a was detected during pre‐BMT chemotherapy. Despite apparent 100% engraftment of donor cells, the patients' PLT counts failed to recover 9‐10 months posttransplant. The patients remained PLT‐transfusion dependent and failed to achieve satisfactory increments following random donor or HLA‐matched PLT transfusions. After the identification of HPA‐1a antibodies, the patients were supported by HPA‐1a(‐) PLTs and satisfactory posttransfusion PLT increments were obtained. These cases illustrate that HPA‐1a antibodies may remain detectable for 10 months following apparently successful donor engraftment and the disappearance of recipient‐derived HLA antibodies. The prolonged persistence of recipient‐derived PLT‐specific antibodies following BMT has to our knowledge not been described previously. CONCLUSION: HPA‐1a antibodies were associated with protracted PLT‐transfusion dependence and significant hemorrhagic complications. Appropriate and timely laboratory investigation for HPA‐specific antibodiesfollowed by transfusion support with HPA‐selected PLTs provided the cornerstone of the hemostatic management in these cases.     

嵌合体的动态定量检测在异基因造血干细胞移植中的应用

目的　建立荧光标记的多重PCR扩增短串联重复序列 (STR PCR)结合毛细管电泳 ,定量检测供体细胞 (DC)嵌合率的方法 ,并探讨该方法的连续定量检测对异基因造血干细胞移植 (allo HSCT)后转归的预警作用。方法　采集 31例接受骨髓移植 (BMT)或非清髓外周血干细胞移植 (NST)患者移植前、移植后不同时段的外周血或骨髓。DNA样本用ProfilerPlus商品化试剂盒扩增后 ,用ABI 310遗传分析仪进行毛细管电泳 ,确定基因位点及峰面积 ,根据供受体基因型的差异选择嵌合率计算公式。结果　 31例患者中 15例 (48.4 % )为性别相合移植 ,只能通过STR PCR进行嵌合体的定量分析 ;性别不合移植患者用STR PCR和荧光原位杂交两种方法定量测得的DC嵌合率一致 ;31对供受体中能区别出供受差别的STR位点有 6 .7(2～ 10 )个 ,所有患者均在移植后 7天 ( 7天 )出现供体来源的细胞 ,BMT组 7天、 14天和 1个月DC中位数均明显低于NST组 ,而在移植中后期无显著性差异。 2 1天时BMT和NST患者均达稳定嵌合 ,DC在 92 %以上 ;中位随访 17(3.5～ 2 9.0 )个月 ,2 6例患者DC≥90 % ,均获得持久植入 ,至今均为无白血病生存。另有 5例患者出现不稳定混合嵌合 (MC)状态 (DC为2 7.3%～ 6 2 .7% ) ,其中 4例复发 ,1例出现移植物被排斥。上述 5例患者均     

Suppression of graft-versus-host disease and amplification of graft-versus-tumor effects by activated natural killer cells after allogeneic bone marrow transplantation.

Bone marrow transplantation (BMT) is currently used for the treatment of a variety of neoplastic diseases. However, significant obstacles limiting the efficacy of allogeneic BMT are the occurrence of graft-versus-host disease (GvHD) and tumor relapse. Natural killer (NK) cells exert a variety of immunologic and homoeostatic functions. We examined whether adoptive transfer of activated NK cells of donor type would prevent GvHD after allogeneic BMT in mice. Lethally irradiated C57BL/6 (H-2(b)) mice, were transplanted with MHC incompatible BALB/c (H-2(d)) bone marrow cells and spleen cells and rapidly succumbed to acute GvHD. In contrast, mice that also received activated NK cells of donor type exhibited significant increases in survival. In determining the mechanism by which the NK cells prevented GvHD, mice were concurrently treated with a neutralizing antibodies to the immunosuppressive cytokine TGFbeta. Anti-TGFbeta completely abrogated the protective effects of the activated donor NK cells indicating that TGFbeta plays an important role in the prevention of GvHD by NK cells. We then examined whether activated NK cells of donor type after allogeneic BMT would induce graft-versus-tumor (GvT) effects without GvHD in mice bearing a murine colon adenocarcinoma (MCA-38). 10 d after receiving the tumor, in which the mice had demonstrable lung metastases, recipients received an allogeneic BMT with or without activated NK cells. Administration of activated NK cells resulted in significant GvT effects after allogeneic BMT as evidenced by increases in median survival and fewer lung metastasis. No evidence of GVHD was detected compared with recipients receiving spleen cells alone which also developed fewer lung metastases but in which all had succumbed to GVHD. Thus, our findings suggest that adoptive immunotherapy using activated donor NK cells combined with allogeneic BMT inhibits GvHD and promotes GvT in advanced tumor-bearing mice. These results also suggest that GvT and GvHD can be dissociable phenomena.     

G-CSF预处理供者的HLA相合同胞异基因骨髓移植治疗慢性粒细胞白血病研究

为了评价供者应用G-CSF的骨髓移植治疗慢性粒细胞白血病的临床疗效,用HLA相合的、混合淋巴细胞培养阴性的同胞供者骨髓,对单一病种慢性粒细胞白血病行移植治疗。供者应用G-CSF 250微克/天,连用7天后供髓的32例为研究组,对照组18例常规采髓移植,在预处理方案,GVHD预防和支持治疗方法相同的情况下,比较研究组和对照组移植后在加速造血重建,降低GVHD发生和延长无病生存的疗效。移植结果显示,供者应用G-CSF在慢性粒细胞白血病移植中造血重建加速,中性粒细胞>0.5×10~9/L和血小板>20×10~9/L的中位天数分别是第15(10-22)天和第17.5(13-28)天,对照组是第21和24天(P<0.01),研究组发生急性Ⅱ-Ⅳ度GVHD 2例(6.3％),对照组5例(27.8％),通过比较,两组差异有显著性(P<0.05),慢性GVHD发生分别是24％和33.3％(P>0.05)。研究组移植相关死亡、复发和无病生存与对照组比较无统计学差异(P>0.05)。结论:使用G-CSF动员供者的HLA相合的异基因骨髓移植,造血重建加快和重度急性Ⅱ-Ⅳ度GVHD减轻,有可能提高CML移植的无病生存率。     

Enhanced allostimulatory activity of host antigen-presenting cells in old mice intensifies acute graft-versus-host disease

Older bone marrow transplantation (BMT) recipients are at heightened risk for acute graft-versus-host disease (GVHD) after allogeneic BMT, but the causes of this association are poorly understood. Using well-characterized murine BMT models we have explored the mechanisms of increased GVHD in older mice. GVHD mortality, morbidity, and pathologic and biochemical indices were all worse in old recipients. Donor T cell responses were significantly increased in old recipients both in vivo and in vitro when stimulated by antigen-presenting cells (APCs) from old mice, which also secreted more TNF-alpha and IL-12 after LPS stimulation. In a B6 --> B6D2F1 model, CD4(+) donor T cells but not CD8(+) T cells mediated more severe GVHD in old mice. We confirmed the role of aged APCs in GVHD using B6D2F1 BM chimeras created with either old or young BM. Four months after chimera creation, allogeneic BMT from B6 donors caused significantly worse GVHD in old BM chimeras. APCs from these mice also stimulated greater responses from allogeneic cells in vitro. These data demonstrate a hitherto unsuspected mechanism of amplified donor T cell responses by aged allogeneic host APCs that increases acute GVHD in aged recipients in this BMT model.     

异基因骨髓移植治疗慢性髓系白血病118例分析

目的 分析异基因骨髓移植治疗慢性髓系白血病患者长期存活的影响因素。方法采用ＴＢＩ 或改良ＢＵ／ＣＹ 预处理方案进行异基因骨髓移植，治疗慢性髓系白血病。１１８ 例患者中慢性期９１ 例，加速期１９ 例，急变期２ 例，第２ 次以上慢性期６ 例。结果 １０９ 例植活。慢性期和加速期患者的５ 年存活概率分别为６９ ．６ ％ 和５１ ．０ ％ ；５ 年复发概率分别为３ ．２ ％ 和１２ ．５ ％ 。结论 病期、预处理方案和脾大对植活时间无影响， 慢性期患者脾大与复发呈正相关； 两种预处理方案对慢性期患者移植效果的影响，差异无显著性。     

转IL-3基因骨髓基质细胞对异基因骨髓移植后小鼠造血重建的促进作用

目的　探讨转IL 3基因的小鼠骨髓基质细胞系QXMSC1对异基因骨髓移植 (allo BMT)小鼠造血功能的促进作用。方法　用重组逆转录病毒载体 (含小鼠IL 3cDNA)感染骨髓基质细胞系QXMSC1(H 2 d) ,构建骨髓基质细胞系QXMSC1IL 3,挑选表达量最高的骨髓基质细胞系QXMSC1IL 3用于以后实验。供体小鼠BALB c(H 2 d)骨髓用抗T细胞单抗anti Thy1.2加补体去除骨髓中T细胞。受体小鼠C5 7BL 6 (H 2 b)经γ射线致死量照射后 ,输入供体骨髓细胞 (1× 10 7 只 )的同时输入QXMSC1IL 3(5× 10 6 只 )细胞。在骨髓移植后第 2 0 ,4 0天 ,分别检测受体小鼠外周血红细胞、白细胞、骨髓有核细胞数 ,CFU S、CFU GM、CFU E和CFU GEMM数以反映骨髓移植后受体小鼠的造血功能。结果　QXMSC1IL 3细胞系可稳定分泌IL 3。allo BMT同时输入QXMSC1IL 3细胞可使allo BMT小鼠外周血红细胞、白细胞明显恢复 ,骨髓中有核细胞数、CFU S、CFU GM、CFU E、CFU GEMM明显增加。结论　基质细胞QXMSC1可作为有效的基因载体进一步促进allo BMT小鼠造血功能重建。     

Acute abdominal pain preceding cutaneous manifestations of varicella zoster infection after allogeneic bone marrow transplantation.

The current communication describes clinical findings in two recipients of allogeneic bone marrow transplantation (BMT) with varicella zoster virus infection who complained of acute severe abdominal pain preceding cutaneous manifestations. Physical examination, laboratory data and gastroscopic findings were nonspecific. In these cases, acyclovir was very effective for the symptoms. Varicella zoster virus infection should be suspected in BMT recipients who have rebellant acute abdominal pain but no characteristic skin eruptions.     

同种反应性自然杀伤细胞在小鼠主要组织相容性复合物半相合骨髓移植中的作用

目的研究同种反应性自然杀伤(NK)细胞在小鼠主要组织相容性复合物(MHC)半相合骨髓移植(BMT)中对宿主粒细胞和T细胞的清除、造血重建、植入及移植物抗宿主病(GVHD)的影响。方法以(C257BL／6×BALB／c)BCF_1(H-2~(d/b+))为供鼠,BALB／c(H-2~d)为受鼠建立小鼠MHC半相合BMT模型。根据照射剂量及NK细胞处理的不同将受鼠分为8．5 Gy对照组及7,6和5 Gy实验组。 8．5 Gy对照组进一步分为单纯照射组和BMT组,7,6及5 Gy实验组均进一步分为单纯照射组、BMT 组、非同种反应性NK(non-alloNK)细胞组及同种反应性NK(alloNK)细胞组。以外周血白细胞和血小板计数、受鼠型粒细胞及T细胞计数、H-2~(d/b+)细胞表达水平以及病理学检查等指标评价同种反应性 NK细胞的预处理作用。结果8．5 Gy单纯照射组生存期为(6．00±0．82)d,其他组生存期均大于60 d,各组均未观察到GVHD的临床及病理学表现;alloNK细胞组造血重建明显快于其他组(P值均< 0．05);移植后1天各照射剂量alloNK细胞组骨髓及脾细胞中受鼠型H-2~(d+)粒细胞和T细胞明显减少, 与相同照射剂量BMT组及non-alloNK细胞组比较差异有统计学意义(P值均<0．05);7,6和5 Gy alloNK细胞组供鼠H-2~(d/b+)细胞植入率显著高于相同照射剂量BMT和non-alloNK细胞组(P值均< 0．05)。结论alloNK细胞在小鼠MHC半相合BMT中具有清除受鼠体内残存粒细胞和T细胞、提高供鼠细胞植入和促进造血重建的作用,且不引起GVHD。     

Human mesenchymal stem cells are not of donor origin in patients with severe aplastic anemia who underwent sex-mismatched allogeneic bone marrow transplant

Stromal defects are part of the etiology of severe aplastic anemia (SAA), and hematopoietic engraftment is poor in unrelated and mismatched transplant. Therefore, we wanted to find out whether human mesenchymal stem cells (MSC) are partly of donor origin in patients with SAA years after successful bone marrow transplant (BMT). Three SAA patients 3, 5, and 8 years after BMT (cyclophosphamide, ATG) with bone marrow from an HLA-identical sibling donor of the opposite sex were investigated. MSC were grown from patients' bone marrow aspirates according to Caplan et al. The number of MSC that were isolated from SAA bone marrow post transplant was about 10 times lower than in normal controls. Primary cultures of adherent MSC and passage-one cells were analyzed by dual-color interphase fluorescence in situ hybridization (FISH) analysis using centromere-specific DNA probes for X and Y chromosome. FISH did not show any clear evidence of donor cells in the adherent MSC: In all cases, less than 0.5% of nuclei showed a donor-type signal pattern that is well within assay limits. In a female patient, the absence of male donor cells was confirmed by sensitive and quantitative, Y chromosome-specific TaqMan PCR (QYCS-PCR). In contrast, Ficoll-separated hematopoietic cells from the same aspirates were greater than 90% of donor origin, as expected. In SAA, as previously found in patients with lysosomal and peroxisomal storage disease, bone marrow MSC remain host-derived despite successful hematopoietic engraftment years after allogeneic BMT.     

Bone marrow processing with the AMICUS™ separator system

ABO incompatible bone marrow transplantation (BMT) requires processing of the donated bone marrow (BM), either erythrocyte depletion, or also a volume reduction. The AMICUS? system was introduced in the field of peripheral blood mononuclear cell collection, showing a good performance regarding efficiency and safety. To evaluate the performance of the MNC collection program of the Amicus device for BM, we analysed our data obtained from the Amicus and the Fenwal CS3000omnix? plus device. Methods: From 2005 to 2008, we performed 22 automated erythrocyte depletions of BM for ABO mismatched BMT in 21 patients, 11 with the Amicus (A; 10 patients) and 11 with the CS3000 (F; 11) device. Results: There were no statistical differences in donor age, recipient age, type of ABO mismatch, and CD34+ cell yield [group A pre 7.03 post 4.93 vs. group F pre 8.55 and post 6.2 × 10E06 cells per kilogram of bodyweight] for both devices. The efficiency for the CD34+ cell collection was lower, but not statistically significant, in the Amicus device (70% ± 12 vs. 84% ± 12; U‐test P = 0.123). The erythrocyte volume in the final product was higher but not statistically significant different in the Amicus device (9.46 ± 2.3 vs. 6.98 ± 3.3 ml; U‐test P = 0.17). During the evaluation period, no technical problems were observed. Allpatients but one, who died at d + 11, showed a sustained engraftment. Conclusions: We conclude that, in principle, the Amicus device can be used for MNC collection from BM to deplete erythrocytes from BM grafts in allogeneic stem cell transplantations. J. Clin. Apheresis 2011. © 2011 Wiley‐Liss, Inc.     

Extrathymic T Cell Deletion and Allogeneic Stem Cell Engraftment Induced with Costimulatory Blockade Is Followed by Central T Cell Tolerance

A reliable, nontoxic method of inducing transplantation tolerance is needed to overcome the problems of chronic organ graft rejection and immunosuppression-related toxicity. Treatment of mice with single injections of an anti-CD40 ligand antibody and CTLA4Ig, a low dose (3 Gy) of whole body irradiation, plus fully major histocompatibility complex–mismatched allogeneic bone marrow transplantation (BMT) reliably induced high levels (>40%) of stable (>8 mo) multilineage donor hematopoiesis. Chimeric mice permanently accepted donor skin grafts (>100 d), and rapidly rejected third party grafts. Progressive deletion of donor-reactive host T cells occurred among peripheral CD4⁺ lymphocytes, beginning as early as 1 wk after bone marrow transplantation. Early deletion of peripheral donor-reactive host CD4 cells also occurred in thymectomized, similarly treated marrow recipients, demonstrating a role for peripheral clonal deletion of donor-reactive T cells after allogeneic BMT in the presence of costimulatory blockade. Central intrathymic deletion of newly developing T cells ensued after donor stem cell engraftment had occurred. Thus, we have shown that high levels of chimerism and systemic T cell tolerance can be reliably achieved without myeloablation or T cell depletion of the host. Chronic immunosuppression and rejection are avoided with this powerful, nontoxic approach to inducing tolerance.     

Experience using bone marrow transplantation in the treatment of hematologic neoplasms and solid tumors

Between October 1983 and October 1985, 12 allogeneic bone marrow transplantations from HLA-identical siblings were performed for treatment of malignant disease (11 haemopoietic malignancies) or severe aplastic anaemia (1 case). All patients showed prompt and complete engraftment of donor cells on average around day 17 after transplantation. 10 patients are alive and well 50-760 days after transplantation, without any signs of recurrence and partly without immunosuppressive therapy. Two patients died, one due to relapse of the leukaemia, and one as a result of CMV interstitial pneumonia. Graft versus host disease was seen in 6 of the 12 patients. Additional immunosuppressive therapy was necessary in 4 of them. The incidence of idiopathic interstitial pneumonia in our group of patients was low (two cases). Also tested was an experimental protocol for the treatment of chemotherapy-resistant metastatic solid tumours. After removal of all clinically detectable tumour tissue by maximal surgical therapy in 5 patients, residual systemic metastases were treated by means of total body irradiation and high-dose cyclophosphamide, followed by autologous bone marrow transplantation with curative intention. Relapse occurred in 4 patients between day 100 and 720 after BMT bone marrow transplantation. Only one patient remains without sign of relapse.