ABO compatibility and acute graft-versus-host disease following allogeneic bone marrow transplantation

If ABO antigens/antibodies play any role in the pathogenesis of acute graft-versus-host disease (GVHD), one would expect the highest incidence of GVHD in recipients of minor ABO-mismatched grafts, followed by ABO-matched grafts, and the lowest incidence in major ABO-mismatched transplants. To test this hypothesis 174 patients receiving an HLA-identical allogeneic bone marrow transplant (BMT) for aplastic anemia (n = 32) or leukemia (n = 142) were analyzed for factors associated with acute GVHD. Variables analyzed included diagnosis, sex, age, blood group of donor and recipient, ABO compatibility, Rhesus compatibility, sex compatibility, number of bone marrow cells given at BMT, year of transplant, day of engraftment, and GVHD prophylaxis. We first carried out an exploratory contingency table analysis: minor ABO incompatibility was associated with a significantly higher risk of severe acute GVHD when compared with ABO-matched and major-ABO mismatched pairs (P = 0.003): 14/9, 57/67, and 5/22 patients developed, respectively, 0-I/II-IV acute GVHD in ABO major-mismatched, matched, and minor-mismatched pairs. Donors of group 0, (P = 0.06), older recipient's age (P = 0.08), fast engraftment (P = 0.03), and older donor's age (0.08) were also associated with a higher risk of GVHD. Recipient's ABO group, diagnosis, year of transplant, Rhesus group of donor or recipient, Rhesus compatibility, sex of donor or recipient, sex compatibility, and type of GVHD prophylaxis were not predictive of GVHD. A Cox multifactorial proportional hazards analysis confirmed that ABO matching was the single most significant factor associated with GVHD (P = 0.006). The cumulative incidence of GVHD grade II+ was 39%, 54%, and 82% for ABO major-mismatched, matched, and minor-mismatched pairs (P = 0.01). This study suggests that ABO antigens may play a role in the development of acute GVHD.     

Hypereosinophilia as a presenting sign of acute graft-versus-host disease after allogeneic bone marrow transplantation

The authors report two cases of hypereosinophilia as the major presenting sign of acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). Tissue biopsies of the skin, salivary gland, gut, and liver showed evidence of acute GVHD (aGVHD). In one case, further investigations have been performed. Elevated levels of interleukin (IL)-5 and soluble IL-2 receptor were found in the blood, and skin biopsy specimens demonstrated high levels of IL-5 messenger ribonucleic acid (mRNA). In contrast, skin biopsy specimens from other patients with aGVHD but without eosinophilia were negative for IL-5 mRNA. The authors also demonstrated the presence of IL-4 and interferon(IFN)-gamma mRNA within the same skin biopsy specimen, suggesting that this case of aGVHD was mediated by both Th1 and Th2 cell type. These two patients were treated by glucocorticoids with resolution of the hypereosinophilia and the symptoms of GVHD. The authors briefly discuss the possible mechanisms of this hypereosinophilia with respect to aGVHD.     

Pretransplant chemotherapy reduces inflammatory cytokine production and acute graft-versus-host disease after allogeneic bone marrow transplantation.

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is known to be a critical effector molecule in the pathogenesis of graft-versus-host disease (GVHD), and elevated levels during bone marrow transplantation (BMT) conditioning are associated with more severe GVHD. Many patients receive chemotherapy prior to BMT, but its effect on subsequent toxicities is controversial. METHODS: We studied the effect of prior chemotherapy on GVHD severity and inflammatory cytokine generation in a well-established murine model of allogeneic BMT (B6-->B6D2F1). RESULTS: Three weeks after a single dose of cyclophosphamide, bone marrow and splenic cellularity was reduced by 50% and the production of TNF-alpha to LPS stimulation by macrophages was also markedly impaired (both before and after total body irradiation). Allogeneic BMT recipients previously treated with cyclophosphamide had significantly less GVHD and improved survival relative to recipients previously pretreated with diluent only. This survival advantage was associated with reduced systemic levels of both TNF-alpha and interleukin-1beta 7 days after BMT. This reduction occurred despite equivalent serum levels of lipopolysaccharide, consistent with the reductions in TNF-alpha and interleukin-1beta production by host macrophages after cyclophosphamide pretreatment. CONCLUSIONS: These data support the notion that patients entering BMT conditioning without prior cytotoxic treatment (e.g., patients with chronic myeloid leukemia) may be at increased risk of posttransplant complications associated with excessive inflammatory cytokine production.     

Chronic graft-versus-host disease in rats after syngeneic bone marrow transplantation

A disease similar to the chronic graft-versus-host disease (cGVHD) seen following transplantation of human bone marrow was observed after syngeneic and allogeneic bone marrow transplantation in rats. Bone marrow grafts were exchanged between donors and recipients that were syngeneic or genetically different for the RT2 erythrocyte antigen locus by the use of AUG/AUG.2B and PVG/PVG.2A congenic pair donor/recipient strain combinations. After an initial period of well-being (120-180 days posttransplantation), several AUG and AUG.2B recipients of syngeneic or RT2-mismatched bone marrow developed clinical signs compatible with cGVHD. The clinical signs of the disease included: erythema, diffuse alopecia, thickened skin folds, and conjunctivitis. Laboratory findings included peripheral blood eosinophilia and impaired in-vitro proliferative responses to third-party spleen cells in the mixed lymphocyte reaction. Histological examination of the tissues of a limited number of rats with cGVHD showed subepidermal mononuclear inflammation with atrophy of the epidermis and adnexa of the skin, as well as plasmacytic hyperplasia of the lymphoid tissues. None of the PVG or PVG.2A recipients of syngeneic or RT2-mismatched marrow developed cGVHD. The development of cGVHD in AUG.2B recipients of syngeneic marrow and the absence of the disease in reciprocal marrow grafts between the PVG/PVG.2A rat strains suggests that the development of the disease in the AUG and AUG.2B recipients of RT2-mismatched bone marrow is not due to the RT2 disparity, but may be due to an autologous immune reaction. Furthermore, the finding that the cGVHD is only observed when the AUG and AUG.2B strains are used as recipients--not when the PVG or PVG.2A strains are used as recipients--suggests that the development of the disease is associated with the genetic background of the host and is independent of the background of the donor. It is possible that the use of high-dose cyclophosphamide treatment is involved in the pathogenesis of cGVHD, because the disease is observed only when the recipients are conditioned for transplantation with this immunosuppressive agent.     

High-dose methylprednisolone treatment for acute graft-versus-host disease after bone marrow transplantation in adults

High-dose methylprednisolone (HDMP) was used to treat 18 episodes of severe (grades III and IV) acute graft-versus-host disease (GVHD) that developed after allogeneic bone marrow transplantation in 12 patients with acute leukemia and in 2 with aplastic anemia. Most of the patients showed rapid improvement in GVHD, with complete resolution of the skin and gut manifestations. However, the response of liver disease to the treatment was slow and incomplete. Complications seen were interstitial pneumonia and fungal and viral infections. Seven patients survived for more than two months following the treatment of acute GVHD. Five of these became long-term survivors with a median survival of 22+ months (range 11-38 months); all five long-term survivors developed chronic GVHD and are alive at the time of this report. It appears that HDMP is an effective treatment for severe acute GVHD. However, its true efficacy can only be ascertained in a randomized study comparing high-dose and conventional-dose methylprednisolone.     

Obstructive lung disease after allogeneic bone marrow transplantation

We report the cases of 3 patients with marked dyspnea and an obstructive ventilation disorder associated with chronic graft-versus-host disease after allogeneic bone marrow transplantation. This disorder was characterized by recurrent pulmonary infections and colonization of the lower respiratory tract by Pseudomonas aeruginosa. Two patients have shown rapidly progressive deterioration with death following due to respiratory failure. Intensive therapy with antibiotics, bronchodilators, high-dose steroids, and azathioprine was not effective in arresting the malignant course of this disorder.     

A chronic pulmonary syndrome associated with graft-versus-host disease after allogeneic marrow transplantation.

Of 143 consecutive patients who survived at least 6 months after bone marrow transplantation (allogeneic [n = 131]; syngeneic [n = 5]; or autologous [n = 7]) and whose pulmonary function was evaluated before and on at least 2 occasions after BMT, 29 (20%) developed a chronic pulmonary syndrome without evidence for an infectious etiology. Twenty-eight (97%) presented with cough and 22 (76%) with dyspnea; abnormal chest signs were crackles in 23 (79%) and wheeze in 22 (76%). Chest roentgenogram showed pulmonary infiltrates in 15 (52%) cases but was normal in 14 (48%). All patients had major reductions in lung volumes (forced expiratory volume in 1 sec [FEV1]; relaxed vital capacity [VC]; and alveolar volume [VA]), and/or diffusing capacity (pulmonary diffusing capacity [TLCO] and single-breath carbon monoxide coefficient [KCO]). The obstructive component varied with only 18 (62%) patients developing overt airways obstruction (FEV1/VC < 75%), and in 6 of this group the fall in lung volumes preceded the onset of airways obstruction. Open lung biopsy (n = 4) showed both bronchiolitis obliterans and chronic patchy interstitial pneumonitis. The development of this syndrome was associated with acute (P < 0.001) and chronic (P < 0.0001) graft-versus-host disease of other organ systems. Twenty-four (83%) patients had a partial or complete response to immunosuppressive agents. Six (21%) have died, five (17%) of pulmonary complications. We suggest that this syndrome may be a manifestation of chronic GVHD involvement of the lung.     

Pemphigoid-like ocular lesions in patients with graft-versus-host disease following allogeneic bone marrow transplantation

We present two patients who developed keratitis sicca and pemphigoid-like symptoms following allogeneic bone marrow transplantation (BMT). The diagnosis of ocular graft-versus-host disease (GvHD) was considerably delayed in both. They were admitted to the reference ophthalmology and posttransplant care departments years after allogeneic BMT, when skin biopsy revealed changes typical for chronic GvHD. In both cases either systemic or local immunosuppressive treatment led to improvement of the clinical condition but did not significantly change patients' quality of life.     

利用脊柱骨来源骨髓细胞建立急性移植物抗宿主病模型

目的探讨利用脊柱骨来源骨髓细胞建立小鼠异基因造血干细胞移植(allogeneic hematopoietic stem cell transplantation,Allo-HSCT)急性移植物抗宿主病(aGVHD)模型的可行性。方法选择C57BL/6(H-2b)雄性小鼠为供体鼠,BALB/c(H-2d)雌性小鼠为受体鼠。制备供体鼠的脾细胞和脊柱骨来源骨髓细胞悬液。受体鼠采用药物加小剂量辐照的预处理方式,于移植前8d～移植前4d腹腔注射氟达拉滨(200mg/kg),接着移植前3d～移植前1d腹腔注射环磷酰胺(60mg/kg),最后在移植前进行全身照射(total-body irradiation,TBI),照射剂量为4Gy(戈瑞)。18只受体鼠经预处理后随机分为3组,每组6只:(1)骨髓移植组,只输入1×107个脊柱骨来源骨髓细胞;(2)aGVHD组,输注1×107个脊柱骨来源骨髓细胞和5×106个脾细胞,建立aGVHD模型;(3)空白对照组,不输入任何细胞。观察3组小鼠生存状态及存活率,取aGVHD组与骨髓移植组存活21d的受体鼠进行病理学检查,取aGVHD组移植后21～28d存活的小鼠的脾脏进行流式细胞术检测骨髓细胞嵌合度。结果骨髓移植组小鼠全部存活,可重建造血,单纯输注骨髓细胞不会诱发aGVHD。aGVHD组小鼠出现aGVHD表现,100%发生aGVHD相关死亡,中位生存期为18d;病理检查结果显示符合aGVHD病理表现,移植后21～28d存活的小鼠诊断为供受体混合嵌合状态,符合aGVHD诊断标准。结论用脊柱骨来源骨髓建立的aGVHD模型完全符合标准,且更加经济,适合大规模建模。     

Six weeks of continuous intravenous cyclosporine and short-course methotrexate as prophylaxis for acute graft-versus-host disease after allogeneic bone marrow transplantation

The feasibility and toxicity of six-week continuous intravenous 3 mg/kg/day cyclosporine (CsA) treatment in conjunction with a short course of methotrexate (MTX) was studied in 69 consecutive patients after HLA genotypically identical bone marrow transplantation. In light of the uncertain efficacy of prolonged oral CsA immunoprophylaxis in preventing de novo chronic graft-versus-host disease (GVHD). CsA treatment was terminated three months after BMT. Sixty-one (88%) patients received the full intravenous regimen and no patient exclusions were necessary due to intolerable adverse effects. Weekly median blood CsA concentrations ranged between 820 ng/ml in the first and 648 ng/ml in the sixth week of treatment. No significant correlation existed between blood CsA concentrations and CsA dosages. Major adverse effects of the regimen included hypertension in 36%, acute nephrotoxicity in 36%, acute hepatotoxicity in 41%, and central nervous system toxicity in 4% of the patients. Since hepatotoxicity occurred predominantly in the early posttransplant period (median onset day 9), the relatively high incidence of this untoward effect might have been additionally caused by MTX and/or the preparative regimen. Blood CsA concentrations and CsA dosages did not significantly correlate with serum creatinine or total and conjugated bilirubin levels. In addition, blood CsA and serum creatinine levels did not differ between hypertensive and normotensive patients. Acute GVHD developed in 16% of the patients. Median CsA doses and blood CsA concentrations were identical for each week after BMT for patients contracting acute GVHD as compared with those without acute GVHD. In 55 patients surviving without acute or secondary chronic GVHD, the cumulative probability of de novo chronic GVHD after termination of CsA treatment was 13%. In conclusion, this regimen was tolerable and provided constant blood CsA concentrations for six posttransplant weeks that were not adversely influenced by the development of acute GVHD. Restriction of CsA treatment to the first three months after BMT appeared not to increase the risk of de novo chronic GVHD, which challenges regimens employing oral CsA immunoprophylaxis for 6-12 months after BMT.