CD16- CD56+ natural killer cells after bone marrow transplantation.

Natural killer (NK) cells are phenotypically defined as lymphocytes expressing the antigens CD56 and mostly CD16 (Fc gamma RIII), but lacking CD3. A small CD3- CD16- CD56+ NK cell subset has been described in normal individuals representing less than 2% of peripheral blood lymphocytes. We analyzed here 70 patients for their reconstitution of the immune system during follow-up after autologous or allogeneic bone marrow transplantation. In 35% of these patients, two different NK cell subsets, namely CD56+dim and CD56+bright cells, were observed. The mean duration of these two subsets after transplant was 4 months. Sixty-five percent of the patients exhibited an increased number of NK cells, but only the typical CD16+ CD56+dim population. The CD56+bright subpopulation represented a particular CD3- CD16- NK subset, with posttransplant frequencies up to 70% of all NK cells and 40% of peripheral blood lymphocytes, respectively. In contrast to normal CD56+dim NK cells, CD56+bright cells coexpressed the activation antigens p75 beta-chain of interleukin-2 receptor (IL-2R), CD2R, and CD26, but were negative for CD16. NK and antibody-dependent cellular cytotoxicity activity of CD56+bright cells was low compared with CD56+dim NK cells. But using IL-2 and interferon gamma, their cytotoxicity could be enhanced even more than in CD56+dim lymphocytes. These different subsets may reflect distinct activation or differentiation steps of NK cells during reconstitution of the immune system. Their differential response to IL-2 may be of functional importance for posttransplant cytokine therapy.     

Aspergillosis in bone marrow transplant recipients

Invasive aspergillosis in bone marrow transplant recipient is associated with a high mortality. Diagnosis is often delayed because the inflammatory response is blunted by immunosuppression. The gold standard of tissue biopsy is often considered too in invasive as the procedure is often complicated by bleeding and secondary infection. Recent finding on non-invasive tests such as serial measurement of peripheral blood galactomannan antigen or DNA appears to be promising. However, the limited availability of such tests and requirement for expertise are still hampering their use in routine clinical management. More often than not, initiation of antifungal therapy is empirical and based on suggestive radiological changes. Amphotericin B remains the gold standard of therapy but liposconal preparation may prove to be less nephrotoxic and equally effective. Treatment outcome depends more on the acceleration of the recovery of the immune system and the reduction of anti-GVHD therapy than the antifungal agent followed by surgical resection. The efficacy of many reported anti-aspergillosis prophylactic regimen has not been proved in randomized control trials. Despite the absence of data, such policy should still be considered in transplant units with high incidence of aspergillus or undergoing renovation.     

Cytogenetic studies in bone marrow transplant recipients

Summary Chromosome studies were performed in 24 patients who underwent allogeneic bone marrow transplantation (BMT) for severe aplastic anaemia (8), chronic myeloid leukemia (5 in chronic, 2 in accelerated phase and 1 in lymphoid blast crisis), acute myeloid leukemia (6), acute lymphoblastic leukemia in relapse (1) and Hodgkin's disease (1). Donor-cell type engraftment was demonstrated in 21 patients: in all 17 sex-mismatched transplants and — as demonstrated by reconstitution with Ph-negative cell populations — in 4 CML patients with a sex-matched donor. Recipient-type mitoses were seen in the bone marrow of 5 cases (1 SAA, 3 CML, 1 AML) after transplantation. They were only observed on one occasion in patients with SAA (4 of 25 on day 33) and AML (44 of 50 on day 14). Despite the continued demonstration of some Ph-positive mitoses in 3 patients with CML up to day 28, 323 and 451 after BMT, respectively, all surviving CML patients are still in complete haematological and clinical remission. So far the significance of these cytogenetically abnormal persisting host cells remains unknown. Present address: Roswell Park Memorial Institute, Department of Genetics and Endocrinology, 666 Elm Street, Buffalo, NY 14 222, USA     

Candida infections in bone marrow transplant recipients

We studied the incidence, outcome and risk factors for systemic Candida infection in 665 recipients of allogeneic, syngeneic and autologous bone marrow transplantations (BMT) between 1979 and 1987. Systemic Candida infection, defined as occurrence of one or more positive blood or CSF cultures for Candida sp., or presence of Candida sp. in culture or biopsy of deep tissue, was detected in 76 patients (12.5%) in the first year following BMT. Candida infection was independently associated with increasing age (p less than 0.0001), detection of one or more positive surveillance cultures for Candida sp. (p less than 0.0001), increased duration of granulocytopenia (p = 0.0005) and total body irradiation as part of the preparative regimen compared with chemotherapy only or chemotherapy and total lymphoid irradiation (p = 0.02). Other patient characteristics including underlying disease, origin of graft, recipient sex, graft-versus-host disease (GVHD) prophylaxis and occurrence of acute GVHD or chronic GVHD were not independently associated with Candida infection following BMT: 60/76 patients with Candida infections have died, and in 19/60 cases death could be directly attributed to Candida infection. Awareness of the serious nature and the risk features for Candida infections may be useful in developing strategies of prevention and treatment.     

TT virus in bone marrow transplant recipients

TT virus (TTV) is a newly discovered transfusion-transmissible DNA virus, which may cause posttransfusion hepatitis. The virus was detected in 12% of Japanese blood donors. The aim of the study is to investigate the prevalence and clinical influence of TTV in bone marrow transplant (BMT) recipients. Sera from 25 BMT recipients obtained 6 to 12 weeks after the transplant were examined for TTV-DNA by the seminested polymerase chain reaction. Serial samples were additionally analyzed in patients with TTV-DNA. Fifteen of 25 recipients (60%) were positive for TTV-DNA after transplant, whereas it was detected in only two of 20 BMT donors (10%). In patients positive for TTV-DNA before BMT, the amount of TTV-DNA decreased to an undetectable level during the myelosuppressed period after BMT. We also found that there was a novel group of TTV, G3, classified by the nucleotide sequences. The median peak alanine aminotransferase (ALT) levels were 135.0 IU/L and 116.5 IU/L (normal range, 4 to 36 IU/L) in TTV-positive and TTV-negative recipients, respectively. In one of the seven TTV-positive patients who developed hepatic injury (ALT > 150 IU/L), a serial change in the serum TTV titer showed a good correlation with the ALT level. We concluded that (1) the prevalence of TTV is high in BMT recipients, (2) TTV might be replicated mainly in hematopoietic cells, (3) transfusion-transmitted TTV may cause persistent infection, (4) a novel genetic group of TTV, G3, was discovered, and (5) TTV does not seem to frequently cause hepatic injury, although one patient was strongly suggested to have TTV-induced hepatitis.     

Lymphokine profile in bone marrow transplant recipients

Immune reconstitution after bone marrow transplantation (BMT) recapitulates immune ontogeny. At birth there is an imbalance in lymphokine production, with decreased production of interferon-gamma (IFN-gamma) compared with interleukin-4 (IL-4) and IL-2. We investigated whether a similar imbalance in lymphokine production occurs in BMT recipients within 6 months after transplantation. Our results show that BMT recipients not treated with immunosuppressive drugs have a decrease in IFN-gamma production and IL-2, in comparison with IL-4. This imbalance was likely to result from impaired signal transduction through surface receptors, because it was detectable on stimulation with Concanavalin A (ConA), but was overcome completely or largely by stimulation with phorbol myristate acetate (PMA) + ionophore, which bypass surface receptors and mimic the effects of second messengers. In contrast, lymphokine production in patients treated with immunosuppressive drugs (cyclosporine A, corticosteroids) was abnormal after stimulation with PMA and ionophore, as well as ConA. Thus, treated BMT recipients exhibit an additional deficit, which affects the signaling cascade down-stream of second messenger generation and results in impaired lymphokine production.     

Aspergillus infections in bone marrow transplant recipients

Aspergillus infection was studied in patients admitted to the Bone Marrow Transplant (BMT) Service at the Johns Hopkins Oncology Center during a 9-year period. The overall incidence was 4% in 549 patients reviewed. The incidence at autopsy was 12% (21 of 174 patients autopsied). There was no difference in frequency of occurrence in allogeneic compared to autologous BMT recipients. However, all infections in autologous BMT patients (5 of 5) occurred during neutropenia before engraftment. In contrast, 16 of 17 infections in allogeneic BMT patients occurred after engraftment (p = 0.0002). This difference presumably related to differences in duration of neutropenia and immunodeficiency. Age, underlying disease, date of BMT, preparative regimen, remission status, prior treatment, interstitial pneumonitis and concomitant cytomegalovirus infection did not predispose patients to aspergillus infection. Different post-BMT immunosuppressive regimens did not affect the risk for aspergillus infection except that patients who were given cyclophosphamide plus methylprednisolone had a higher incidence of aspergillus infection than those given methotrexate (12% versus 1%, p = 0.03). Acute graft-versus-host disease imposed a slight risk for infection (p = 0.06).     

CD16+ CD56- NK cells in the peripheral blood of cord blood transplant recipients: a unique subset of NK cells possibly associated with graft-versus-leukemia effect

A marked increase in CD16+ CD56- NK cells in the peripheral blood (PB) was observed in a cord blood transplant (CBT) recipient with refractory acute myeloid leukaemia (AML) in association with attaining molecular remission. CD16+ CD56- NK cells isolated from the patient became CD16+CD56+NKG2D+ when they were cultured in the presence of IL-2. Although cultured CD16+CD56- NK cells retained the killer-cell immunoglobulin receptor (KIR)-ligand (KIR-L) specificity and the patient's leukemic cells expressed corresponding KIR ligands, they killed patient's leukemic cells expressing ULBP2. The cytotoxicity by cultured CD16+CD56- NK cells was abrogated by anti-ULBP2 antibodies. When leukemic cells obtained at relapse after CBT were examined, both the ULBP2 expression and susceptibility to the cultured NK cells decreased in comparison to leukemic cells obtained before CBT. An increase in the CD16+CD56- NK cell count (0.5 x 10(9)/L or more) in PB was observed in seven of 11 (64%) CBT recipients but in none of 13 bone marrow (BM) and eight peripheral blood stem cell (PBSC) transplant recipients examined during the similar period after transplantation. These findings suggest an increase in CD16+CD56- NK cells to be a phenomenon unique to CBT recipients and that mature NK cells derived from this NK cell subset may contribute to the killing of leukemic cells expressing NKG2D ligands in vivo.     

Tuberculosis among allogeneic bone marrow transplant recipients in India.

Allogeneic bone marrow transplant recipients have severe impairment of cell-mediated immunity and hence a higher incidence of mycobacterial infections might be expected in regions where tuberculosis is common. We reviewed the case records of 217 patients who underwent allogeneic bone marrow transplantation during the period 1986-1999 at our center in India. Mycobacterial infections were diagnosed in three patients (1.38%). All patients presented with extrapulmonary disease. Two patients had disseminated tuberculosis with one of these being diagnosed on autopsy studies. The third patient had tuberculosis involving the cervical lymph node and dorsal spine. Two patients treated with antituberculous therapy are well. Infection with Mycobacterium tuberculosis is not a common problem in allogeneic bone marrow recipients even in an endemic area, but when it occurs, it is usually disseminated with predominantly extrapulmonary involvement.     

Invasive mold infections in allogeneic bone marrow transplant recipients.

Invasive mold infections (IMIs) are an important cause of morbidity and mortality in patients who are undergoing bone marrow transplantation (BMT). To examine the epidemiology, risk factors, and outcome of IMIs in allogeneic BMT recipients, all cases of mold infection among 94 adult patients who underwent allogeneic BMT at this institution from 1 January 1997 through 31 December 1998 were reviewed retrospectively. Fifteen cases of IMI were identified; infection occurred a median of 102 days after BMT. Aspergillus species was the most common cause of disease, and species other than Aspergillus fumigatus were present in 53% of patients. By multivariate analysis, the variable associated with infection risk was systemic glucocorticosteroid use. Prophylactic antifungal therapy that was targeted to high-risk patients had little effect on disease incidence. These observations suggest that early identification of high-risk patients and better approaches to prevention should be explored, to reduce incidence and severity of disease in this population.     

Functional analysis of the CD8+CD57+ cell population in normal healthy individuals and matched unrelated T-cell-depleted bone marrow transplant recipients

The biological activities of CD8+ that co-express CD57 remain poorly defined. It is unclear whether all CD8+ cells have the potential to become CD57+ or whether they represent a unique subset with distinct functions. Several studies have reported the association between elevated numbers of CD8+CD57+ and a wide range of clinical disorders such as viral reactivation of human cytomegalovirus (HCMV). In this study, we have investigated the relationship between viral reactivation and the effect of diminished interleukin (IL)-2 production. Using CD8+ cells isolated from patients at various times after allogeneic transplants and in vitro models of HCMV infection, we determined their combined effect on CD8+CD57+. Our results show that high numbers of CD8+CD57+ correlated with diminished killing of HCMV-infected targets. In addition, we showed a synergistic effect between IL-2 and HCMV in the expansion of CD8+CD57+ cells. Furthermore, these cells after anti-CD3 stimulation did not produce tumour necrosis factor (TNF)-alpha or interferon (IFN)-gamma. Interestingly, IL-10 production was elevated in several patients which appeared to be associated with the time from transplant.     

Cytomegalovirus immune plasma in bone marrow transplant recipients

The effects of passive immunization on cytomegalovirus infection and interstitial pneumonia in marrow transplants were evaluated in a randomized, controlled trial. Twenty-four patients received cytomegalovirus immune plasma before and after transplantation, and 24 patients were controls. Although the incidence of cytomegalovirus infection was similar in the control and plasma groups, symptomatic infection (12 of 24 versus five of 24, p = 0.07) and interstitial pneumonia (11 of 24 versus five of 24, p = 0.12) occurred less frequently in the group receiving plasma. Cytomegalovirus infection occurred in 11 of 13 recipients of leukocyte transfusions and in 16 of 35 patients not given leukocyte transfusions (p = 0.02). Among patients not given leukocyte transfusions, the incidence of cytomegalovirus infection was similar in the control and plasma groups, but symptomatic infection (eight of 18 versus one of 17, p = 0.03) and interstitial pneumonia (nine of 18 versus one of 17, p = 0.01) were significantly less in the group receiving plasma. These results suggest that passive immunization modifies cytomegalovirus infection in humans and prevents interstitial pneumonia in marrow transplants especially when leukocyte transfusions are not used.     

Early measles vaccination in bone marrow transplant recipients

Measles vaccination has been recommended after the second year following bone marrow transplant (BMT) in patients not receiving immunosuppressive drugs. During a measles outbreak, we vaccinated all patients after the first year of transplant, and conducted a prospective trial to evaluate safety, effectiveness and sustained immunity after early vaccination. Patients received attenuated virus vaccine between 9 and 18 months after BMT. A total of 51 patients were evaluated and 27 of them (52.9%) were receiving immunosuppressive drugs. Only mild adverse reactions were noted. Nine patients (17.6%) were susceptible (IgG< or =100 mIU/ml) at vaccination, and all seroconverted. In those immune at vaccination, a four-fold increase in measles IgG titers was found in one of 34 patients (2.9%) with specific IgG> or =200 mIU/ml compared to 14 of 17 (82.3%) with IgG<200 mIU/ml (P< 0.0001). Sustained immunity after 24 months was more likely to occur in patients with specific IgG levels< or =200 or > or =500 mIU/mL (83.4 and 100%, respectively) in comparison to patients with 200相似文献   

Abnormal cervical cytology in bone marrow transplant recipients

Particular human papillomavirus (HPV) subtypes are implicated in the genesis of abnormal cervical cytology and cervical cancer. While most immunocompetent hosts clear HPV infection with no sequelae, some develop premalignant cytological changes of whom a minority subsequently progress to overt carcinoma. Immunocompromised patients, such as renal allograft recipients and HIV-infected individuals, have a higher rate of cytological abnormalities. This is thought to be due to prolonged persistence of virus due to impaired clearance by the immune system. We undertook a retrospective review of the cervical cytology of all women who underwent BMT at two transplant centres and who had cervical smears performed between 1990 and 1998. The rate of cytological abnormalities was significantly higher than in the general population before BMT (age-adjusted odds ratio (OR) 2.2, P = 0.02) and after BMT (OR 7.0, P < 0.0001). After BMT, allogeneic recipients had a higher rate of abnormalities than did autologous patients (OR 2.6, P = 0.02) although only allogeneic recipients had a higher rate of abnormalities post-BMT compared to pre-BMT (allogeneic OR 6.8, P = 0.004). These observations suggest that pre-transplant disease and treatment factors increase the risk of cytologic abnormalities and that transplant-related factors such as conditioning therapy and immunosuppression further increase this risk. These data suggest that more frequent screening may be required in these at-risk groups, especially allogeneic recipients. Prospective studies are required to further evaluate cytological abnormalities and HPV shedding in these populations.     

Catheter-related right-sided endocarditis in bone marrow transplant recipients

Bone marrow transplant recipients are at increased risk of severe central venous catheter-related septicemias that may be complicated by endocardial infection. In view of this, we prospectively evaluated 141 consecutive patients receiving allogeneic or autologous bone marrow infusion. Seven (5%) of 141 patients developed eight episodes of a clinical syndrome compatible with catheter-related right-sided infective endocarditis; this diagnosis was confirmed at autopsy in two patients who died. Staphylococcus epidermidis was the most frequent isolate (four cases). Other offending pathogens were, in one case each, Enterococcus faecalis, Corynebacterium jeikeium, Pseudomonas alcaligenes, and Achromobacter xylosoxidans plus Candida species. Three- to 7-week courses of antibacterial therapy were associated with a favorable outcome in six of the seven cases. Infective endocarditis may be a complication of the use of central venous catheters and should be actively sought in septicemic bone marrow transplant recipients.     

Preventing opportunistic infections in bone marrow transplant recipients

In 1996, a Center for Disease Control and Prevention (CDC)-sponsored working group began developing guidelines for preventing opportunistic infections (OIs) in bone marrow transplant (BMT) recipients. The purposes of the guidelines are to: a) summarize current data regarding the epidemiology of OIs in BMT recipients; b) produce an evidence-based statement of recommended strategies for preventing OIs in BMT recipients; c) decrease the incidence, morbidity, and mortality of OIs in BMT recipients; and d) define directions for future OI prevention research. Each recommendation is given two ratings: one indicating the strength of the recommendation, and another indicating the strength of evidence supporting the recommendation. The target audience for the guidelines includes transplant and infectious disease physicians and BMT unit and clinic staff. The BMT OI guidelines include sections on viral, bacterial, fungal, protozoal, and helminth infections, immunization, infection control, and blood and stem cell safety. The disease-specific sections address preventing exposure and disease among both adult and pediatric recipients of allogeneic and autologous BMTs. The immunization section addresses: a) immunization of BMT recipients, their household contacts, and health care workers; b) travel immunizations for BMT recipients; and c) passive immunization with immune globulin products. The infection control sections address room ventilation, isolation and barrier precautions, and prevention of nosocomial and other infections (e.g. infections acquired from visitors, plants, food, pets, construction sites, etc.). The blood safety section contains recommendations on preventing transmission of infections to BMT recipients from infected donated cells. After the guidelines are made available for public comment, they will be finalized and published in the Morbidity and Mortality Weekly Report and placed on the CDC web site ( Note Presented in part at the First World Congress of Transplant Infectious Disease, 1–4 April 1998, Orlando, Florida.
).