Graft-versus-leukaemia activity associated with cytomegalovirus antibody positive bone marrow donors in acute myeloid leukaemia.
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Antibodies, Viral↗
Biomedical subjects
N Jacobsen
Publications and source records attributed to N Jacobsen.
The immunodeficiency of bone marrow-transplanted patients. II. CD8-related suppression by patient lymphocytes of the response of donor lymphocytes to mitogens, antigens, and allogeneic cells.
Lymphocytes from 21 patients sampled 1-6 months after bone marrow transplantation (BMT) were tested for functional suppressor activity against marrow-donor lymphocytes in the lymphocyte transformation test. Suppression of donor responses to allogeneic (i.e. mixed lymphocyte reaction, MLR) and antigenic stimulation by irradiated (7600 rad) post-BMT cells was observed in about two-thirds of the combinations tested (N = 20 and N = 9). The suppression of donor MLR and antigen responses ranged between 5-52% and 10-46%, respectively. Irradiated post-BMT cells significantly suppressed donor responses to suboptimal concentrations of phytohaemagglutinin (PHA) (median suppression: 28%; P less than 0.05; N = 7) and concanavalin A (Con A) (median suppression: 31%; P less than 0.05; N = 6). A clearly suppressive effect of post-BMT cells was observed when the ratios of CD4+/CD8+ post-BMT cells were lower than 0.5 (P less than 0.01). In three experiments, the depletion of the CD8- but not of the CD4-positive subset abrogated the suppression of the donor MLR by post-BMT cells. The suppression by post-BMT cells (irradiated) of MLR and mitogen responses was comparable whether the responding cells were derived from the donor or from HLA-DR-incompatible, unrelated individuals. The proliferative capacity of post-BMT cells compared to that of donor cells was assayed in the MLR with unrelated, HLA-DR-incompatible stimulator cells. A significantly decreased proliferative capacity (median 20% of that of donor cells) was found (P less than 0.01; N = 16). A weak inverse correlation (P less than 0.05; N = 16) between the proliferative and the suppressive capacity of post-BMT cells in the MLR was observed. These findings indicate that the decreased proliferative capacity upon mitogen, antigen, and alloantigen stimulation observed in most patients within 1-6 months after BMT may be partly due to non-specific suppression by CD8+ cells.
Adolescent↗
Increased frequency of HLA-DPw3 in severe aplastic anemia (AA).
Thirteen patients with severe aplastic anemia (AA) were HLA-DP typed using primed lymphocyte typing (PLT). The frequency of HLA-DPw3 was significantly increased to 69% in AA as compared to 22% in 160 controls (p less than 0.001; corrected p less than 0.01, RR = 8.0).
Adolescent↗
HLA-DP and bone marrow transplantation: DP-incompatibility and severe acute graft versus host disease.
Thirteen recipients of HLA-haploidentical, DR compatible bone marrow (BM) and the corresponding BM donors were HLA-DP typed using primed lymphocyte typing (PLT). Severe acute GVHD (greater than or equal to grade 2) developed within 3 months after BM-transplantation in all of eight recipients of DP incompatible BM, but in none of five recipients of DP-compatible BM. This difference was highly significant (p less than 0.001, Fisher's exact test). Moreover, severe acute GVHD was significantly increased in recipients of haploidentical, DR compatible, but DP incompatible BM as compared to severe acute GVHD in 88 recipients of HLA-identical BM (p less than 0.0001). In contrast, there was no difference in acute GVHD between recipients of haploidentical, DR and DP compatible BM and recipients of HLA-identical BM. The data presented here provide strong evidence for the first time that HLA-DP antigens play a role as transplantation antigens.
Bone Marrow Transplantation↗
Graft-versus-leukaemia activity associated with cytomegalovirus seropositive bone marrow donors but separated from graft-versus-host disease in allograft recipients with AML.
To elucidate whether a relationship existed between bone marrow donor cytomegalovirus (CMV) immune status and the probability of staying in remission after transplantation, a retrospective multicentre analysis was performed in 69 patients who received allogeneic bone marrow transplantation during relapse or second remission of AML, or second remission of ALL. None of 12 AML patients with CMV seropositive donors had posttransplant relapse, in contrast to 7 of 10 AML patients with seronegative donors. Kaplan-Meier estimates of the 2-yr probability of staying in remission for the two groups were 100% and 0%, respectively (p less than 0.0005). This effect was independent of disease stage, donor and recipient age, recipient pretransplant CMV immune status and the occurrence of posttransplant CMV infection in recipients, and was not mediated through an increased occurrence of overt graft-versus-host disease (GvHD) in recipients with CMV seropositive donors. The increased probability of staying in remission was associated with an increased probability of 3-yr disease-free survival (p less than 0.01). No similar effect was observed in patients with ALL. This study may suggest an allograft-versus-leukaemia effect in AML, associated with CMV seropositive donors, which seems separate from GvHD and independent of the occurrence of posttransplant CMV infection.
Adolescent↗
The metabolism of 2,5-diphenyloxazole (PPO) in human lymphocytes and rat liver microsomes.
The oxidative metabolism of 2,5-diphenyloxazole (PPO) is associated with 3-methylcholanthrene inducible cytochrome P-450. The major metabolite formed has m/z of 237, corresponding to hydroxylated PPO. All the possible hydroxylated metabolites of PPO were synthesized and characterized, enabling the assignment of a structure for the major metabolite and two minor metabolites. The metabolites are easily extracted and their fluorescence is quantifiable in alkaline medium with a sample fluorescence to blank fluorescence ratio of 400:1. A sensitive HPLC assay of PPO metabolism was also developed. PPO metabolism is readily catalyzed by 3-methylcholanthrene-induced rat liver microsomes and strongly inhibited by alpha-naphthoflavone, but poorly inhibited by metyrapone or SKF 525A, indicating the involvement of cytochrome P-448 or P1-450 in the metabolism of PPO. With human lymphocytes the method has proven to be a good indicator of "aryl hydrocarbon hydroxylase" (AHH) activity, correlating well with AHH assays using benzo(alpha)pyrene (BP) as a substrate. Both the induced BP and PPO metabolism by human lymphocytes is inhibited by alpha-naphthoflavone, but not by metyrapone.
Animals↗
Admission level and students' performance at a Norwegian dental school.
Data on students' performance at the Oslo Dental Faculty for 1977-86 were divided in two 5-year periods and analyzed in accordance with admission levels, largely on the basis of academic performance in junior college. During these years admission level decreased considerably, whereas the frequency of 'not passed', 'dropouts', and candidates using prolonged student time increased. The dental school grade average and the distribution of high- and low-performance candidates varied with the admission level. This trend was visible most clearly in the first 5-year period, when the admission point range included a considerable number of high admission level students. However, the admission level was not a good predictor of students' performance in the large middle or low admission level groups prominent in the second 5-year period. Poor preclinical results were not compensated for by clinical skills. All comparison of students' performance gave results in favor of the female students, but no sex-related differences were statistically significant. Most dropouts left dental school during the 1st year without visible examination difficulties. Students with several 'not passed' tended to repeat examinations, dropping out at a later stage or graduating after prolonged student time with poor results. With low interest in odontology, selection of students on the basis of minute differences in academic performance in the lower admission point scale is of limited value as a predictor of students' performance.
Achievement↗
Strict protective isolation in allogenic bone marrow transplantation: effect on infectious complications, fever and graft versus host disease.
Complete microbial decontamination (laminar air flow room, sterile nursing and oral administration of cefamandole, gentamicin and nystatin) was carried out in 65 consecutive patients prior to allogeneic BMT for leukaemia (n = 58) or aplastic anaemia (n = 7). Very few microorganisms persisted during the post-transplant treatment period, and the gut became sterile in all except for Candida in 11 patients. Six uncomplicated septicaemias, all with persistent organisms simultaneously present in the mouth (Pseudomonas 3, Serratia 1, Candida 2) occurred during a total of 1,360 days with granulocyte counts less than 0.5 X 10(9)/l. Post-transplant fever occurred in 52 patients, exceeding 40 degrees C in 25. Guided by the surveillance cultures only 46% of 43 unexplained febrile reactions were treated with systemic antimicrobials. Significant acute graft versus host disease (AGVHD) occurred in 14 (27%) of 52 patients receiving standard prophylaxis and HLA-matched grafts; immunosuppressive treatment was needed in 8 cases (16%). Thus, the additional costs of total microbial decontamination appear partially regained by a decreased morbidity and a reduced need for antimicrobial and immunosuppressive treatment, although neither fever nor AGVHD could be prevented.
Adolescent↗
[Treatment of sensitive dentin using acupuncture].
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Acupuncture Therapy↗
Defective monocyte function in Legionnaires' disease complicating hairy cell leukaemia.
We describe a case of Legionnaires' disease in a 64-year-old man, in which hairy cell leukaemia was diagnosed after the onset of the infection. Immunological studies revealed a complete suppression of blood monocyte chemotactic and oxidative burst activities. We suggest that in hairy cell leukaemia both monocytopenia and defective functions of monocytes underlie the increased susceptibility to intracellular infections including Legionnaires' disease.
Diabetes Mellitus, Type 2↗
Interaction between cyclosporin A and phenobarbitone.
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Anemia, Aplastic↗
Correlation between donor cytomegalovirus immunity and chronic graft-versus-host disease after allogeneic bone marrow transplantation.
Chronic graft-versus-host disease (GvHD) in bone marrow allograft recipients is frequently preceded by a cytomegalovirus (CMV) infection. To elucidate whether an immune reaction of transplanted donor cells against CMV was involved in the pathogenesis of chronic GvHD, the effect of donor pretransplant CMV immune status on chronic GvHD incidence was analyzed. In 43 bone marrow recipients at risk, the 2-yr cumulative chronic GvHD probability was 55% when the donor was immune, in contrast to 16.5% when the donor was non-immune (p less than 0.002). No correlation between recipient pretransplant CMV immunity and chronic GvHD was observed. Donor CMV immunity did not correlate with acute GvHD or posttranplant CMV infection and seemed to predispose for chronic GvHD regardless of donor and recipient age. However, the proportion of CMV immune donors increased with increasing donor and recipient age. This may account for the higher incidence of chronic GvHD in older patients. The present study suggests that chronic GvHD may be mediated by a reaction of immune donor cells against CMV infected recipient cells.
Acute Disease↗
Marrow transplantation for non-Hodgkin's lymphoma: a multi-centre study from the European Co-operative Bone Marrow Transplant Group.
Twenty-five patients with intermediate- or high-grade non-Hodgkin's lymphoma (NHL) were treated by allogeneic bone marrow transplantation. For the nine patients transplanted in first complete remission the disease-free survival was 100%; of the nine patients transplanted in subsequent remissions four (44%) achieved long-term disease-free survival but two died of relapsed lymphoma. For the seven patients transplanted at a time when they had active disease, the initial complete remission rate was high but four died of progressive lymphoma and no patient achieved long-term disease-free survival. The incidence of complications associated with allogeneic bone marrow transplantation was similar to that observed in other series of patients transplanted for haematological malignancy and was related to the status of the disease at the time of transplant. Thus allogeneic bone marrow transplantation is a radical but effective treatment for patients with NHL who have 'minimal residual disease'. Efforts to define further the subset of patients who can most successfully be treated by transplantation may improve the overall results.
Adolescent↗
Ferrochelatase-inhibitory activity and N-alkylprotoporphyrin formation with analogues of 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC) containing extended 4-alkyl groups: implications for the active site of ferrochelatase.
The ferrochelatase-inhibitory activity, porphyrin-inducing activity, and cytochrome P-450- and heme-destructive effects of a variety of analogues of 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC) were studied in chick embryo liver cells. The ferrochelatase-inhibitory activity of the 4-butyl, 4-pentyl, 4-hexyl, and 4-cyclopropylmethyl analogues of DDC was considered to be due to the formation of the corresponding N-alkylporphyrins. These N-alkylporphyrins were isolated from the livers of phenobarbital-pretreated rats following administration of the corresponding DDC analogues. The 4-isobutyl analogue did not have ferrochelatase-inhibitory activity despite its ability to cause formation of an N-isobutylporphyrin in rat liver. The 4-chloromethyl analogue of DDC inhibited ferrochelatase activity. The inability to isolate an N-alkylporphyrin from rat liver with this analogue may be due to its lability. The porphyrin-inducing activity of these analogues depended on their ferrochelatase-inhibitory potency and lipophilicity. The DDC analogues caused cytochrome P-450 and heme destruction. The relative ferrochelatase-inhibitory activity of the DDC analogues has implications for a postulated model of the binding of porphyrins in the ferrochelatase active site.
Alkylation↗
The immunodeficiency of bone marrow-transplanted patients. The effect of patient lymphocytes on the response of donor lymphocytes to mitogens and allogeneic cells.
Lymphocytes from patients after bone marrow transplantation (BMT) are in most cases predominantly of the Leu-2+ (cytotoxic/suppressor) phenotypes and are almost unresponsive to mitogens. In contrast, normal Leu-3+-depleted, Leu-2+-enriched lymphocyte suspensions retain approximately 50% of the mitogenic response compared with that of unseparated cells. To investigate whether this discrepancy was due to active suppression, we selected nine BMT patients from whom sufficient numbers of cells were available and whose lymphocyte phenotypes were predominantly Leu-2+ after BMT. These post-BMT lymphocytes were tested for functional suppressor activities against donor and recipient pre-BMT lymphocytes in the lymphocyte transformation test. None of these post-BMT cells suppressed the response of donor or pre-BMT cells to phytohaemagglutinin A or concanavalin A. In contrast, the response of donor cells in mixed lymphocyte cultures to HLA-DR-different third-party cells was suppressed by highly X-irradiated post-BMT cells by approximately 40%. Addition of T-cell growth factor (= interleukin 2 (IL-2)) or X-irradiated donor cells to post-BMT lymphocytes partially restored the mitogenic response. These findings indicate that the early post-BMT cells lack production of IL-2 but are capable of responding to IL-2 and that the almost extinct mitogen response of these cells is due to immaturity rather than active suppression. The suppression of the allogeneic but not the mitogenic response might be explained by differences in the modes of activation; for example, the allogeneic response must involve the T-cell receptor, while the mitogenic response may not.
Bone Marrow Transplantation↗
Intravenous hyperimmune globulin prophylaxis against cytomegalovirus interstitial pneumonitis after allogenic bone marrow transplantation.
In an attempt to reduce the incidence of lethal cytomegalovirus (CMV) interstitial pneumonitis after allogenic bone marrow transplantation 49 patients were randomized in a multicenter controlled study to receive either CMV-hyperimmune globulin or a control immune globulin with low anticytomegalovirus titer. Immune globulin was administered intravenously 6 times with 20 days interval, starting on day 7 before transplantation. Patients receiving CMV hyperimmune globulin or control immune globulin were comparable with regard to age, diagnosis, pretransplant anti-CMV titer, incidence of graft-versus-host disease and transfusions. In each group, the incidence of histologically proven CMV interstitial pneumonitis during the first 110 days post BMT was recorded. Six of 23 patients in the control group versus 1 of 26 in the CMV hyperimmune globulin group died of CMV interstitial pneumonitis (p less than 0.05). No significant effect on idiopathic pneumonitis or survival was observed.
Bone Marrow Transplantation↗
Cytomegalovirus infection after bone marrow transplantation: relation of pneumonia to postgrafting immunosuppressive treatment.
Five fatal cases of CMV associated interstitial pneumonia occurred among 20 patients who had received allogenic bone marrow transplantation for acute leukemia or aplastic anaemia. This outcome was analysed in relation to prospectively obtained data on complement fixing (CF) and IgM anti-CMV titres and excretion of CMV in urine or pharynx. Altogether 16 patients had primary or reactivated CMV infection. Five of these patients receiving corticosteroids at the time of infection, at a dose of more than 1 mg/kg/day, failed to mount a significant CF antibody response, excreted large amounts of virus, and died from pneumonia, while the remaining 11 infected patients obtained high CF antibody titres and showed no severe symptoms related to CMV infection. IgM antibodies occurred simultaneously with CF antibodies in most cases of primary and reactivated infection. The results of the study suggest a protective role of the humoral immune response to CMV infection in BMT recipients, and passive immunisation with CMV hyperimmune globulin should be attempted especially in patients given additional immunosuppression with high dose corticosteroids.
Adolescent↗
Hepatitis B serum markers and oral health in a group of Norwegian male prisoners.
In 138 male Norwegian prisoners the prevalence of hepatitis B virus (HBV) serum markers was 30.4% and closely related to their drug abuse. The highest frequency of the markers (82.8%) was found in young drug addicts admitting intravenous abuse and the lowest (14.3%) in prisoners denying such abuse. For comparison, the frequency of HBV serum markers in the general male population in Norway is about 4.1%. In young prisoners (less than 30 years), DMF teeth, percentage of gingival bleeding, and percentage of periodontal pockets greater than 4 mm were on an average 18.8, 38.2%, and 7.0%, respectively. These corresponding figures in the older age group (greater than 30 years) were 21.7, 38.5%, and 15.2%. These findings indicate a dental health status somewhere between that of the general population and disadvantaged groups in Norway previously surveyed. Other oral pathological conditions were present in more than one third of the prisoners, but mucosal lesions and disorders of psychosomatic origin did not extend normal ranges. No characteristic lesions attributable to drug abuse were observed. Dental care was given a low priority by the prisoners. Emergency procedures had been the treatment of choice at infrequent, irregular visits to the dentist, leading to enhanced risk of bleeding and of HBV transmission.
Adult↗