HLA-DR antibodies and HTLV-III antibody ELISA testing.
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Antibodies↗
Biomedical subjects
D L Mann
Publications and source records attributed to D L Mann.
Human T-cell leukemia/lymphoma virus I and/or Epstein-Barr virus-infected B-cell lines spontaneously produce acid-labile alpha-interferon.
B-cell lines were established as spontaneous outgrowths of cell cultures from patients with adult T-cell leukemia (ATL). Three such lines were shown to have integrated human T-cell leukemia/lymphoma virus 1 (HTLV-I) proviral sequences as well as Epstein-Barr virus (EBV) infection. Supernatant fluids from these cultured cells were assayed for interferon (IFN) production. Acid-stable alpha-IFN was found to be produced by one cell line (CF), and acid-labile alpha-IFN by the other two (HS, MJB). In contrast, HTLV-I-infected T-cell lines did not produce IFN. Some EBV-infected B-cell lines produce acid-labile alpha-IFN, while others do not. Since alpha-IFN, both acid stable and acid labile, is found in sera from patients with the polyclonal activation of B cells as a constitutive part of the disease, the above observations suggest a possible role of polyclonal B-cell activation in alpha-IFN production in these diseases.
B-Lymphocytes↗
HTLV-I infection of T and B cells of a patient with adult T-cell leukemia-lymphoma (ATLL) and transmission of HTLV-I from B cells to normal T cells.
We analysed the DNA of different tissues of a patient (HS) with adult T-cell leukemia/lymphoma virus (HTLV-I). We detected viral sequences in fresh specimens from spleen, thymus, liver, skin and peripheral blood neoplastic lymphocytes. The pattern of HTLV-I integration is identical in the leukemic cells and in all other tissues analysed, but the signal intensity is strongest in the leukemic cells, indicating the source of HTLV-I proviral sequences was the leukemic T-cells which had infiltrated these tissues. In fact, the cultured skin fibroblasts of the patient did not contain HTLV-I sequence. However, cultured lymphocytes of this patient was consistently an immortalized B-cell line containing HTLV-I sequences in a manner indicative of a polyclonal infection. This cell line was also infected with the Epstein-Barr virus (EBV). In order to determine whether HTLV-I alone was sufficient for B-cell immortalization, we obtained single cell clones by limiting dilution. The DNA of all the cell clones that we analysed contained both the HTLV-I and EBV genomes, suggesting that immortalization of the B-cell was more likely due to the EBV rather than HTLV-I. Infectious HTLV-I viruses produced by the B-cell line still had the propensity to infect and transform T-lymphocytes in normal human umbilical cord blood. Unlike the parental B cells, the transformed T lymphocytes were clonally selected. Our results indicate that although the predominant infected cell population of the patient was his leukemic T lymphocytes, some of his EBV-positive B-lymphocytes were also polyclonally infected. The latter had a growth advantage in culture over the T lymphocytes but the virus produced by these immortalized B cells has not been adapted and has maintained its tropism for T cells.
B-Lymphocytes↗
Absence of cardioversion-induced ventricular arrhythmias in patients with therapeutic digoxin levels.
To determine the incidence of cardioversion-induced ventricular arrhythmias in patients with therapeutic serum levels of digoxin, 19 patients (average age [+/- standard deviation] 61 +/- 12 years) undergoing elective direct current cardioversion for atrial fibrillation were studied. Only patients with therapeutic serum digoxin levels (range 0.5 to 1.9 ng/ml; mean 1.1 +/- 0.5) at the time of cardioversion were included. Patients with acute myocardial ischemia or unstable angina, serious electrolyte disturbance or those requiring class I antiarrhythmic agents for control of ventricular or supraventricular arrhythmias were excluded. Ambulatory electrocardiograms were recorded for 24 hours before and 6 hours after cardioversion. No patient developed malignant ventricular arrhythmias (ventricular triplets or tachycardia) in the immediate 3 hour period after cardioversion. Furthermore, there were no significant (p less than 0.05) differences in the frequency of ventricular premature beats or couplets before and after cardioversion. To determine whether the level of serum digoxin or the strength of the applied shock had a significant effect on the development of postcardioversion arrhythmias, the change in frequency of single premature ventricular beats after cardioversion was compared with the serum digoxin level (ng/ml) and the applied energy level (joules) by means of linear regression analysis. There was no significant (p less than 0.05) relation between these variables. These findings suggest that patients with therapeutic serum levels of digoxin may safely undergo cardioversion without the concomitant use of class I antiarrhythmic agents.
Adult↗
Detection of benzo[a]pyrene diol epoxide-DNA adducts in peripheral blood lymphocytes and antibodies to the adducts in serum from coke oven workers.
Coke oven workers are exposed to high levels of carcinogenic polycyclic aromatic hydrocarbons, including benzo[a]pyrene (B[a]P), and are at increased risk of lung cancer. Since B[a]P is enzymatically activated to 7 beta,8 alpha-dihydroxy(9 alpha, 10 alpha)epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (B[a]PDE) that forms adducts with DNA, the presence of these adducts was measured in DNA from peripheral blood lymphocytes by synchronous fluorescence spectrophotometry and enzyme radioimmunoassay. Approximately two-thirds of the workers had detectable levels of B[a]PDE-DNA adducts. Antibodies to the DNA adducts were also found in the serum of 27% of the workers. B[a]PDE-DNA adducts were not detectable in lymphocytes and antibodies to the adducts were not detected in sera from a control group of nonsmoking laboratory workers. DNA adducts and/or antibodies to the adducts indicate exposure to B[a]P and its metabolic activation to the carcinogenic metabolite that covalently binds to and damages DNA. Detection of adducts and antibodies to them may also be useful as internal dosimeters of the pathobiological effective doses of chemical carcinogens.
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
Decreased helper T lymphocytes in homosexual men. I. Sexual contact in high-incidence areas for the acquired immunodeficiency syndrome.
In June 1982, sexual and other behavioral patterns were examined in 245 homosexual men in relationship to T-lymphocyte phenotypes that are characteristic of the acquired immunodeficiency syndrome (AIDS). Mean helper T-cell counts in New York City (579 +/- 32 cells/mm3) and Washington, DC, homosexual men with sexual contacts in areas at high risk (endemic) for AIDS (567 +/- 24 cells/mm3) were significantly lower than in Washington, DC, residents without such contacts (672 +/- 36 cells/mm3, p = 0.04 by analysis of variance). Helper T-cell counts in the Washington men were inversely correlated with a greater number of endemic-area homosexual contacts (p = 0.005), even after adjustment for multiple confounding variables (p = 0.02). The 31 Washington men with more than 15 endemic-area partners had a mean helper T-cell count of 517 +/- 44 cells/mm3, and 12 of those 31 men had helper T-cell counts less than 400 cells/mm3. AIDS patients are known to have a marked reduction in the number and function of helper T-lymphocytes. The data suggest that deficits of helper T lymphocytes can be acquired by homosexual contact with men in cities where AIDS is common. This supports the hypotheses that low helper T-cell counts may be caused by a sexually transmissible agent and that frequent homosexual exposure to residents of high-risk areas for AIDS may be an important means of spread of this agent.
Acquired Immunodeficiency Syndrome↗
Decreased helper T lymphocytes in homosexual men. II. Sexual practices.
In June 1982, the sexual practices of 245 homosexual male outpatients of private physicians were evaluated in relationship to decreased numbers of helper T lymphocytes, an abnormality that is characteristic of the acquired immunodeficiency syndrome (AIDS). Three risk groups were defined a priori--85 high-risk men from central Manhattan ("New York"), 96 intermediate-risk men from Washington, DC, with AIDS-area homosexual contacts ("Washington-exposed"), and 64 low-risk Washington, DC, men without such contacts ("Washington-unexposed"). An increasing number of homosexual partners was correlated with decreasing helper T-cell counts (R = -0.29, p = 0.009) and decreasing helper:suppressor T-cell ratios (R = -0.32, p = 0.005) in the entire study group combined and in New York subjects separately. Suppressor T-cell counts were unrelated to the number of partners in all three groups. Increasingly frequent receptive anal intercourse correlated with decreasing helper T-cell counts most clearly in the New York City group (R = -0.23, p = 0.04), somewhat less so in the Washington-exposed group (R = -0.18, p = 0.07), and not at all in the Washington-unexposed group (R = -0.09, p = 0.48). This association persisted in the New York and Washington-exposed groups after adjusting for seven other sexual practices, the number of homosexual partners, and five other potentially confounding variables. A transmissible agent associated with receptive anal intercourse best explains these data. The cause of these low helper T-cell counts may also be the cause of AIDS.
Acquired Immunodeficiency Syndrome↗
Interferon regulation of DR antigen expression and alloantigen-presenting capabilities of the promyelocytic cell line HL60.
Our research suggests that interferon may have an immunoregulatory role in the initiation phase of immune responses. Recent evidence has demonstrated that lymphokines regulate monocyte cell surface expression of DR antigens and, consequently, the ability of monocytes to activate T lymphocytes in an antigen-specific manner. In this report cloned interferons and a homogeneous cell line were used to demonstrate that interferon possesses these immunoregulatory functions. Cells of the promyelocytic cell line HL60, when incubated in vitro with recombinant gamma (IFN-gamma) and with alpha interferons (IFN-alpha), expressed enhanced levels of DR antigen as determined by both cytotoxicity and fluorescence-activated cell sorter analyses. Lower concentrations of IFN-gamma than IFN-alpha were needed to induce DR expression, and a higher percentage of monocytes were induced to express DR antigen by IFN-gamma than IFN-alpha. HL60 cells preincubated with lymphocyte-derived lymphokines or IFN-alpha also stimulated a significantly better in vitro allogeneic response in the mixed leukocyte reaction than untreated HL60 cells. Thus, interferon both the phenotypic expression of DR antigens of HL60 cells and their functional ability to initiate T-lymphocyte responses to an alloantigen.
Antigen-Presenting Cells↗
Type 1 human T-cell leukemia virus small envelope protein expressed in mouse cells by using a bovine papilloma virus-derived shuttle vector.
In an attempt to express the small (transmembrane) envelope protein p21e of type 1 human T-cell leukemia (lymphotrophic) virus (HTLV-1) exclusive of other viral gene products, we have constructed a recombinant plasmid clone (pMBE-1) in a bovine papillomavirus-derived mammalian expression vector. Mouse C127 cells transfected with the pMBE-1 plasmid expressed the introduced HTLV-1 viral gene(s) as demonstrated by Northern blot and indirect immunofluorescence with natural human antisera. The transfected mouse cells were injected into BALB/c mice, and a monoclonal antibody was recovered which specifically recognizes a 21-kilodalton protein present in HTLV-1 virions, indicating that the pMBE-1 plasmid encodes the small envelope protein.
Animals↗
Biochemical and molecular epidemiology of human cancer risk.
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Aryl Hydrocarbon Hydroxylases↗
Determinants of retrovirus (HTLV-III) antibody and immunodeficiency conditions in homosexual men.
A cohort of homosexual men at high risk of the acquired immunodeficiency syndrome (AIDS) was monitored to examine the relation between lifestyle, clinical conditions, T-lymphocyte subsets, and antibody to the AIDS-associated human retrovirus, human T-cell leukaemia virus III (HTLV-III). HTLV-III antibodies were present in 35 (53%) of the 66 subjects tested in June, 1982. 4 of the seronegative subjects had HTLV-III antibodies when re-tested one year later, a seroconversion rate of 1.2% per month. In the HTLV-III seropositive subjects, AIDS developed at a rate of 6.9% per year (minimum incidence of AIDS = 4.6% per year) and other clinical signs of immunodeficiency (lesser AIDS) at 13.1% per year. All 6 of the AIDS cases and at least 8 of the 10 lesser AIDS cases had detectable HTLV-III antibodies 1 week to 21 months before diagnosis. Of 24 other subjects with stable lymphadenopathy, 19 (79%) had or acquired HTLV-III antibodies. Lower helper T-cell counts were very closely related to HTLV-III seropositivity (r = -0.53, p = 0.0001), even in the 26 healthy subjects with no clinical abnormalities (r = -0.37, p = 0.07). In both univariate and multivariate analyses, the lifestyle risk factors for HTLV-III seropositivity were large number of homosexual partners (p less than or equal to 0.03) and receptive anal intercourse (p less than or equal to 0.03), with an apparent synergistic interaction between these two activities (chi 2 = 8.71, p = 0.003). These data suggest that frequent receptive anal intercourse with many homosexual partners predisposes to HTLV-III infection with the consequent emergence of lymphadenopathy and the various manifestations of lesser and fully fledged AIDS.
Acquired Immunodeficiency Syndrome↗
Immune T cells reactive against human T-cell leukaemia/lymphoma virus.
Six patients with malignant disorders associated with human T-cell leukaemia/lymphoma virus (HTLV) were studied to see whether long-term cultures of immune T cells reactive against HTLV-infected tumour cells could be achieved. Immune T-cell lines could not be developed from the cells of five patients who died or eventually had a relapse of disease, but in one patient who had an unusually long remission of his disease after therapy, immune T-cell lines were propagated that could produce their own T-cell growth factor and proliferate upon stimulation with autologous tumour cells and also specifically lyse HTLV-infected target cells. These immune T cells recognised the presence of circulating HTLV-bearing neoplastic cells in another patient with HTLV-associated T-cell leukaemia, who had been in clinical remission after chemotherapy when this study started, thereby providing early evidence of relapse.
Cell Line↗
Low T-lymphocyte ratios in homosexual men. Epidemiologic evidence for a transmissible agent.
To investigate risk factors for immunologic abnormalities among homosexual men, T-lymphocyte helper/suppressor (OKT4/OKT8) ratios were determined in 78 healthy Danish homosexual men. Ratios in 26 men (33%) were low (less than 1.00). Visiting the United States in 1980 to 1981 was a strong (7.7-fold) risk factor for having a ratio less than 1.00. Among nine travelers who visited only once, the risk of having a low ratio increased significantly if the visit had occurred in 1981. A risk of similar magnitude (6.9-fold) was found among the three men who had not been to the United States but who reported homosexual contact with a Danish man who became ill with Kaposi's sarcoma. Risk of low ratios did not correlate with age or years of homosexual activity. Promiscuity was not a significant risk factor, but these men generally had fewer sex partners than that which has been reported from the United States. Neither nitrite inhalant use nor cytomegalovirus antibody (prevalence or titer) was associated with low ratios. These data support the hypothesis that a transmissible biologic agent may be etiologically responsible for the low helper/suppressor ratios in homosexual men.
Adult↗
Methylation of human T-cell leukemia virus proviral DNA and viral RNA expression in short- and long-term cultures of infected cells.
Leukemic peripheral blood lymphocytes from individuals infected with the human T-cell leukemia/lymphoma virus (HTLV) were found to express little or no viral RNA before being put into tissue culture. Within 24-48 hr, viral RNA expression increased at least four- to eightfold. Established HTLV-infected cell lines constitutively express viral RNA. Southern blots of DNA from HTLV-infected cells digested with the methylation-sensitive restriction enzyme HpaII showed that the proviral DNA was methylated in all of the uncultured peripheral blood cells tested. In contrast, no proviral methylation was detected in any of the cell lines examined, suggesting a functional correlation between methylation and viral RNA expression. However, DNA from HTLV-infected lymphocytes cultured for 48 hr (by which time increases in viral RNA expression are evident) did not differ detectably with respect to proviral DNA methylation from uncultured cells, suggesting that the increase in viral RNA expression after short-term culture is mediated by mechanisms independent of changes in DNA methylation.
Cells, Cultured↗
Differential methylation of class I histocompatibility antigen genes in T-cell lines derived from two different types of T-cell malignancies.
We have previously shown that two human T-cell lines (HSB and 8402) derived from patients with childhood T-cell ALL (T-ALL) do not synthesize detectable mRNA for HLA-DR alpha. The DR alpha genes in both cell lines are hypermethylated relative to the same genes in T-cell lines infected with human T-cell leukemia virus (HTLV) and derived from patients with adult T-cell leukemia/lymphoma (ATL). These latter cell lines do express HLA-DR alpha-mRNA, as well as HLA-DR surface antigens. We report here that the genes for HLA class I antigens are also highly methylated in the T-ALL T-cell lines relative to the same genes in the ATL T-cell lines, normal peripheral blood T cells, and autologous normal B-cell lines. In spite of substantial differences in the extent of methylation of class I-related genes, no obvious differences exist among these cell types in their levels of expression of HLA-A and -B antigens. The data clearly indicate, however, that the class I and class II components of the major histocompatibility complex are unusually hypermethylated in several T-ALL-derived cell lines, while ATL T-cell lines do not substantially differ in this respect from normal peripheral blood T-cells.
Acute Disease↗
DNA methylation and expression of HLA-DR alpha.
B-cell lines established from two individuals with T-cell acute lymphocytic leukemia (T-ALL) express HLA-DR antigens, whereas the isogenic T-cells do not. The lack of expression correlates with a lack of detectable HLA-DR mRNA. All of the DR alpha DNA sequences detected by a cloned DR alpha cDNA probe are contained in a BglII fragment which varies slightly in size (4.0 to 4.8 kilobases) from one individual to another. In DNA from the T-cells not expressing DR alpha mRNA, all of the potential HpaII sites within the BglII fragment appeared to be methylated. In contrast, at least some of these sites were not methylated in DNA from the B-cells expressing high levels of DR alpha mRNA. Treatment of these T-cells with 5-azacytidine resulted in the induction of DR surface antigen expression, the appearance of DR alpha mRNA, and the partial demethylation of the DR alpha DNA sequences. T-cell lines established from human T-cell leukemia-lymphoma virus associated T-cell neoplasias, in contrast to the T-cell acute lymphocytic leukemia cell lines, expressed both DR antigens and DR alpha mRNA; the HpaII sites within the BglII fragment of DR alpha DNA of these human T-cell leukemia-lymphoma virus-positive T-cell lines were in all cases at least partially unmethylated. Uncultured peripheral blood T-cells from human T-cell leukemia-lymphoma virus-infected individuals expressed DR antigens at a low level, and the DR alpha locus was partially unmethylated. After 48 h in culture, DR antigen expression was substantially increased, but no significant changes were observed in methylation of the DR alpha locus or in the amount of DR mRNA which was present. This suggests that expression of DR antigens also can be modulated post-transcriptionally.
Adult↗
Identification of the human T cell lymphoma virus in B cell lines established from patients with adult T cell leukemia.
Cell lines were established from the peripheral blood of two patients with adult T cell leukemia. In contrast to our previous experience, where all such lines expressed T cell markers, these two cell lines expressed B cell antigens and Ig light chains (kappa on CF-2, lambda on HS). Human T cell lymphoma proviral (HTLV) sequences were demonstrated in both cell lines. Since only a portion of the cells in culture expressed Ig light chains, experiments were carried out to exclude the possibility that the cultures were not a mixture of B and T or non-B cells. Cells that expressed kappa- or lambda-light chains were separated by cell sorting from kappa- or lambda-negative cells and replaced in culture. Light chain negative cells reexpressed light chains after time in culture. After 5-azacytidine treatment of the cell lines, all cells expressed Ig light chains. These studies show that the human retrovirus HTLV, which has been demonstrated to be associated with certain T cell malignancies, can infect B cells or B cell precursors.
Adult↗
Generation of an HLA-restricted cytotoxic T cell line reactive against cultured tumor cells from a patient infected with human T cell leukemia/lymphoma virus.
Lymphocytes from a patient who had an unusually long survival after therapy for a human T cell leukemia/lymphoma virus (HTLV)-associated T cell lymphoma were stimulated in vitro with an autologous tumor cell line, and the generation of cytotoxic T lymphocytes (CTL) was studied. CTL generated were directed against autologous (HTLV-associated tumor cells. These propagated CTL were OKT3+, OKT4-, and OKT8+. The cytotoxic activity required target tumor cells that were infected with HTLV and also expressed histocompatibility antigens in common with the patient, suggesting a major histocompatibility complex-restricted associative recognition of target antigens expressed on the tumor cell membrane.
Animals↗