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Biomedical subjects

M H Kaplan

Publications and source records attributed to M H Kaplan.

At least 55 records · Page 3Linked to original sources
PubMed1996

Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice.

Interactions between cytokine and receptor lead to the activation of multiple signalling molecules, including the family of signal transducer and activator of transcription (STAT) proteins. STAT4 is one member of this family, and is activated only in response to the cytokine interleukin (IL)-12 (refs 5, 6). By gene targeting, we have generated mice deficient in STAT4 to determine whether the function of this transcription factor is redundant with other signalling molecules activated by IL-12. IL-12-induced increases in the production of interferon (IFN)-gamma cellular proliferation and natural killer (NK) cell cytotoxicity are abrogated in lymphocytes from STAT4-deficient mice. The development of Th1 cells in response to either IL-12 of Listeria monocytogenes is also impaired in the absence of Stat4. Furthermore, Stat4-deficient lymphocytes demonstrate a propensity towards the development of Th2 cells. These results demonstrate that Stat4 is essential for mediating responses to IL-12 in lymphocytes, and regulating the differentiation of both Th1 and Th2 cells.

Animals↗
PubMed1996

Seroepidemiology of cytomegalovirus in patients with advanced HIV disease: influence on disease expression and survival.

To determine the prevalence and effect of cytomegalovirus (CMV) co-infection on clinical outcome, the seroepidemiology of CMV was examined in 196 demographically diverse patients with advanced HIV disease. Thirty-six (18.4%) were seronegative for CMV; 31 of these 36 (86.1%) were both non-black and non-homosexual. Invasive CMV disease developed in 41 of 160 (25.6%) seropositive patients and 0 of 36 (0%) seronegative patients (p = 0.00015). Among seropositive patients, the frequency of CMV disease varied markedly according to risk group for acquisition of HIV infection. CMV disease occurred in 26 of 73 (35.6%) homosexual men and 11 of 33 (33.3%) heterosexuals, but only 2 of 47 (4.3%) injection drug users. Sexual exposure as the only risk factor for the acquisition of HIV was a highly significant independent risk factor for invasive CMV when other covariables were considered in a proportional hazards model (risk ratio 5.4, p = 0.0019). The cumulative proportion of all seropositive patients developing CMV disease after 3 years was 31%. CMV serologic status had no effect on occurrence of AIDS-related illnesses other than CMV disease and no effect on survival. Risk for the development of CMV disease varies substantially among different groups of patients with advanced HIV disease and can be assessed using serologic and demographic criteria. The results of this study may be used to influence clinical management and help target prophylactic interventions for CMV disease to high-risk individuals.

AIDS-Related Opportunistic Infections↗
PubMed1996

Origin and interstate spread of a New York City multidrug-resistant Mycobacterium tuberculosis clone family.

OBJECTIVE: To determine whether isolates of Mycobacterium tuberculosis from New York and elsewhere that are resistant to four or more primary antimicrobial agents and responsible for widespread disease in the 1990s represent a newly emerged clone or a heterogeneous array of unrelated organisms. SETTING: New York City area and selected locations in the United States. PATIENTS: M tuberculosis isolates from 1953 patients in New York and multidrug-resistant isolates from six patients from other US communities. DESIGN: Convenience sample of all M tuberculosis strains (M tuberculosis isolates resistant to rifampin, streptomycin, isoniazid, and ethambutol, and sometimes ethionamide, kanamycin, capreomycin, or ciprofloxacin) submitted to the Public Health Research Institute Tuberculosis Center since 1991 and samples submitted to the Centers for Disease Control and Prevention from throughout the United States. The samples submitted were representative of the New York City strains of M tuberculosis. MAIN OUTCOME MEASURE: Characterization of resistant M tuberculosis strains studied by IS6110 and polymorphic GC-rich repetitive sequence (PGRS) hybridization patterns, multiplex polymerase chain reaction (PCR) analysis, and automated DNA sequencing of genes containing mutations associated with resistance to rifampin (rpoB), isoniazid (katG and inhA locus), and streptomycin (strA and rrs). RESULTS: Multidrug-resistant M tuberculosis isolates were recovered from 253 New York City patients and had the same or closely allied IS6110 and PGRS patterns, multiplex PCR type, and gene mutations associated with resistance to rifampin, isoniazid, and streptomycin. Isolates with these same molecular characteristics were recovered from patients in Florida and Nevada, health care workers in Atlanta, Ga, and Miami, Fla, and an individual who recently moved from New York City to Denver, Colo, and caused disease or skin test conversion in at least 12 people in a nursing home environment. CONCLUSIONS: The results document the molecular origin and spread of progeny of a closely related family of multidrug-resistant M tuberculosis strains that have recently shared a common ancestor and undergone clonal expansion. The multidrug-resistant phenotype in these organisms arose by sequential acquisition of resistance-conferring mutations in several genes, most likely as a consequence of antibiotic selection of randomly occurring mutants in concert with inadequately treated infections. Dissemination of these difficult-to-treat bacteria throughout New York City and to at least four additional US cities has adverse implications for tuberculosis control in the 21st century.

Antitubercular Agents↗
PubMed1996

Stat6 is required for mediating responses to IL-4 and for development of Th2 cells.

Interleukin-4 (IL-4) stimulation of cells leads to the activation of multiple signaling pathways, one of which involves Stat6. We have generated Stat6-deficient mice by gene targeting in embryonic stem cells to determine the role of this transcription factor in mediating the biologic functions of IL-4. IL-4-induced increases in the cell surface expression of both MHC class II antigens and IL-4 receptor are completely abrogated, and lymphocytes from Stat6-deficient animals fail to proliferate in response to IL-4. Stat6-deficient B cells do not produce IgE following in vivo immunization with anti-IgD. In addition, Stat6-deficient T lymphocytes fail to differentiate into Th2 cells in response to either IL-4 or Il-13. These results demonstrate that, despite the existence of multiple signaling pathways activated by IL-4, Stat6 is essential for mediating responses to IL-4 lymphocytes.

Animals↗
PubMed1995

The immunoglobulin heavy-chain matrix-associating regions are bound by Bright: a B cell-specific trans-activator that describes a new DNA-binding protein family.

B lymphocyte-restricted transcription of immunoglobulin heavy-chain (IgH) genes is specified by elements within the variable region (VH) promoter and the intronic enhancer (E mu). The gene encoding a protein that binds a VH promoter proximal site necessary for induced mu-heavy-chain transcription has been cloned. This B-cell specific protein, termed Bright (B cell regulator of IgH transcription), is found in both soluble and matrix insoluble nuclear fractions. Bright binds the minor groove of a restricted ATC sequence that is sufficient for nuclear matrix association. This sequence motif is present in previously described matrix-associating regions (MARs) proximal to the promoter and flanking E mu. Bright can activate E mu-driven transcription by binding these sites, but only when they occur in their natural context and in cell lines permissive for E mu activity. To bind DNA, Bright requires a novel tetramerization domain and a previously undescribed domain that shares identity with several proteins, including SWI1, a component of the SWI/SNF complex.

Amino Acid Sequence↗
PubMed1995

Treatment of adult T-cell leukemia-lymphoma with a combination of interferon alfa and zidovudine.

BACKGROUND: Infection with the human T-cell lymphotropic virus type I, a retrovirus, can cause a distinctive cancer, adult T-cell leukemia-lymphoma. The median survival of patients with the acute and lymphomatous forms of the disease is short, despite the use of cytotoxic chemotherapy. METHODS: We treated 19 patients with acute or lymphomatous forms of adult T-cell leukemia-lymphoma with oral zidovudine (200 mg five times daily) and interferon alfa (Intron A, 5 to 10 million units subcutaneously each day). Seven of these patients had either relapsed after multiagent cytotoxic chemotherapy or failed to respond to that treatment. RESULTS: Major responses were achieved in 58 percent of the patients (11 of 19), including complete remission in 26 percent (5 of 19). Four patients in whom prior cytotoxic therapy had failed had major responses, two of which were complete remissions. Six patients have survived for more than 12 months, with the longest remission since the discontinuation of treatment lasting more than 59 months. CONCLUSIONS: The combination of zidovudine and interferon alfa has activity against adult T-cell leukemia-lymphoma, even in patients in whom prior cytotoxic therapy has failed. This regimen should be evaluated further for its role in the treatment of adult T-cell leukemia-lymphoma.

Adolescent↗
PubMed1995

Interleukin-10 is an autocrine growth factor for acquired immunodeficiency syndrome-related B-cell lymphoma.

Interleukin-10 (IL-10) is an acid-sensitive protein of 35 kD that has pleiotropic effects including inhibition of cytotoxic T-cell response, induction of major histocompatibility complex type II in B lymphocytes, induction of B-cell growth and differentiation, and autocrine growth factor activity in monocytes. We and others have shown that IL-10 is produced spontaneously by blood mononuclear cells from human immunodeficiency virus-seropositive patients. In an attempt to ascertain the potential role of IL-10 in acquired immunodeficiency syndrome (AIDS)-related B-cell lymphoma, we evaluated the expression of human IL-10 in both tumor-derived B-cell lines and primary tumor cells. Expression of human IL-10 (hIL-10) mRNA and protein was detected in four of five cell lines examined. An IL-10 antisense oligonucleotide inhibited IL-10 mRNA expression and IL-10 protein production. The proliferation of all B-cell lines was inhibited by an antisense oligonucleotide in a dose-dependent manner that was abrogated by the addition of recombinant hIL-10 protein. No effect of antisense oligonucleotide was observed in the B-cell line not producing hIL-10. Evaluation of primary tumor cells from patients with AIDS-lymphoma cells showed similar production and response to IL-10. These data suggest an autocrine growth mechanism for IL-10 in AIDS-related lymphoma cells and that IL-10 may be important in its pathogenesis.

B-Lymphocytes↗
PubMed1995

Human herpesvirus-like nucleic acid in various forms of Kaposi's sarcoma.

The association between a new human herpesvirus-like agent and various forms of Kaposi's sarcoma was examined by PCR. The DNA sequences of this agent were detected in 7 of 8 classic Kaposi's sarcoma specimens, 12 of 12 AIDS-associated specimens from the United States, and 7 of 10 specimens from African endemic Kaposi's sarcoma. Polymorphism of the herpesvirus-like DNA in the Kaposi's tissue from different populations was observed by both single-strand conformational polymorphism and direct sequencing. Furthermore, the presence and expression of the virus was detected in some Kaposi's tumours by Southern and northern blotting. This herpesvirus may be involved in the pathogenesis of different kinds of Kaposi's sarcoma seen among distinct and unrelated populations.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Human herpesvirus-6 infection in children with first febrile seizures.

We evaluated febrile convulsions prospectively in 42 children to investigate the association between acute human herpesvirus-6 (HHV-6) infection and first-time febrile convulsions, using both virologic and serologic methods. Eight children had primary HHV-6 infection documented by viral culture and an additional three by acute- and convalescent-phase serologic studies. These findings indicate that acute HHV-6 infection is a frequent cause of febrile convulsions in young children.

Adolescent↗
PubMed1995

Cell culture-PCR technique for detection of infectious cytomegalovirus in peripheral blood.

We determined the efficacy of PCR for the direct detection of infectious cytomegalovirus (CMV) in specimen-inoculated MRC-5 tube cultures (cell culture-PCR [CC-PCR]). Parallel testing was performed by a shell vial assay-indirect immunofluorescence assay (SVA-IFA) and isolation (conventional MRC tube cultures [TC-CPE]. The sensitivity, specificity, and positive and negative predictive values for CC-PCR, SVA-IFA, and TC-CPE were 81, 99, 94, and 94%, 86, 100, 100, and 96%, and 77, 100, 100, and 93%, respectively. Future application of CC-PCR may be directed toward its use as a screening tool for cytomegalovirus genotypic variants.

Blood↗
PubMed1994

Pathogenesis of HIV.

To understand the pathogenesis of AIDS, we must first understand the unique features of HIV that make it such a formidable pathogen. These features and their different qualities are discussed in this article.

CD4-Positive T-Lymphocytes↗
PubMed1994

Evaluation of a rapid diagnostic test for respiratory syncytial virus (RSV): potential for bedside diagnosis.

OBJECTIVE: Rapid detection of respiratory syncytial virus (RSV) infection can assist clinicians in decisions regarding antiviral therapy with ribavirin as well as instituting infection control measures. The Abbott TestPack RSV is a rapid RSV detection immunoassay that can be performed on respiratory secretions in 20 to 30 minutes without special laboratory equipment. The purpose of this study was to evaluate housestaff performance of the TestPack RSV at bedside as compared with laboratory testing of aliquots of the same specimen by tissue culture inoculation, direct fluorescent antibody (DFA) testing and TestPack RSV. METHODS: During the 1991 through 1992 RSV season, 137 nasopharyngeal aspirates or washes obtained from pediatric patients < 4 years of age suffering from acute respiratory disease were assayed by the Food and Drug Administration-approved TestPack RSV as well as conventional tube culture and DFA testing. RESULTS: 66 of 137 (48%) specimens were positive for RSV as defined by: isolation and DFA-positive (n = 48) and DFA testing positive with negative culture (n = 18); blocking assay experiments using TestPack RSV confirmed culture-negative DFA-positive specimens as positive in 8/8 instances in which material for retesting was available. Using these definitions, the sensitivity and specificity for the assays were: housestaff TestPack RSV: 92%, 93%; laboratory TestPack RSV: 97%, 98%; virus isolation: 72%, 100%. CONCLUSION: From these data, it appears that the TestPack RSV EIA in the field setting is reliable, although laboratory confirmation of results is important.

Child, Preschool↗
PubMed1993

Identification of a G protein coupled receptor induced in activated T cells.

Many genes are induced after T cell activation to make a cell competent for proliferation and ultimately, function. Many of these genes encode surface receptors for growth factors that signal a cell to proliferate. We have cloned a novel gene (clone 6H1) that codes for a member of the G protein-coupled receptor superfamily. This gene was isolated from a chicken activated T cell cDNA library by low level hybridization to mammalian IL-2 cDNA probes. The 308 amino acid open reading frame has seven hydrophobic, presumably transmembrane domains and a consensus site for interaction with G proteins. Tissue distribution studies suggest that gene expression is restricted to activated T cells. The message appears by 1 h after activation and is maintained for at least 45 h. Transcription of 6H1 is induced by a number of T cell stimuli and is inhibited by cyclosporin A, but not by cycloheximide. This is the first description of a member of this superfamily expressed specifically in activated T cells. The gene product may provide a link between T cell growth factors and G protein activation.

Amino Acid Sequence↗
PubMed1993

Acquired ichthyosis in concomitant HIV-1 and HTLV-II infection: a new association with intravenous drug abuse.

BACKGROUND: Papulosquamous eruptions are common in HIV-1-infected patients. Acquired ichthyosis may occur after profound T-cell depletion. Intravenous drug users infected with HIV-1 can be coinfected with human lymphotropic virus II (HTLV-II). OBJECTIVE: We examined the relation between acquired ichthyosis and concomitant infection with HIV-1 and HTLV-II in intravenous drug users. METHODS: We examined 184 male and female HIV-1-positive intravenous drug users for acquired ichthyosis. Enzyme-linked immunosorbent assay was used to screen these patients for antibody to HTLV-I/II. Western blot, viral isolation, and the polymerase chain reaction were used to confirm that serologic responses were from HTLV-II and not HTLV-I. RESULTS: Acquired ichthyosis occurred in 6.3% of white, 16.4% of Hispanic, and 21.7% of black patients. It occurred only after profound helper T-cell depletion, in association with increasing age, and with concomitant infection with HTLV-II (22.2% vs. 6.8% in HIV-1 singly infected patients [p < 0.038]). CONCLUSION: Acquired ichthyosis may be a marker of concomitant infection with HIV-1 and HTLV-II in intravenous drug users and occurs after profound helper T-cell depletion.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Molecular cloning, expression, and biological characterization of an HTLV-II envelope glycoprotein: HIV-1 expression is permissive for HTLV-II-induced cell fusion.

The human T cell leukemia virus II (HTLV-II) is a type C retrovirus closely related to the human transforming retrovirus HTLV-I. In contrast to HTLV-I, the role of HTLV-II in human disease is controversial. However, HTLV-II infection has been documented in several cases of a clinically benign hairy cell leukemia and has also been suggested as a cofactor for HIV-1 disease progression. We report that an HTLV-II isolate (designated FLW) derived from a serum-positive white male can induce cell fusion and significant cytopathic effects in tissue culture. This HTLV-II isolate induced syncytium formation with human T and B cell lines, several human fibroblast cell lines, and, interestingly, HIV-1- and HIV-2-infected cell lines. To elucidate the role in the FLW envelope in this phenomenon, we have cloned the envelope glycoproteins gp46 and gp21 of this isolate. The envelope glycoproteins expressed in the absence of the rest of the viral genome were sufficient to drive syncytium formation in vitro, and preserved the cellular tropism for syncytium formation observed with the native retroviral isolate. Amino acid (aa) sequence analysis demonstrated 88% overall similarity with other HTLV-II envelope glycoproteins. Interestingly, only cells infected by HIV-I, but not parental H9 cells, form syncytia with FLW env-transfected cells as well as with HTLV-II/FLW-infected BJAB-WH cells. Furthermore, antibodies directed at the CD4 receptor failed to inhibit the induction of giant cell formation, implying that the FLW envelope protein was responsible for driving syncytium formation in this system. These observations may be important for the understanding of the processes involved in human retroviral-mediated syncytium formation and may suggest a mechanism whereby HTLV-II could influence the disease process in individuals dually infected with HIV-1 and HTLV-II.

Amino Acid Sequence↗
PubMed1993

Human retroviruses and neoplastic disease.

Human retroviral infections result in significant neoplastic disease. Human T cell lymphotropic virus I (HTLV-I), the first human retrovirus to be discovered, is associated with the development of acute T cell leukemia with characteristic hypercalcemia and skin lesions after many years of chronic infection of CD4+ cells. HTLV-I also produces myelopathy. A minor T cell immunodeficiency occurs in HTLV-I acute T cell leukemia with associated strongyloidiasis and Pneumocystis carinii pneumonia. Human T cell lymphotropic virus II (HTLV-II) is found to be endemic in Amerindians and intravenous drug users (IVDUs) and has been linked to some cases of hairy-cell leukemia. HTLV-II infects the CD8+ population, with significant cell-associated viremia. Clinical neurological disease is rare, with one patient with myelopathy having been described. Immunodeficiency does not seem to occur. Human immunodeficiency virus 1 (HIV-1) produces aggressive large cell and Burkitt's lymphoma in as many as 10% of HIV-1-infected patients. More than 20% of homosexual men infected with HIV-1 develop Kaposi's sarcoma (KS). The pathogenesis of KS is better understood through studying KS-like cell lines that induce angiogenic factors. In some patients HIV-1 and HTLV-I or HTLV-II infections occur concomitantly. HIV-1 accelerates the tumorigenesis of HTLV-I and produces unusual skin diseases when combined with HTLV-II. Immunodeficiency occurs in all HIV-1-infected patients.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Characterization of stimulatory surface molecular expression on avian T cells.

We have characterized a monoclonal antibody (AT389), produced by immunization of mice with 4-day-old avian Concanavalin A blasts, which recognizes a 38-40 kDa homodimer present on the surface of all chicken T cells. AT389 increased the spontaneous and IL-2-driven proliferation of 3-day-old T-cell blasts. This antibody, in synergy with IL-2, increased cellular proliferation and cell survival of T-cell blasts over time. Together, these data suggest that AT389 recognizes a surface protein on avian T cells which may be related to known stimulatory surface markers on mammalian T cells.

Animals↗