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Biomedical subjects

S Broder

Publications and source records attributed to S Broder.

At least 181 records · Page 10Linked to original sources
PubMed1985

Suppression of retroviral propagation and disease by suramin in murine systems.

Retroviral propagation crucially depends on reverse transcriptase (RT). We have developed murine models to test the biological effectiveness of the RT inhibitor suramin. The drug was active in our assay system, which includes (i) inhibition of RT activity in the murine T-cell tropic virus SL3-3 and Rauscher murine leukemia virus (MuLV), (ii) inhibition of plaque formation in the XC plaque assay, (iii) inhibition of viral infection of cultured murine T cells, and (iv) inhibition of splenomegaly induced by Rauscher MuLV in BALB/c mice. Suramin decreases viral titers significantly, even if started 36 hr after infection. Viral titers and number of infected cells increased to control levels after removal of the drug. BALB/c mice treated i.v. with 40 mg of suramin per kg twice per week following infection with Rauscher MuLV showed a 35% decrease in splenomegaly. Suramin is an active antiretroviral agent whose effect on retroviral propagation is reversible. We conclude that it acts as a virustatic drug and that long-term administration of suramin will be necessary if it is used for experimental treatment of human retroviral illnesses such as the acquired immune deficiency syndrome.

Animals↗
PubMed1985

Implications of the discovery of HTLV-III for the treatment of AIDS.

The recent discovery of HTLV-III, a cytopathic member of the family of human T-cell lymphotropic viruses (HTLV), and its identification as the etiological agent of acquired immunodeficiency syndrome (AIDS) have important implications for the treatment of this disorder. The pathogenesis of AIDS involves the destruction of helper/inducer T-lymphocytes by active viral infection, and drugs which inhibit the replication of HTLV-III or monoclonal antibodies directed at viral antigens may be important components of future therapeutic strategies. There are a number of steps in the replication of HTLV-III which might potentially be susceptible to antiviral agents. One drug, suramin, which was originally developed as an antitrypanosomal agent, has been found to be an inhibitor of reverse transcriptase. This drug has been shown to block the infectivity and cytopathic effect of HTLV-III [Mitsuya, H., Popovic, M., Yarchoan, R., Matsushita, S., Gallo, R. C., and Broder, S. Science (Wash. DC), 266: 172-174, 1984]; in addition, it is able to block the in vitro replication of another member of the HTLV family, HTLV-I, at concentrations of 25 to 75 micrograms/ml. Lymphocyte proliferation in vitro is minimally inhibited at these concentrations of suramin, and the ratios of helper/inducer to cytotoxic/suppressor T-lymphocytes are not affected. Clinical trials are being initiated to study the effect of suramin on patients with AIDS. Evaluation of this and other antiviral treatments for AIDS will optimally involve direct assessment of its effects on HTLV-III replication in vivo. Recent evidence, however, suggests that these patients have a low level of viral replication in lymphoid tissue which may spontaneously fluctuate, making such evaluation complex.

Acquired Immunodeficiency Syndrome↗
PubMed1985

Cytogenetic studies in human T-cell lymphoma virus (HTLV)-positive leukemia-lymphoma in the United States.

Cytogenetic studies were conducted on fresh and cultured cells from 11 patients with human T-cell leukemia virus-associated adult T-cell leukemia-lymphoma. Clones with abnormal karyotypes were detected in 9 of the 11 patients. Chromosome numbers were near-diploid in cells from all but 1 patient who also had a tetraploid clone. The chromosome abnormalities in these cells were extensive; numerous complex structural changes were seen in every chromosome pair. Structural abnormalities occurred most frequently in chromosome 6. The 6 patients with chromosome 6 deletions had breakpoints at bands q11, q13, q16q23, q21q23, q22q24, and q23q24. The characteristic clinical features of these 6 patients were aggressive course, short survival, poor response to chemotherapy, high white blood cell counts, hypercalcemia, and bone lesions, whereas cytogenetically abnormal patients without chromosome 6q deletions tended to have a more indolent course. The precise role of the 6q deletion cannot be established with certainty from these data. However, this abnormality appears to occur with a greater than expected frequency in this large cell aggressive lymphoma, in association with hypercalcemia and lytic bone lesions.

Adult↗
PubMed1985

Pharmacological inhibition of infectivity of HTLV-III in vitro.

Acquired immunodeficiency syndrome (AIDS) is a pandemic immunosuppressive disease that predisposes to life-threatening opportunistic infections and unusual forms of neoplasms. A recently discovered member of the human T-lymphotrophic virus (HTLV) family, designated HTLV-III, has been shown to be the etiological agent of AIDS. We have shown previously that a trypanosomicidal drug, suramin, can block the in vitro infectivity and cytopathic effect of HTLV-III at doses that are attainable in human beings. In the present work we report our findings that suramin can block the cytopathic effect of HTLV-III even after a defined exposure of the target helper/inducer T-cells to the virus and that the T-cells protected by suramin remain immunologically functional.

B-Lymphocytes↗
PubMed1984

Suramin protection of T cells in vitro against infectivity and cytopathic effect of HTLV-III.

A recently discovered member of the human T-cell leukemia virus (HTLV) family of retroviruses has been etiologically linked to the acquired immune deficiency syndrome (AIDS). This virus, which has been designated HTLV-III, is tropic for OKT4-bearing (helper-inducer) T cells. Moreover, the virus is cytopathic for these cells. Suramin is a drug used in the therapy of Rhodesian trypanosomiasis and onchocerciasis, and it is known to inhibit the reverse transcriptase of a number of retroviruses. Suramin has now been found to block in vitro the infectivity and cytopathic effect of HTLV-III at doses that are clinically attainable in human beings.

Cell Line↗
PubMed1984

Functional properties of antigen-specific T cells infected by human T-cell leukemia-lymphoma virus (HTLV-I).

Tetanus-toxoid specific helper-inducer T-cell clones, which had been infected and transformed by human T-cell leukemia-lymphoma virus (HTLV-I), were obtained from an antigen-specific human T cell line by using a limiting dilution technique in the presence of the virus. These HTLV-I-infected T-cell clones proliferated specifically in response to soluble tetanus toxoid but, unlike normal T cells, they could do so in the absence of accessory cells. The HTLV-I-infected T-cell clones did not present the antigen to autologous antigen-specific T cells that were not infected with HTLV-I. The capacity of helper-inducer T cells to retain antigen-specific reactivity after infection by HTLV-I, while losing the normal T-cell requirement for accessory cells, has clinical and theoretical implications.

Antigens, Surface↗
PubMed1984

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↗
PubMed1984

Transformation and cytopathogenic effect in an immune human T-cell clone infected by HTLV-I.

Human T-cell leukemia-lymphoma virus (HTLV) is a human C-type retrovirus that can transform T lymphocytes in vitro and is associated with certain T-cell neoplasms. Recent data suggest that, in the United States, patients with acquired immunodeficiency syndrome (AIDS), homosexual men with lymphadenopathy, and hemophiliacs have had significant exposure rates to HTLV, whereas matched and unmatched control American subjects have rarely been exposed to this agent. In the present experiments, T cells specifically reactive against HTLV were propagated from a patient whose HTLV-bearing lymphoma was in remission. The T cells were cloned in the presence of the virus and an HTLV-specific cytotoxic T-cell clone was isolated. This clone was infected and transformed by the virus, with one copy of an HTLV-I provirus being integrated into the genome. This T-cell clone did not exhibit the normal dependence on T-cell growth factor (interleukin-2) and proliferated spontaneously in vitro. Exposure of the clone to HTLV-bearing, autologous tumor cells specifically inhibited its proliferation and resulted in its death. These results may have implications for HTLV-associated inhibition of T-cell responses.

Acquired Immunodeficiency Syndrome↗
PubMed1984

NIH conference. T-cell lymphoproliferative syndrome associated with human T-cell leukemia/lymphoma virus.

Human T-cell leukemia/lymphoma virus is a unique family of T-cell tropic, human, type-C retroviruses. The discovery of this class of retroviruses provides the first proven link between retroviruses and cancer in humans. This virus is endemic in certain parts of the world, including the southeastern United States, and is associated with the development of adult T-cell leukemia/lymphoma, a fulminant lymphoproliferative disorder frequently accompanied by opportunistic infections and hypercalcemia. Over the last few years, major advances have been made in understanding the clinical, epidemiologic, molecular biologic, and immunologic features of this unique class of human RNA tumor viruses.

Acquired Immunodeficiency Syndrome↗
PubMed1984

Human T-cell leukemia virus: its discovery and role in leukemogenesis and immunosuppression.

We have highlighted the events leading to the discovery of the first human RNA tumor virus and then reviewed what is currently known about its biology. From this, it is clear that we have only begun to appreciate the biologic diversity, the geographic distribution, and the disease spectrum of this family of human T-lymphotropic retroviruses which we collectively term HTLV. At a basic level, HTLV provides a unique opportunity to study in vitro and in vivo mechanisms of cell transformation. Given its close association with adult T-cell leukemia and its ability to efficiently immortalize primary cells in vitro, we believe that HTLV will very likely harbor clues to the biology of cell growth, differentiation, and transformation. At a more clinical level, the close association between HTLV and a malignancy of clonally expanded (HTLV-containing) mature T-cells argues strongly for a causal relationship, although the mechanism for such is currently unknown. It is likely that further study of the molecular and cellular biology of this virus will bring together these basic and clinical findings and elucidate, at least in part, one mechanism for human leukemogenesis. From a more speculative viewpoint, the role of HTLV in the pathogenesis of human disease appears even broader. As discussed in this chapter, there are indications that all subtypes of HTLV may produce immunosuppression both in vitro and in vivo, and there is now exciting new data to suggest that a novel member of this family of viruses, HTLV-III, is causally linked to the AIDS syndrome. Moreover, the possibility has been raised that the immunosuppressive properties of HTLV could predispose patients to non-T-cell malignancies as occurs in patients with AIDS or chemically induced immunosuppression. Finally, by employing the experimental strategies which were successful in isolating HTLV-I, HTLV-II, and HTLV-III, it may be possible in the future to identify still other human retroviruses.

Acquired Immunodeficiency Syndrome↗
PubMed1984

Protection of T cells against infectivity and cytopathic effect of HTLV-III in vitro.

A recently discovered member of the human T-cell leukemia virus (HTLV) family of retroviruses has been etiologically linked to the acquired immunodeficiency syndrome (AIDS). This virus, which has been designated HTLV-III, is tropic for OKT4+ (helper/inducer) T-cells. Moreover, the virus is cytopathic for these cells. Suramin is a drug used in the therapy of Rhodesian trypanosomiasis and onchocerciasis, and it inhibits the reverse transcriptase of a number of retroviruses including HTLV-III. In the present work, we report our findings that suramin can block the in vitro infectivity and cytopathic effect of HTLV-III at doses that are clinically attainable in human beings. We believe these results may have relevance in planning experimental therapeutic strategies for various diseases associated with members of the HTLV-family of pathogenic human retroviruses.

Acquired Immunodeficiency Syndrome↗
PubMed1983

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↗
PubMed1983

Clinical course of retrovirus-associated adult T-cell lymphoma in the United States.

We studied the clinical features of 11 patients with adult T-cell lymphoma associated with the human T-cell lymphoma virus. The patients were predominantly young, black, and born in the southeastern United States. They had an aggressive course, with the rapid onset of disseminated skin lesions or symptoms related to hypercalcemia and other metabolic disturbances, or both. Common findings included rapid enlargement of peripheral, hilar, and retroperitoneal lymph nodes, with sparing of the mediastinum; invasion of the central nervous system, lungs, or gastrointestinal tract; and opportunistic infections. A paraneoplastic syndrome characterized by increased bone turnover, abnormal bone scintigraphy, and hypercalcemia was present in all patients. Intensive combination chemotherapy produced prompt complete clinical remissions, which were generally of short duration. Similar features have been described in patients in Japan and the West Indies who had adult T-cell lymphoma, which is also associated with the human T-cell lymphoma virus. This syndrome should be suspected in patients presenting with the acute onset of widespread T-cell lymphoma in association with metabolic bone disease and hypercalcemia. The presence of the syndrome can be confirmed by appropriate serologic and virologic studies.

Adult↗
PubMed1983

Regulation of the humoral immune response: from immunoglobulin genes to regulatory T cell networks.

Leukemic lymphocytes were used in studies to define the rearrangements of immunoglobulin genes and the networks of immunoregulatory T cells that are important to the control of immunoglobulin synthesis in humans. Leukemic B cells displayed rearrangements of their expressed mu and k or lambda genes. Surprisingly, the k constant region genes were deleted or rearranged in all lambda-expressing B lymphocytes examined. Most non-T, non-B lymphocytic leukemias had immunoglobulin gene rearrangements, which indicates that these cells were committed to B cell development at the immunoglobulin gene level. The pattern of immunoglobulin gene rearrangements in the B cell precursor and B cell leukemias suggests an ordered hierarchy of somatic rearrangements with mu genes preceding light chains and k light chain genes preceding lambda. Some of the leukemic T cells studied were homogeneous populations of cells that retained immunoregulatory functions with many Sézary T leukemic cells functioning as helper cells in their interactions with B lymphocytes. In contrast, malignant cells from patients with the adult T leukemia of Japan frequently functioned as suppressor cells. In contrast to normal unactivated T cells or other leukemic T cells, the leukemic T cells from all adult T cell leukemia patients studied had an activated receptor for T cell growth factor. The malignant cells of a patient with an acute T cell leukemia functioned as prosuppressor cells. Under the influence of normal T cells or their secreted inducer products, these leukemic cells matured both functionally and in terms of cell surface antigens into suppressor effector cells.

Adult↗
PubMed1983

Disorders of B cells and helper T cells in the pathogenesis of the immunoglobulin deficiency of patients with ataxia telangiectasia.

The pathogenesis of the immunoglobulin deficiency of 20 patients with ataxia telangiectasia was studied using an in vitro immunoglobulin biosynthesis system. 10 patients had no detectable IgA in their serum as assessed by radial diffusion in agar and 3 had a reduced serum IgA concentration. The peripheral blood mononuclear cells of 17 of the patients and 17 normal controls were cultured with pokeweed mitogen for 12 d and the immunoglobulin in the supernatants measured. The immunoglobulin synthesis was below the lower limit of the normal 95% confidence interval for IgM in 5 patients, for IgG in 8, and for IgA in 14. The mononuclear cells from 9 of the 10 patients with a serum IgA concentration less than 0.1 mg/ml failed to synthesize IgA in vitro. None of the patients manifested excessive suppressor cell activity. All patients had reduced but measurable helper T cell activity for immunoglobulin synthesis by co-cultured normal pokeweed mitogen-stimulated B cells (geometric mean 22% of normal). Furthermore, the addition of normal irradiated T cells to patient peripheral blood mononuclear cells led to an augmentation of IgM synthesis in 15 of 17 and to increased IgG synthesis in 9 of the 17 patients studied, including 9 of the 12 patients who had synthesized IgG before the addition of the irradiated T cells. In addition, IgA synthesis was increased in all eight patients examined that had serum IgA concentrations greater than 0.1 mg/ml. These studies suggest that a helper T cell defect contributes to the diminished immunoglobulin synthesis. However, a helper T cell defect does not appear to be the sole cause since there was no IgA synthesis by the peripheral blood mononuclear cells of 9 of the 10 patients with a profoundly reduced serum IgA even when co-cultured with normal T cells. Furthermore, the cells of the nine patients with profoundly reduced IgA levels examined also failed to produce IgA when stimulated with the relatively helper T cell-independent polyclonal activators, Nocardia water soluble mitogen or Epstein-Barr virus. Taken together these data support the view that the reduced immunoglobulin synthesis of these patients is due to defects of both B cells and helper T cells. Such a broad defect in lymphocyte maturation taken in conjunction with our demonstration of persistent alpha fetoprotein production by ataxia telangiectasia patients provides support for the proposal that these patients exhibit a generalized defect in tissue differentiation.

Ataxia Telangiectasia↗