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Biomedical subjects

J A Sonnabend

Publications and source records attributed to J A Sonnabend.

At least 19 recordsLinked to original sources
PubMed1998

Vascular endothelial growth factor and basic fibroblast growth factor present in Kaposi's sarcoma (KS) are induced by inflammatory cytokines and synergize to promote vascular permeability and KS lesion development.

All forms of Kaposi's sarcoma (KS) are characterized by spindle cell proliferation, angiogenesis, inflammatory cell infiltration, and edema. We have previously reported that spindle cells of primary KS lesions and KS-derived spindle cell cultures express high levels of basic fibroblast growth factor (bFGF), which is promoted by the inflammatory cytokines identified in these lesions. These cytokines, namely, tumor necrosis factor, interleukin-1, and interferon-gamma, induce production and release of bFGF, which stimulates angiogenesis and spindle cell growth in an autocrine fashion. Here we show that both AIDS-KS and classical KS lesions co-express vascular endothelial growth factor (VEGF) and bFGF. VEGF production by KS cells is promoted synergistically by inflammatory cytokines present in conditioned media from activated T cells and in KS lesions. KS cells show synthesis of VEGF isoforms that are mitogenic to endothelial cells but not to KS spindle cells, suggesting a prevailing paracrine effect of this cytokine. This may be due to the level of expression of the flt-1-VEGF receptor that is down-regulated in KS cells as compared with endothelial cells. KS-derived bFGF and VEGF synergize in inducing endothelial cell growth as shown by studies using both neutralizing antibodies and antisense oligodeoxynucleotides directed against these cytokines. In addition, VEGF and bFGF synergize to induce angiogenic KS-like lesions in nude mice and vascular permeability and edema in guinea pigs. These results indicate that inflammatory cytokines present in KS lesions stimulate the production of bFGF and VEGF, which, in turn, cooperate to induce angiogenesis, edema, and KS lesion formation.

Animals↗
PubMed1992

Modulation of alpha interferon levels by AZT treatment in HIV-seropositive patients.

The effect of AZT on serum HIV p24 antigen and endogenous serum alpha interferon levels was studied in AIDS and ARC patients. Following administration of AZT there was a rapid decline in the serum levels of both HIV p24 antigen and alpha interferon. When AZT treatment was interrupted, the levels of both HIV p24 antigen and of interferon rapidly increased. These findings suggest that HIV or some other AZT sensitive microorganism is the inducer of interferon which is characteristically found in the serum of AIDS and symptomatic HIV infected patients. They also suggest that the rapid decline in interferon levels may underlie some of the symptomatic benefit that follows administration of AZT.

HIV Antigens↗
PubMed1986

Hematologic correlates and the role of erythrocyte CR1 (C3b receptor) in the development of AIDS.

Circulating immune complexes (CICs) are common in patients with the acquired immunodeficiency syndrome (AIDS) as in anemia. In our previous reports, we observed that the deposition of CICs on erythrocytes via C3b receptors (CR1) resulted in a defective CIC clearing system of erythrocytes and in high membrane osmotic fragility of such erythrocytes. We investigated the functional activity of erythrocyte CR1 in 89 patients with AIDS, 41 with AIDS related complex (ARC), 102 healthy homosexual volunteers, and 37 heterosexual males, in relation to the presence of CICs, antibody to lymphadenopathy associated virus/human T lymphotropic virus-III (LAV/HTLV-III), anemia, and the direct and indirect Coombs' tests. CICs were frequently found in all groups except heterosexual males. Absence of CR1 activity was observed in 85% of patients with AIDS, and in 59% with ARC. Impaired CR1 activity also occurred in the homosexual volunteer group. Positive direct Coombs' test and the presence of CICs correlated inversely with CR1 activity while a lowered hematocrit and the presence of antibody to LAV/HTLV-III correlated directly. Neither the sera nor the eluates from erythrocytes with a positive IgG Coombs' test contained IgG antibody against erythrocytes. This suggests decremental loss of CR1 activity progressing from asymptomatic LAV/HTLV-III antibody positive homosexual volunteers to the prodromal spectrum of ARC and finally progressing to a total disappearance in overt AIDS. Of 8 homosexuals volunteers demonstrating the composite of impaired CR1 activity, positive antibody to LAV/HTLV-III, and polyvalent positive direct Coombs' test (with gamma, mu, and C3b), all developed ARC or overt AIDS within 2 years of these observations.

AIDS-Related Complex↗
PubMed1984

Interferon-related leukocyte inclusions in acquired immune deficiency syndrome: localization in T cells.

Blood samples from a series of 12 patients with Kaposi's sarcoma or infectious complications of the acquired immunodeficiency syndrome (AIDS) and from 18 homosexual contacts of AIDS patients were screened for interferon-related tubuloreticular inclusions (TRI) in circulating leukocytes. In the AIDS patients, TRI were detected by transmission electron microscopy in 1.5 to 10% of mononuclear cell sections. They were most frequent in patients with a decreased fraction of T helper cells and T4/T8 ratios less than 0.2. Only rare TRI-positive sections were found in 3/12 homosexual contacts with lymphadenopathy and 1/6 asymptomatic contacts. Serum interferon was found to be elevated in each AIDS case tested, but was not a sufficient condition for detection of TRI in homosexual contacts. Active DNA virus infections, including cytomegalovirus, were common to the AIDS cases and possibly contributed to the TRI pathogenesis. Localization of TRI in T suppressor/cytotoxic cells was demonstrated with monoclonal anti-Leu 2a antibodies. The pathophysiologic significance of interferon stimulation with formation of TRI in immunocompetent cells requires further investigation.

Acquired Immunodeficiency Syndrome↗
PubMed1983

Generalized lymphadenopathy in homosexual men.

The cases of 90 homosexual or bisexual men with generalized lymphadenopathy were studied by epidemiologic, clinical, pathologic, immunologic, and genetic methods. The patients ranged in age from 20 to 52 years and had histories of multiple sexually transmitted diseases and both recreational and prescription drug use. Histologically, their lymph nodes showed three patterns: explosive follicular hyperplasia; follicular involution with expansion of the paracortical area; and a mixed pattern of follicular hyperplasia and follicular involution in the same lymph node. The frequency of HLA-DR5 was significantly increased in these patients (p less than 0.005) compared with that in controls. All patients had impaired cell-mediated immunity. Opportunistic infections, lymphomas, or Kaposi's sarcoma subsequently developed in 15 patients who had had severe immune dysfunction for the previous 3 to 13 months. We suggest that generalized lymphadenopathy is part of the spectrum of a disorder manifested by acquired immunodeficiency, opportunistic infections, Kaposi's sarcoma, and malignant lymphomas.

Adult↗
PubMed1982

Acid-labile human leukocyte interferon in homosexual men with Kaposi's sarcoma and lymphadenopathy.

Some immunologic parameters in homosexual patients with Kaposi's sarcoma (KS) or unexplained lymphadenopathy resemble findings in patients with autoimmune diseases such as systemic lupus erythematosus (SLE). Many patients with SLE have an unusual acid-labile form of human leukocyte interferon (HuIFN-alpha) in their serum. Sera from 91 homosexual men were tested for the presence of HuIFN. Of 27 patients with KS, 17 had significant titers of HuIFN in their serum. Ten of 35 patients with lymphadenopathy and three of four patients with other clinical symptoms also had circulating HuIFN. In contrast, only two of 25 apparently healthy subjects had serum HuIFN. All 32 samples of HuIFN had antiviral activity on bovine cells, a characteristic of HuIFN-alpha, and all of 14 representative samples tested were neutralized by antibody to HuIFN-alpha. In addition, the HuIFN-alpha in six of eight representative patients was inactivated at pH 2 and therefore appears to be similar to the HuIFN-alpha found in patients with SLE. These findings suggest that an autoimmune disorder may underly lymphadenopathy and KS in homosexual men.

Homosexuality↗
PubMed1978

Studies on the mechanisms of vaccina virus cytopathic effects. I. Inhibition of protein synthesis in infected cells is associated with virus-induced RNA synthesis.

The mechanism of vaccinia virus-induced inhibition of protein synthesis was studied in LLC-MK2, HeLa and L cells. Removal of cycloheximide (300 microgram/ml) from cells infected at a multiplicity of infection (m.o.i.) of 300 particles/cell at 4 h after infection resulted in the resumption of both host and virus protein synthesis in LLC-MK2 cells, but not in HeLa and L cells. In order to determine whether virus-induced RNA synthesis, which occurs in infected cells in the presence of cycloheximide, is related to the inhibition of protein synthesis, (cut-off), the rate of virus-induced RNA synthesis in the presence of cycloheximide was measured in all three cell types. In L cells and HeLa cells the rate of virus-induced RNA synthesis increased with time, whereas in LLC-MK2 cells it remained constant for at least 4 h. However, when higher multiplicities (900 and 2700 particles/cell) were used to infect LLC-MK2 cells, the rate of RNA synthesis in the presence of cycloheximide did increase with time and was greater at the higher multiplicity. Under these conditions there was a direct relationship between the extent of virus RNA synthesis and the degree of cut-off after the removal of cycloheximide. In HeLa and L cells infected at 300 particles/cell, the longer the exposure to cycloheximide, the greater was the cut-off observed upon removal of the drug. As was the case the LLC-MK2 cells, there was a direct relationship between the rate of RNA synthesis and the degree of inhibition of protein synthesis. Since virus-induced RNA synthesis occurs in the presence of cycloheximide, the effects of actinomycin D and cordycepin on host polypeptide synthesis were tested. Inhibition of host cell protein synthesis was virtually abolished when HeLA cells were infected in the presence of cordycepin (50 and 25 microgram/ml) or actinomycin D (20 microgram/ml). These results indicate that, as the rate of virus-induced RNA synthesis increased, regardless of the type of cell used, protein synthesis was inhibited at earlier times and to a greater extent. These observations are consistent with the hypothesis that the cut-off phenomenon is related to the synthesis of an early virus-induced RNA(s).

Cell Line↗
PubMed1978

Studies on the mechanisms of vaccinia virus cytopathic effects. II. Early cell rounding is associated with virus polypeptide synthesis.

Vaccinia virus-induced morphological lesions were studied in LLC-MK2, HeLa and L cells. In LLC-MK2 cells, cell rounding occurs within 30 to 60 min after infection with 300, 900 or 2700 particles/cell and the time of appearance of these changes is dependent on the multiplicity of infection (m.o.i.). When cycloheximide (300 microgram/ml) is added to cultures at the time of infection, early cell rounding is prevented regardless of the m.o.i. However, cell rounding does occur when cycloheximide is removed, and its time of appearance and extent depends upon the time of removal of the compound and the m.o.i. Upon removal of cycloheximide at I or 2 h after infection early cell rounding occurs, and virus polypeptide synthesis is evident in cells infected at all three multiplicities. However, when the drug is removed at 4 hr after infection, cell rounding and virus polypeptide synthesis occur only in cultures infected at 300 particles/cell. Early morphological changes are also prevented in HeLa and L cells infected at 300 particles/cell in the presence of cycloheximide. These changes occur only if the compound is removed up to 2 h after infection in HeLa cells and up to 40 min after infection in L cells. Early morphological lesions are not seen if the compound is removed at later times. The occurrence of early morphological changes in HeLa and L cells is also correlated with the synthesis of virus polypeptides. All cell types, when infected at 2700 particles/cell in the presence of cycloheximide, or inhibitors of RNA synthesis, display cell fusion. Thus, whereas early morphological changes require virus protein synthesis to become manifest, cell fusion occurs in the absence of virus RNA or protein synthesis and may be mediated by a component of the virion.

Cell Fusion↗
PubMed1977

Effects of interferon on vesicular stomatitis virus transcription and translation.

The effect of interferon on the synthesis of the RNA species and proteins of vesicular stomatitis virus has been studied in two cell types. Virus protein synthesis is inhibited by interferon despite the apparent presence of near normal amounts of virus RNA with sedimentation values characteristic of virus messenger RNA. The synthesis of those virus RNA species which are completely dependent on virus protein synthesis is preferentially inhibited in interferon-treated cells. These results are most consistent with a model of interferon action postulating a primary effect on translation of virus messenger RNA.

Animals↗