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Biomedical subjects

M S Hirsch

Publications and source records attributed to M S Hirsch.

At least 181 records · Page 10Linked to original sources
PubMed1984

T-lymphocyte subset interactions in the cell-mediated immune response to Epstein-Barr virus.

The T-lymphocyte subset interactions in the cell-mediated response to Epstein-Barr virus (EBV) were studied in an in vitro system in which the ability of T lymphocytes to inhibit outgrowth of autologous EBV-transformed B lymphocytes is assessed. Inhibition could be demonstrated within lymphocytes of both the T4 and T8 surface phenotypes. Outgrowth inhibition was observed more frequently when the effector T-cell population contained cells of both surface phenotypes. In blocking experiments the OKT3 antibody completely prevents development of outgrowth inhibitory activity; the OKT4 and OKT8 antibodies were less effective in interfering with outgrowth inhibitory function. Maximal blocking activity occurred when antibody addition occurred in the early phase of generation of suppressor function. Pharmacologically achievable concentrations of interferon-alpha restored outgrowth inhibitory activity after blocking with monoclonal antibody. EBV reactivation was easily demonstrable in a group of 10 renal allograft recipients who received OKT3 antibody for treatment of acute rejection. These studies suggest that the immunoregulatory control of proliferation of EBV-transformed B lymphocytes is complex, and involves a collaborative interaction of lymphocytes of both the T4 and T8 surface phenotypes.

Adult↗
PubMed1984

Effect of interferon alpha on natural killer cell cytotoxicity in kidney transplant recipients.

Natural killer (NK) cell cytotoxicity was monitored in 32 kidney transplant recipients during a double-blind, placebo-controlled trial of interferon alpha prophylaxis. During the first month following transplantation, NK cytotoxicity diminished in both interferon and placebo-treated patients. Thereafter, mean values for NK cytotoxicity decreased further in interferon recipients, whereas they returned toward baseline in placebo recipients. Paradoxically, interferon alpha consistently augmented NK cytotoxicity of all patients in vitro. Various immunosuppressive regimens were employed in these patients. NK cytotoxicity was slightly diminished in patients receiving prednisone and azathioprine, moderately depressed in those who received prednisone, azathioprine, and OKT3 antibody. Three or four placebo recipients with clinically severe cytomegalovirus (CMV) infections had diminished NK cell function. These studies indicate that a variety of factors including exogenous interferon, immunosuppressive regimens, and CMV infections can influence NK cytotoxicity in renal transplant recipients.

Antilymphocyte Serum↗
PubMed1984

Infection of human endothelial cells by human T-lymphotropic virus type I.

We studied the effects of human T-lymphotropic virus type I (HTLV-I) on human endothelial cells in vitro. During cocultivation with an HTLV-I producer cell line (C91/PL), endothelial cells formed characteristic multinucleated syncytial giant cells. Inoculation with concentrated cell-free supernatant fluid from C91/PL cultures produced similar cytopathic effects, which were neutralized by pretreatment with HTLV-I specific human serum. HTLV-I antigens were detected in the cytoplasm of the multinucleated cells by indirect immunofluorescence. When endothelial cells showed maximal cytopathic changes, reverse transcriptase activity was demonstrated in the supernatant fluid and HTLV-I was isolated by cocultivation with peripheral blood mononuclear cells. This study demonstrates that HTLV-I tropism is not limited to lymphoid cells but extends to human endothelial cells as well.

Antigens, Viral↗
PubMed1984

Prevention of Epstein-Barr virus-induced B-cell outgrowth by interferon alpha.

An in vitro system for determining the efficacy of interferon alpha (IFN-alpha) in preventing B-cell outgrowth due to Epstein-Barr virus (EBV) was developed. Unfractionated cord blood mononuclear cells, T-cell-depleted cord blood mononuclear cells, or adult T-cell-depleted mononuclear cells were exposed to IFN-alpha for 18 to 20 h followed by incubation with the B95-8 strain of EBV for 2 h. B-cell outgrowth was monitored by microscopic examination, [3H]thymidine incorporation, and Epstein-Barr nuclear antigen detection. Cell density and viral inoculum both affected the sensitivity of outgrowth to IFN-alpha. IFN-alpha was most effective when added at each feeding after infection as well as before infection with EBV. The mean of the lowest IFN-alpha concentration tested at which transformation failed to occur after infection with the B95-8 strain of EBV at a 50% transforming dose of 10(2.0) to 10(3.0)/ml was similar for unfractionated cord blood mononuclear cells, T-cell-depleted cord blood mononuclear cells, and adult T-cell-depleted mononuclear cells. The B95-8 strain and clinical EBV isolates required similar IFN-alpha concentrations to prevent outgrowth. In this system, IFN-alpha at pharmacologically achievable concentrations prevented EBV-induced B-cell outgrowth. These data indicate that IFN-alpha deserves further study as a potential therapeutic agent for EBV-induced syndromes.

Adult↗
PubMed1983

Drug therapy. Treatment of herpesvirus infections.

Guidelines for the prophylaxis or therapy of herpesvirus infections are shown in Table 1. Progress is so rapid in this area that frequent revisions of such guidelines will be necessary. Newer drugs or new formulations of older agents are constantly being developed. Combination therapies--e.g., interferon plus acyclovir--appear promising in laboratory models of herpesvirus infections and will undoubtedly receive clinical investigation in the years ahead. The problem of dealing with latent virus infections still eludes us, and major breakthroughs will be necessary before we can discuss cure of recurrent infections. Nevertheless, important strides have been made in the past few years, and further progress is predictable in the years ahead.

Acyclovir↗
PubMed1983

Central-nervous-system lymphoma related to Epstein-Barr virus.

We have studied five cases suggesting a relation between Epstein-Barr virus infection and primary lymphoma of the central nervous system. A 48-year-old man had primary lymphoma of the central nervous system in the absence of systemic lymphoma or immunosuppression. Development of the tumor was associated with serologic evidence suggesting a recent primary infection with Epstein-Barr virus. DNA preparations from tumor tissue, but not from adjacent normal brain tissue, contained Epstein-Barr virus genomes when hybridized with a probe consisting of the BamHI K fragment of Epstein-Barr virus strain FF41. Evaluation of serum samples from four additional patients with central-nervous-system lymphoma revealed patterns of Epstein-Barr virus-specific antibody that were suggestive of an ongoing infection with EBV. Our results suggest induction of the lymphoma by Epstein-Barr virus.

Antibodies, Viral↗
PubMed1983

Effects of interferon-alpha on cytomegalovirus reactivation syndromes in renal-transplant recipients.

We have previously demonstrated that six weeks of prophylaxis with interferon-alpha delays cytomegalovirus excretion and decreases viremia in recipients of kidney transplants. In a double-blind trial to evaluate the effects of a longer course of prophylaxis, we gave either 3 X 10(6) units of interferon or placebo intramuscularly to 42 patients before transplant surgery was performed. After surgery, doses were given three times a week for six weeks and then twice a week for eight weeks (total of 102 X 10(6) units). Clinical signs of cytomegalovirus infection were markedly reduced in interferon recipients. These signs developed in 7 of 22 placebo recipients and 1 of 20 interferon recipients (P = 0.03). Opportunistic superinfections (Aspergillus fumigatus and Pneumocystis carinii) occurred only in patients given placebo. Cytomegalovirus-associated glomerulopathy developed in one interferon recipient and three placebo recipients. Survival of patients and grafts was equivalent in both treatment groups, and minimal toxicity was observed with interferon. In seropositive renal-transplant recipients, interferon-alpha affords effective prophylaxis against serious cytomegalovirus infections.

Adult↗
PubMed1983

Association of herpesvirus infections with T-lymphocyte-subset alterations, glomerulopathy, and opportunistic infections after renal transplantation.

We studied the interrelation among herpes-virus infections, T-lymphocyte subsets, opportunistic infections, and renal histopathology in 28 recipients of renal allografts. All primary or reactivated herpesvirus infections occurring in the first three months after transplantation in recipients of cadaveric grafts accompanied persistent inversions in the ratio of OKT4 (helper/inducer) to OKT8 (cytotoxic/suppressor) lymphocytes. In the less heavily immunosuppressed recipients of organs of living related donors, these inversions were seen only in association with clinically apparent cytomegalovirus infections. Five of seven opportunistic infections occurred in patients with OKT4/OKT8 ratios of less than 1.0. Biopsy specimens from patients with renal dysfunction occurring in association with a low OKT4/OKT8 ratio frequently revealed glomerular damage rather than acute cellular rejection. Monitoring of T-lymphocyte subsets provides early evidence of herpesvirus infections and identifies patients at increased risk for opportunistic infection after renal transplantation.

Biopsy↗
PubMed1983

Functional properties of T lymphocytes and their subsets in cytomegalovirus mononucleosis.

Cytomegalovirus (CMV) mononucleosis is associated with diminished lymphocyte responses to mitogens and herpes virus antigens, and a reversal in the normal ratio of helper-inducer (OKT4-positive) to cytotoxic-suppressor (OKT8-positive) cells. In this report, we investigate the proliferative and cytotoxic functions of lymphocyte subpopulations from patients with CMV mononucleosis. Both mitogen responsiveness and the ability to generate cytotoxic lymphocytes against allogeneic Laz 156 cells in vitro were markedly diminished. Mononuclear cells enriched for OKT8+ lymphocytes showed little or no responsiveness to Con A; cells enriched for OKT4+ lymphocytes were considerably more responsive. During CMV mononucleosis, the predominant T cell subset is a hyporesponsive OKT8+ cell. In vitro culture of peripheral blood lymphocytes, however, resulted in a selective loss of OKT8+, OKIa+ cells, so that the remaining T cell population was composed primarily of Con A-responsive OKT4+ cells. Convalescence was associated with the return of OKT8+ responsiveness to Con A, a greater stability of OKT8+ cells during culture, and the partial recovery of ability to develop cytotoxic lymphocytes after in vitro sensitization.

Antibodies, Monoclonal↗
PubMed1982

Methylation of the viral genome in an in vitro model of herpes simplex virus latency.

An in vitro model of latency of herpes simplex virus type 1 (HSV-1) in a lymphoid cell line has been developed recently. CEM cells persistently infected with HSV-1 transiently ceased to produce virus for 24 days. This nonproductive state could either be reversed with phytohemagglutinin or maintained with concanavalin A. This system was used to study the relationship between DNA methylation and HSV-1 latency. DNA was probed for methylation by comparing the cleavage patterns generated by two pairs of restriction endonucleases (Sma I vs. Xma I and Hpa II vs. MspI); these enzymes show differential activity reflecting methylation of the recognition sequences. Viral DNA in the concanavalin A-treated cells (not producing virus) was found to be extensively methylated. By contrast, no methylated copies were detected in viral DNA from producer cells. About 800 days after the initial infection, the productive culture once again became nonproductive. Viral sequences in the latter cells were also methylated. Reconstitution experiments revealed 1-2 copies of viral DNA in cells from the latent stages and 40-80 copies in cells from productive stages. Most (if not all) of the viral genome is present in cells from various productive and latent stages. No differences in sequence arrangement were detected (although a terminal fragment of intracellular HSV-1 DNA appeared to be under-represented in latent cells). These results suggest a role for DNA methylation in the mechanism of HSV-1 latency in this system.

Cell Line↗