Paul H. Black

Controlled clinical trial of prophylactic human-leukocyte interferon in renal transplantation. Effects on cytomegalovirus and herpes simplex virus infections.

A double-blind, placebo-controlled trial of interferon prophylaxis against viral infections was conducted in renal-transplant recipients receiving standard immunosuprressive therapy with or without antithymocyte globulin. Interferon was administered for six weeks, beginning on the day of transplantation. Cytomegalovirus excretion began earlier and viremia was more frequent in placebo-treated than in interferon-treated patients. Cytomegalovirus viremia correlated with clinical syndromes was more frequent in recipients of antithymocyte globulin. In contrast, neither interferon nor antithymocyte globulin altered excretion of herpes simplex virus. Reversible leukopenia and thrombocytopenia occurred in seven interferon recipients. Patient and graft survival were comparable in interferon and placebo groups. There preliminary results suggest that a six-week course of prophylactic interferon delays shedding of cytomegalovirus and decreases the incidence of viremia after transplantation. In contrast, antithymocyte globulin appears to increase the severity of infection from cytomegalovirus among these patients.

Epstein-Barr Virus Infection in Renal Transplant Recipients: Effects of Antithymocyte Globulin and Interferon

We studied Epstein-Barr (EB) virus excretion and antibody in 41 renal transplant recipients enrolled in a placebo-controlled trial of human leukocyte interferon. Half the patients were also treated with antithymocyte globulin. Epstein-Barr virus excretion occurred more often in recipients of cadaver kidneys (P = 0.03) and those receiving antithymocyte globulin (P = 0.04) and less often in patients given interferon (P = 0.08). Antibody to viral capsid antigen increased fourfold or more in 12 of 22 patients treated with antithymocyte globulin and in none of the non-antithymocyte globulin-treated group (P = 0.0002). Antibody to the restricted component of early antigen rose fourfold or more in eight patients and appeared related to the occurrence of syndromes similar to those attributed to cytomegalovirus in transplant recipients. We conclude that increasing immunosuppression augments the rate of EB virus reactivation and that EB virus may be an important pathogen in heretofore ill-defined syndromes.

Shedding from Normal and Cancer-Cell Surfaces

The release of products from cells is commonly called secretion. Secretion implies the release of the soluble contents of secretory vesicles by a process known as exocytosis. In recent years, howev...

Proteolytic enzymes, cell surface changes, and viral transformation.

Publisher Summary This chapter reviews the evidence for and against the view that proteolysis plays a role in determining some of the phenotypic characteristics of virus-transformed cells. It discusses some aspects of the structure of the cellular membrane surface because one possible mechanism by which proteases might alter cell properties is via the selective proteolysis of cellular membrane surface components. It also reviews the current knowledge of some cellular phenotypic characteristics that are known to be altered by viral transformation and for which there exists at least suggestive evidence for the involvement of a proteolytic enzyme. The research into the involvement of the limited proteolytic enzymes of serum, in particular plasmin and thrombin, in virus-induced cell transformation has only just begun. It is possible to outline several mechanisms by which the plasmin or the thrombin system, or both, could, by limited proteolysis of the cellular membrane surface, produce several of the phenotypic changes characteristic of virus-transformed cells. A large body of circumstantial evidence implicating these enzyme systems in causing the altered phenotypic characteristics of virus-transformed cells has recently been obtained. However, critical experiments to prove that plasmin, thrombin, or other serum proteases modify the cellular membrane surface under the usual conditions of cell culture, in the presence of serum protease inhibitors, remain to be performed.

Leukemia Virus Activation during Homograft Rejection

Activation of murine leukemia viruses, as detected by the mixed culture cytopathogenicity (XC) assay, followed the transplantation of A/J skin onto immunosuppressed BALB/c mice. Virus was found in most of the mice receiving both skin grafts and antilymphocyte serum, but not in animals receiving either the serum alone, skin graft alone, or no treatment.

Canine Systemic Lupus Erythematosus. TRANSMISSION OF SEROLOGIC ABNORMALITIES BY CELL-FREE FILTRATES

The presence of viruses was sought in a colony of dogs bred from parents with systemic lupus crythematosus (SLE). Cell-free filtrates prepared from the spleens of these animals were injected into newborn dogs, mice, and rats. The canine recipients developed antinuclear antibody (ANA) and positive lupus erythematosus (LE) cell tests: ANA and, in some cases, antinative DNA antibodies were produced by the murine recipients: no abnormalities were detected in the rats. Serial passage of spleen cells or cell-free filtrates of spleen tissue in syngeneic mice reduced the time required for appearance of ANA from 9 to 4 mo. Some murine recipients of the canine filtrate developed malignant lymphomas. Murine leukemia viruses were identified in these tumors by electron microscopic, virologic, and serologic technics. These neoplasms, but not other tumors known to contain murine leukemia viruses, were associated with the production of ANA. Puppies inoculated with the canine filtrate-induced mouse lymphoma developed ANA and positive LE cell tests within 4 mo. THE RESULTS WERE INTERPRETED TO INDICATE THE PRESENCE IN CANINE SLE OF A VIRUS CAPABLE OF: (a) inducing the serologic abnormalities of SLE in normal dogs and mice: (b) activating latent murine leukemia viruses: and (c) spreading by both horizonal and vertical routes.

Activation of Mammalian Leukemia Viruses

Publisher Summary Successful transmission of murine leukemia by the passage of cell-free filtrates from leukemic tissue was first described in 1951. Viruses have subsequently been shown to be causally related to a wide variety of leukemias and lymphomas in many different mammalian species. Many of these viral agents were initially derived from tumors other than leukemias and some of them induce neoplasias uncharacteristic of those generally seen in nature. Others, however, were recovered initially from spontaneous or induced leukemias and induce similar tumors in the recipients. Still a third group of viruses were derived from apparently the normal tissues and were found to be capable of inducing leukemias or lymphomas either in the same or in a different genus or species of mammal. In these instances, the viral genetic information may vary from being unexpressed, partially or fully expressed. When viral information initially present in covert form becomes expressed in overt form, the process can be described as virus activation or induction. Many events, both physiological and pharmacological, are associated with the activation of leukemia viruses in vivo and in vitro . Among these events are radiation, treatment with hormones or chemicals, certain specific immunological reactions, and sometimes even aging itself. This chapter covers in vivo and in vitro activation of endogcnous mammalian leukemia viruses, both descriptively and analytically. It attempts to relate the phenomena described both to the current theories of viral oncogenesis and to the pathogenesis of mammalian cancer.

Analysis of SV40-induced transformation of hamster kidney tissue in vitro: VI. Characteristics of mitomycin C induction☆

Abstract Certain SV40-transformed hamster kidney cell lines can be reproducibly induced with mitomycin C to produce infectious SV40. Mitomycin C concentrations of 0.3–5.0 μg/ml are effective, and infectious virus first appears 3 days after treatment is begun. The induction process is sensitive to cytosine arabinoside between 24 and 36 hours after the beginning of mitomycin C treatment, indicating that DNA synthesis, probably of viral origin, is essential during that period for infectious virus to be produced. The induction process is also sensitive to homologous interferon, indicating that a viral gene(s) is susceptible to inhibition by the interferon system. Passage of an SV40-transformed hamster kidney cell line, not inducible by mitomycin C, through hamsters resulted in its becoming inducible. Attempts to induce SV40-transformed cells from species other than hamster with mitomycin C were unsuccessful. The findings that SV40-transformed cells contain an integrated viral genome(s) which can be induced directly by chemical means to produce infectious virus suggests that the virus:cell relationship in cells transformed by oncogenic DNA viruses has many similarities to bacterial lysogeny.

Evidence for membrane association of plasminogen activator activity in mouse macrophages

Production and release of high levels of plasminogen activator, a serine protease often referred to as a secretory product, has been considered as a biochemical index for mouse macrophage “activation”. Although the mechanism for plasminogen activator release is not known, several characteristics of the release process suggest that the enzyme may be shed from the cell surface of activated macrophages rather than secreted. In this paper, we show that plasminogen activator activity in thioglycollate elicited macrophages is predominantly associated with a subcellular fraction consisting mainly of membranes and granules which are pelletable at 100,000 x g. Furthermore, plasminogen activator activity can be solubilized only by detergents and not by treatments which are known to release granule-bound contents as well as loosely associated peripheral membrane proteins. Thus, these results suggest that macrophage plasminogen activator is firmly found to cellular membranes.

Cellular immunity in the mouse. V. Further studies on leukemia virus activation in allogeneic reactions of mice: stimulatory parameters.

Abstract The relationship between activation of thymic (T)-derived lymphocytes and mouse leukemia virus (MuLV) induction were studied in vivo and in vitro . The results indicate that there is no simple relationship between the severity of GVH, assayed by splenomegaly, alteration of T-cell reactivity in vitro , the activation of mouse leukemia viruses, and the subsequent development of lymphoma. Allogeneic stimulation either in vivo or in vitro is a potent activator of MuLV, as is the drug iododeoxyuridine. However, nonspecific T-cell mitogens such as PHA or Con-A, the drug cyclophosphamide, or specific antigenic stimulus such as sheep red blood cells after in vivo sensitization are not effective virus activators. The source of the cell supporting MuLV replication in vitro appears to be a theta-positive (T) lymphoblast.