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J G Sinkovics

Publications and source records attributed to J G Sinkovics.

At least 19 recordsLinked to original sources
PubMed2005

A notable phenomenon recapitulated. A fusion product of a murine lymphoma cell and a leukemia virus-neutralizing antibody-producer host plasma cell formed spontaneously and secreting the specific antibody continuously.

In the mid-1960s the #620 cell passage line of a murine lymphoma-leukemia was developed at the Section of Clinical Tumor Virology and Immunology, Department of Medicine, The University of Texas M.D. Anderson Hospital in Houston, TX. The diploid lymphoma cells released a retrovirus and were antigenic in young adult Swiss (YAS) mice. Small lymphoma cell inocula were rejected with immunity acquired against large inocula of lymphoma cells. Tissue sections revealed the "starry sky" configurations. In one of the tissue cultures set up from lymphoma #620, a cell line consisting of large round poly- or tetraploid cells arose and was referred to as lymphoma cell line #818. The #818 cells grew in suspension cultures and in the form of large, lethal ascitic tumors in YAS mice. Diploid #620 lymphoma cells stained for retroviral antigens; #818 cells stained both for retroviral antigens and immunoglobulins. Fluids withdrawn from #818 cultures neutralized the leukemia virus in spleen focus assays. Immunoglobulin precipitated from #818 suspension culture fluids strongly and specifically neutralized the leukemia virus. The growth of #620 or #818 cells in YAS mice treated with rabbit anti-lymphoma cell immune sera was strongly inhibited but culture fluids of #818 cells showed weak and insignificant inhibition against leukemia-lymphoma #620 (in one experiment, unpublished). In two experiments #620 lymphoma cells were co-inoculated with immune spleen cells into the peritoneal cavities of YAS mice. The immune spleen cells derived from mice that rejected #620 cell inocula or were actively immunized with a photodynamically inactivated mouse leukemia virus vaccine. In the peritoneal cavities of mice co-inoculated with #620 cells and immune spleen cells, clones of large round cells emerged with tetra- or polyploid chromosomal modes. These cells stained for leukemia viral antigens and immunoglobulins. When passaged in YAS mice these cells induced lethal ascites tumors. It was concluded as early as in 1968-69 that an immune plasma cell can fuse with a lymphoma cell, if the lymphoma cell expresses retroviral antigens against which the plasma cell is producing a specific antibody. Some human lymphoma-leukemia cells express retroviral antigens and/or budding retroviral particles, whether due to the acquisition of new env sequences by incomplete resident endogenous retroviral genomes or due to the entry of exogenous retroviruses into lymphopoietic stem cells. In the Discussion illustrations are provided for the human cell line #778 established from a patient with "lymphosarcoma cell leukemia" in 1966. The malignant cells released unidentified retrovirus-like particles and fused with one another and with reactive lymphoid cells of the host. It should be investigated further if human lymphoma-leukemia cells could fuse with an immune plasma cell of the host and thus alter the clinical course of the disease.

Animals↗
PubMed2001

The place of viruses in the "tree of life".

Ribozymal entry into vesicle containing autocatalytically replicating oligopeptides engendered RNA proliferation and enzyme synthesis within units whose RNA genomes derived from ancestors of viroids. There is good reason to consider the coexistence of proto- or spheroplastic forms of ancient prokaryotes and archaeons. Predecessors of extant mycoplasmavirus L3 or archaeal fuselloviruses could induce cell fusions among these entities. The possibility that the first eukaryotic cells arose consequentially to virally mediated fusions of prokaryotic and archaeal proto- or spheroplasts is presented. Retrotransposons and endogenous retroviruses might have emerged in theropod dinosaurs when Aves evolved; and directed the development of syncytiotrophoblasts in the placentae of the first mammals. As viruses coevolved with their hosts descendants of ancient viruses diverged from one another. Certain phenotypical features could connect extant phages and eukaryotic viruses to common ancestors.

Animals↗
PubMed2001

Virological and immunological connotations of apoptotic and anti-apoptotic forces in neoplasia.

Against the background of its earliest recognition, programmed cell death (PCD) or apoptosis (A) is presented in its fundamental biological contexts. Techniques of its demonstration are listed. Former original works of the authors encompass designs for genetically engineered oncolytic viruses. Presented here are observations on mesenchymal stromal cells of the bone marrow serving as feeder layers to chronic lymphocytic leukemia (CLL) cells (recently rediscovered elsewhere as subverted "nurse cells" protecting CLL cells from A). A-resistant human melanoma cells are shown to expropriate the Fas ligand to Fas receptor (CD95; APO-1) (FasL-->FasR) system for their autocrine growth loop not only in melanoma cells coexpressing CD95 and its ligand but also in CD95-positive melanoma cells undergoing divisions when exposed to CD95 ligand. Bi-directional A-induction is demonstrated upon the encounter of cytotoxic lymphocytes and targeted tumor cells as exemplified with lymphomas; and chemotherapy-induced A of malignant cells as exemplified by paclitaxel-induced PCD of Reed-Sternberg (RS) cells in a case of chemotherapy-resistant Hodgkin's disease (HD). A list of interventions capable of inducing A in tumor cells is provided. These interventions are of potential therapeutic value. The balance of apoptotic and anti-apoptotic forces in virally infected normal and malignant cells is discussed.

Adenosine Triphosphate↗
PubMed2000

Newcastle disease virus (NDV): brief history of its oncolytic strains.

BACKGROUND: While genetically engineered viruses are now being tested for the virus therapy of human cancers, some naturally occurring viruses display unmatched oncolytic activity. Newcastle disease virus (NDV) excels as an oncolytic agent. OBJECTIVES: As its virulence versus attenuation can be explained on molecular biological bases, it may be possible to develop or select highly oncolytic strains of NDV without adverse toxicity. STUDY DESIGN: Questions are posed as to the mechanisms of viral oncolysis, the appropriateness of tests to predict oncolytic activity of a given NDV strain and the best modes of administration for oncolytic effects. Answers are provided based on specific data or on considerations drawn from experience (the authors use NDV oncolysates to immunize against melanoma and kidney carcinoma) or from analogous clinical situations (therapeutic use of mumps or measles viruses). RESULTS AND CONCLUSIONS: NDV oncolysates probably suit better for immunotherapy (providing also active tumor-specific immunization) than massive repeated inoculations of NDV strains, especially when the NDV strain used is not proven to be oncolytic by appropriate pre-clinical tests.

Antigens, Viral↗
PubMed2000

Vaccination against human cancers (review).

Classical and molecular immunological means of active tumor-specific immunization against human cancers yielded whole cell or tumor cell lysate vaccines of preventive value (reduced relapse rates) and dendritic cell-peptide or genetically engineered vaccines that may induce remissions even in metastatic disease. Active tumor-specific immunization was often successful in the past 50 years against experimental tumors maintained in the laboratory. During the epochs of classical and molecular immunology several vaccines were generated and used for the reduction of relapse rates of human cancer after surgical removal of the primary or metastatic tumors. Whole cell vaccines consist of X-irradiated autologous or allogeneic tumor cells coadministered with immunostimulants (BCG, Detox). Tumor cells haptenized biologically (as in viral oncolysates) or chemically were also used. Dendritic cell vaccines are prepared by transfection or transduction with tumor antigen-encoding DNA or by pulsing the cells with antigenic peptides in vitro; or collecting dendritic cells that engulfed apoptotic tumor cell DNA and/or peptide antigens in vivo for reinjection into the patient. Genetically engineered tumor cells are prepared in vitro to express MHC and peptides, costimulatory molecules (B7.1) and cyto- or lymphokines (interferons, interleukins, hematopoietic growth factors) for vaccination of patients. Antibody- and immune T cell-mediated immune reactions to autologous tumor cells are newly generated and/or quantitatively increased in immunized patients but do not always correlate with clinical response. Most vaccines are claimed to have reduced relapse rates presumably by inducing effective host immunity against micrometastases. Dendritic cell-peptide vaccines could induce partial or occasionally complete remissions in metastatic disease. The wrong antigenic presentation may result in tolerance induction toward the tumor; occasionally tumor enhancement may occur. Human tumor antigens when presented appropriately (with costimulatory molecules and with IL-2, IL-12) break the host's natural tolerance toward its tumor and induce rejection strength immune reactions even in patients with metastatic disease. Immune T cells thus generated could be collected for adoptive immunotherapy. For successful active specific immunization against human cancers the understanding of the immunoevasive maneuvers of the tumor cell (through FasL --> Fas; TRAIL; CD40L --> CD40; TGFbeta etc. systems) is essential.

Cancer Vaccines↗
PubMed1999

Cancer vaccines with emphasis on a viral oncolysate melanoma vaccine.

Biotherapy of malignant diseases has become the fourth treatment modality besides surgery, chemo- and radiotherapy. Whole cell melanoma vaccines with or without BCG and other adjuvants, purified ganglioside and shed antigens, recombinant viruses carrying tumor antigens, dendritic cells pulsed with antigenic peptides etc. are in clinical trials. Efficacious viral oncolysate vaccines induce the host to mount tumor-specific cytotoxic T-cell response and prevention of relapses is supported by clinical trials. The use of "polyvalent" whole cell vaccines vs. purified or genetically engineered single antigen vaccines is justified as i. only very few single tumor antigens are present in all tumors of a given histological type; and ii. antigen modulation occurs in tumors rendering them resistant to immune attack generated by vaccine against a single antigen. Thus polyvalent vaccines immunize against several antigens vs. against a selected antigen.

Adjuvants, Immunologic↗
PubMed1999

Kaposi's sarcoma: breeding ground of herpesviridae - A tour de force over viral evolution (review).

After reviewing the molecular biological basis of prominent theories for the integration of viruses into the earliest forms of living matter, an account is given on the immunoevasive strategies viruses have had to acquire in order to secure their existence against the most sophisticated anti-viral defensive mechanisms evolving in their hosts. Herpes-viridae and Kaposi's sarcoma illustrate the complexity of host-virus relationship. In following the evolutionary steps of simians and hominoids to Homo, it becomes evident that: a) Epstein-Barr virus evolved in Africa and its ancestral viruses are present in cercopithecines and hominoids; b) human herpes-virus-8-related viruses are present in macaques, in S. American primates and in Homo but such isolates from the great apes are missing. Thus interspecies transfer occurred from lower monkeys to Homo but when and at what geographical location? The human retrolentiviruses also jumped species barriers: this occurred recently in Africa, from great apes (chimpanzee and bonobo) to Homo sapiens (except when HIV-2 was transferred to mankind from sooty mangabeys). The matter is further complicated by the long coevolutionary cooperative interactions between herpes- and retrolentiviruses. Of pathological entities suspected to be etiologically affected by such complex viral cooperation, the origin of Reed-Sternberg cells of Hodgkin's disease is singled out for critical analysis. In this article the senior author summarizes his own 52 years of studentship in virology.

Animals↗
PubMed1997

Malignant lymphoma arising from natural killer cells: report of the first case in 1970 and newer developments in the FasL-->FasR system.

In 1970 at the University of Texas MD Anderson Hospital, Houston TX, we attended a patient with malignant lymphoma and "lymphosarcoma cell leukaemia". The malignant cells were large with fine granular cytoplasm. The patient was febrile without positive cultures and exhibited wasting resembling "graft-vs-host" disease. Both his lymphoma cells collected from the blood, and his serum, exerted strong cytotoxicity toward a battery of human tumour cell lines established in culture. We reported him as the first case of a new entity; "cytotoxic lymphoma". Later, elsewhere, natural killer (NK) cells were characterized, and cases of malignant lymphomas arising from large granular lymphocytes were described, as those of NK cells. Malignant NK cells constitutively express Fas ligand (L), both membrane-bound (m) and soluble (s). Upon binding FasL Fas receptor (R)-positive hosts cells succumb to apoptotic death. Patients with FasL-producer lymphoma cells suffer from anaemia, neutropenia, hepatotoxicity and autoimmunity. The FasL-->FasR system regulates normal lymphocyte homeostasis. This system is used by the placental trophoblast against maternal lymphocytes; by transplants against host lymphocytes; and by donor lymphocytes exerting graft-vs-host-reaction. In tumour immunology, FasR+ tumour cells can be killed by FasL+ lymphocytes and, vice versa, FasL+ tumour cells can induce apoptotic death of FasR+ host lymphocytes ("counterattack on lymphocytes"). Some tumour cells co-express FasL, FasR and bcl-2 and not only escape programmed cell death but also utilize the FasL-->FasR system as an autocrine growth loop ("counterattack on apoptosis").

Fas Ligand Protein↗
PubMed1995

Can virus therapy of human cancer be improved by apoptosis induction?

Direct virus inoculations and viral oncolysates may induce temporary remissions and prolong life with reduced tumor burden, or decrease relapse rates but fall short of curing human cancers. We propose: (i) investigations of Cassel's 73-T, an Ehrlich's mouse ascites carcinoma-adapted Newcastle disease virus (NDV) strain that so effectively reduced relapse rates in malignant melanoma if it is an admixture or a recombinant with a murine parvovirus; (ii) transfection of prostatic carcinoma cells with the TRMP gene; (iii) transfection of sarcoma cells with the fas gene followed by treatment with anti-fas monoclonal antibodies, and (iv) treatment of metastatic tumors with a parvovirus incorporating the apoptosis-inducer Ad5 E1A gene.Thus, replicating virions and haphazard generation of cytokines in the inoculated host could be replaced with transfection of single genes of well-defined, limited but selected efficacy.

Adenovirus E1A Proteins↗
PubMed1994

Autologous activated lymphocyte therapy in a community hospital.

In the authors' institution patients suffering from metastatic melanoma, renal cell carcinoma or mesothelioma, resistant to conventional therapeutic modilities, are treated with adoptive immunotherapy. Tumour infiltrating lymphocytes (TIL) are prepared from surgical samples and expanded ex vivo in the presence of recombinant interleukin-2 (rIL-2). When sufficient amount of cells are available (5 x 10(9)-10(10)) they are being reinfused. The patients also receive rIL-2 subcutaneously to support the activity and proliferation of reinfused TIL, and to avoid side effects caused by bolus or continuous intravenous administration. Leukapheresed lymphocytes activated by conditioned medium from OKT3 stimulated autologous lymphocytes and rIL-2 (autologous activated lymphocytes, AAL) are used as an alternative when TIL is not available or until it can be produced in sufficient amount. Subcutaneous IL-2 and oral cimetidine are also administered to support the reinfused AAL and to inhibit activation of CD8+ suppressor cells, respectively. Expression of activation markers CD25 and HLA-DR are monitored by flow cytometry as well as cytotoxicity is measured against K562 (NK specific target), HeLa (AALT specific) and against allogeneic or autologous tumour cell targets with a non-radioactive test. Methods are discussed by which the therapeutic efficiency of infused lymphocyte preparations can be improved.

Carcinoma, Renal Cell↗
PubMed1994

Adoptive immunotherapy with activated peripheral blood lymphocytes.

Adoptive immunotherapy is used to treat malignant tumors resistant to conventional therapeutic modalities. Patients with metastatic melanoma, renal cell carcinoma or mesothelioma are most likely to benefit from this treatment. Tumor infiltrating lymphocytes (TIL) contain tumor specific killer cells and are found to be the most effective. When TIL is not available or until it can be produced in sufficient amount, autologous activated lymphocytes (AAL) are an alternative. AAL are leukapheresed lymphocytes, activated by conditioned medium from OKT3 stimulated autologous lymphocytes. Subcutaneous IL-2 and oral cimetidine are also administered to support the reinfused AAL and to inhibit activation of CD8+ suppressor cells, respectively. To improve the yield and activation of reinfused lymphocytes, addition of IL-2 to the culture medium was tested in different time intervals after the onset of the culture. Interleukin-2 added in the first or second day i) improved the yield of activated lymphocytes; ii) increased the expression of activation markers CD25 (IL-2 receptor) and HLA-DR and iii) augmented killing of tumor cells. Later addition of IL-2 had no or negative effects. In vitro priming of peripheral blood mononuclear cells with autologous or allogeneic but histologically identical tumors was used to increase tumor-specificity of AAL. Autologous serum, containing antibodies specific to tumor cells, facilitated antigen presentation and yielded cytotoxic lymphocytes capable of efficiently killing tumor cells.

Humans↗
PubMed1993

Multiple pathogens may induce growth factor cascade resulting in KS.

While lipopolysaccharide endotoxin is the most prominent inducer of the kinecascade (TNF alpha, IL-1, 4, 6, 8) that leads to shock and multiple organ failure, bacterial exotoxins and products of certain gram positive bacteria can induce the same end results. We theorize that more than one pathogen can induce the sequence of protooncogene activation and growth factor release that results in the formation of KS. If KS has its own unique viral etiology, this virus has not as yet been isolated or identified but we continue to search for it. However, it is entirely possible that these lesions do not have a single well-defined etiologic agent but are the result of multiple agents cooperating in a set sequence. An endogenous, or apathogenic exogenous, retrovirus may replace HIV for initiator growth factor induction in CD4 cells in the classical (Mediterranean) or iatrogenic disease; and other pathogens co-exist or sequentially replace each other in the African endemic disease; whereas an array of viral pathogens (prominent among them CMV) take over growth factor induction in endothelial cells proliferating in response to the initiator growth factor (oncostatin M) released from HIV-infected CD4 lymphocytes in AIDS-KS.

Acquired Immunodeficiency Syndrome↗