Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1998-10-29
2003-01-14
Spector, Lorraine (Department: 1646)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
Reexamination Certificate
active
06506892
ABSTRACT:
BACKGROUND OF THE INVENTION
Epstein-Barr Virus (EBV) is a lymphotropic virus in humans that is closely associated with two malignancies, Burkitt's lymphoma, and nasopharyngeal carcinoma, as well as a lymphoproliferative disorder, infectious mononucleosis. Also, in recent years, several EBV-associated proliferative syndromes and malignancies have been described in the profoundly immunocompromised host.
There are two main types of EBV carrying B lymphocyte lines, i.e., Burkitt's Lymphoma derived (BL) and lymphoblastoid (normal lymphocyte) derived cell line (LCL). BL lines, which are derived from malignant cells in tumor biopsies, are monoclonal, usually aneuploid with a specific chromosomal translocation, bear a characteristic glycoprotein pattern, and are tumorigenic in nude mice. The LCL lines are derived from normal B cells, are polyclonal, have a normal diploid karyotype, a glycoprotein pattern similar to stimulated normal B cells, and do not grow when explanted subcutaneously into nude mice. LCLs, however, do grow in nude mice when inoculated intracerebrally, suggesting that immunological restriction is important in controlling outgrowth of EBV-carrying cells, even in a xenogeneic host. Reports of polyclonal outgrowths of karyotypically normal EBV-carrying cells in immunodeficient individuals confirm this observation (Houweling, A., P. J. van den Elsen, A. J. van der Eb [1980]
Virology
105:537; Rassoulzadegan, M., A. Cowie, A. Carr, N. Glaichenhaus, R. Kamen, F. Cuzin [1982]
Nature
300:713; Treisman, R., U. Novak, J. Favaloro, R. Kamen [1981]
Nature
292:595; Giovanella, B., K. Nilsson, L. Zech, O. Yim, G. Klein, J. S. Stehlin [1979]
Int. J. Cancer
24:103).
In general, tumor cells develop from normal cells by a multistage process. Two critical stages include (a) immortalization, i.e., the ability to divide perpetually without exogenously supplied mitogenic stimuli, and (b) acquisition of resistance to negative homeostatic signals that normally regulate growth. These stages may be associated with cytokines because regulation of proliferation and differentiation in most eukaryotic cells is accomplished by the interaction of specific cytokines with cell surface receptors. Receptor activation is followed by transmembrane signal transduction which leads to the generation of specific second messenger molecules. These receptor dependent events result in a defined series of cytoplasmic and/or nuclear changes leading to regulation of cellular activity.
Autonomous growth, as a result of transformation associated events, occurs in normal B cells transformed in vitro by EBV, and also in B cells derived from EBV positive and negative malignancies. EBV-transformed normal B lymphocytes divide continuously in culture without help from T cells or macrophages. Factor dependent autostimulatory growth for EBV-carrying B lymphocytes has now been reported by many groups. This secreted growth enhancing activity is specific for mature lymphoid cells. In addition, immortalized EBV-carrying B cells respond differently than normal B cells to certain cytokines, e.g., they proliferate in response to TGF&bgr; and IL-6. After EBV infection, B lymphocytes have an altered morphological appearance, produce immunoglobulin, and become independent of exogenous differentiation factors and resistant to saturation conditions in cell culture.
How lymphoid cells communicate with each other to affect cell growth, differentiation, and functional activities has been a major focus of investigation. The immune response to foreign antigens is dependent on the interactions of several different cell types, including macrophages, T, and B lymphocytes. The first described soluble growth factor of lymphoid origin, T cell growth factor (IL-2), was found in supernatants of lectin stimulated peripheral blood lymphocytes. Since the discovery of IL-2, various studies have described many additional growth factors and have begun to delineate the mechanisms controlling lymphocyte proliferation.
For the B lymphocyte, our understanding of the regulation of growth and differentiation has increased in complexity in the past few years. A plethora of factors, including BCGF (12 and 60 kD), IFN&ggr;, TNF&agr;, lymphotoxin, TGF&bgr;, IL-1&agr;, IL-1&bgr;, IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12, IL-15 and C3 fragments have been reported to modulate the growth of human and/or murine B lymphocytes in cell culture studies. These effects include growth augmentation (BCGF), differentiation (IL-6), and inhibition of proliferation (TGF&bgr;). It appears that many of the T lymphocyte derived immunomodulatory molecules which direct B lymphocyte activities also regulate pleomorphic T cell functions. Some affect growth (IL-2), whereas others can also cause changes in cellular differentiation (IL-3). IL-2 functions as a direct growth factor for T lymphocytes, but other factors (IL-1) are described as comitogens or “helper” factors for cells stimulated by antigen or mitogen. IL-1, however, has recently been reported to function as a direct growth factor for one T cell sub-clone (Orencole, S. F., C. A. Dinarello [1989]
Cytokine
1:14). For murine lymphocytes, two distinct CD4 expressing helper T cell subsets, Th1 and Th2, have been identified which differ in terms of factor response and production. Strictly similar subsets of distinct human T lymphocytes have not yet been described. Murine Th2 T cells secret IL-10, a 17 kD molecule which can inhibit Th1 cell activity. IL-10 has extensive homology with an uncharacterized EBV gene, BCRF1 (Baer, R., A. T. Bankier, M. D. Biggin, P. L. Deininger, P. J. Farrell, T. J. Gibson, G. Hatfull, G. S. Hudson, S. C. Satchwell, C. Sequin, P. S. Tuffnell, B. G. Barrell [1984]
Nature
310:207).
Several growth factors have been proposed to have stimulatory activity for EBV transformed cells. These include BCGF (Ambrus, J. L., A. S. Fauci [1985]
J. Clin. Invest.
75:732), IL-1 (Blazar, B. A., L. M. Sutton, M. Strome [1986]
Canc. Immunol.
22:62), CD23 (Swendeman, S., D. A. Thorley-Lawson [1987]
EMBO J.
6:1637), an unidentified lymphokine, called autocrine B Growth Factor, aBGF (Buck, J., U. Hammerling, M. K. Hoffmann, E. Levi, K. Welte [1987]
J. Immunol.
138:2923), and, most recently, IL-6 (Muraguchi, A., H. Nishimoto, N. Kawamura, A. Hori, T. Kishimoto [1986]
J. Immunol.
137:179). Thus far, none of these molecules has been shown to be universally present or absolutely required for growth of EBV positive lymphoblastoid cell lines. BCGFs of 25-30 kD and 60 kD, which are similar to T cell derived lymphokines, have been identified in supernatants from EBV-carrying cells. 60 kD BCGF has been purified to homogeneity and, although an activator of stimulated normal B cells, it is not produced by all EBV-carrying lines or even by all cells in individual secretor lines. BCGF production has also been reported for activated normal B lymphocytes (Muraguchi et al., supra).
Certain EBV-carrying cells have been reported to function as antigen presenting cells, contain IL-1 like activity in their supernatants, and express mRNA for IL-1. One laboratory reported the purification of a novel IL-1 from an EBV-carrying line (Bertoglio, J., J. Dosda, R. Stancou, E. Wollman, D. Fradelizi [1989]
J. Mol. Cell Immunol.
4:139) but later revised their findings (Bertoglio, J., E. Wollman, A. Shaw, L. Rimsky, D. Fradelizi [1989]
Lympho. Research
8:19). This same laboratory now reports that an IL-1-like activity (ADL) is elicited by a 12 kD protein produced by both EBV and HTLV-1 transformed cells (Wakasugi, H., N. Wakasugi, T. Trusz, Y. Tagaya, J. Yodoi [1989]
J. Immunol.
142:2569; Tagaya, Y., Y. Maeda, A. Mitsui, N. Kondo, H. Matsui, J. Hamuro,, N. Brown, K. Arai, T. Yokota, H. Waksugi, J. Yodoi [1989]
EMBO J.
8:757). Cloning of this protein, ADL, indicates it is a member of the human thioredoxin family with no direct relatedness to IL-1, although it may enhance IL-1 f
Blazar Beverly A.
Webb Andrew C.
Saliwanchik Lloyd & Saliwanchik
Spector Lorraine
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