Drug – bio-affecting and body treating compositions – Lymphokine
Patent
1987-02-02
1990-05-01
Teskin, Robin L.
Drug, bio-affecting and body treating compositions
Lymphokine
530387, 530389, 435 29, 4352402, 424 852, 424 95, 424101, A61K 3900, C07K 1300
Patent
active
049216678
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION.
This invention relates to a method for increasing antibody production and enhancing humoral immune response. According to this method, delta-immunoglobulin (IgD) is used to induce lymphocytes (especially T cells) that initiate or mediate immunostimulatory action.
BACKGROUND OF THE INVENTION
IgD is one of five known classes of immunoglobulins. It is present on the surface of mature B cells (where it is co-expressed with IgM) but its serum levels are low. In contrast to other Ig isotypes, IgD is not secreted following antigenic stimulation of the B cells that bear it.
Although, apparently, surface IgD (sIgD) can function as a receptor for stimulation of B cells to enter the cell cycle, IgD has not been assigned a clear, specific function in immune response. At this time, more is known about what IgD does not do than what it does.
There are indications that IgD may play an important role in resistance to induction of antigen tolerance: see, Vitetta, E.S. and Uhr, J.W. Science 189:964 1975, who report that the B cells of young mice (that typically show tolerance) express only IgM, not IgD. The onset and increase of tolerance resistance parallels the ability of the B cells of the growing mouse to express IgD. The observed decrease in surface IgD of B cells subsequent to antigen stimulation is consistent with the tolerance resistance hypothesis.
Finkelman, F.D. et al. J. Immunol. 133:550, 1984 and N.Y. Acad. Sci. 399:316, 1982 have shown that administration to mice of goat anti-(mouse IgD) caused the B cells of the mice to produce significantly higher amounts of polyclonal IgGl antibodies. The authors interpreted these results as indicating the existence of nonspecific T help in the mouse system. The authors also observed an apparent suppression of antibody production when they administered high levels of goat anti-(mouse IgD).
There is evidence of the existence of T-cell sub-populations that are isotope-specific for IgA, IgE, IgG and IgM both in humans and in mice. IgA-specific T cells (T.sub.a)--but not T.sub.e, T.sub.g, or T.sub.m --have been induced by IgA-secreting plasmacytomas. These T.sub.a cells have been studied extensively but have not been found to augment humoral immune responses.
In Scand. J. Immunol. 11:377-382, 1980, 0. Sjoberg reported that a small percentage of normal human lymphocytes (0-6.5%) formed rosettes with IgD-coated latex particles. This is the earliest report known to the present inventors suggesting the existence of lymphoid cells with a receptor for IgD. However, the reported incidence of these cells does not exceed background levels for isolated peripheral blood leukocytes, which is what Sjoberg used in this study. Therefore, the results reported in this article are inconclusive. Moreover, the author does not suggest any therapeutic or other use for cells with IgD receptors.
IgD-producing plasmacytomas were discovered by Finkelman, F.D. et al. 1981 J. Immunol. 126:680, incorporated herein by reference. These plasmacytomas were induced by injecting Balb/c mice intraperitoneally with 0.5 ml of tetramethylpentadecane (pristane).
In Xue, B., et al., J. Exp. Med 159:103-113 (Jan. 1984) the authors (who include the present inventors) report the following observations for mice only: IgD-containing whole ascites fluid from plasmacytoma-bearing mice exhibit enhanced antibody production upon subsequent challenge with antigen. This was observed for antibodies of both the IgM and the IgG isotype. only.
The authors postulated that the immunoaugmenting effect was due to T cells having a receptor for IgD that were elicited following injection of IgD.
The practical significance of the work reported in this article is limited for several reasons. First, the ability of IgD-plasmacytoma or IgD-plasmacytoma ascites fluid to stimulate IgG production cannot be used for therapeutic applications in humans. Introduction of tumor cells and ascites fluid from ascites tumor bearing mice would be hazardous to the recipients.
Second, increased production of IgM is not as desirable a
REFERENCES:
patent: 4490289 (1984-12-01), Stern
patent: 4689400 (1987-08-01), Finkelman
Coico et al., J Exp. Med., vol. 162, pp. 1852-1861., Dec. 1985, "Physiology of Igd. Transfer of the . . . Helper Cell Populations".
Finkelman et al., JImm, vol. 129, pp. 638-646, "Polyclonal Activation of the Murine Immune System . . . IgD".
Cuchens et al., J Tmm, vol. 121(6) Dec. 1978, "The Effects of Anti-IgD on Serum Immunoglobulins, Antibody Production, and Immunoglobulin-Bearing Cells".
Xue et al., J Exp Med., vol. 159, pp. 103-113, Jun. 1984, "Physiology of IgD Enhancement of Antibody Production".
Coico et al., Nature, vol. 316, Aug. 1985, pp. 744-746, "T Cells With Receptors for IgD".
Khorobrykh et al., Biol Abst., 1978, vol. 66, No. 246264, "Effect of Antisera to Aggregated Mouse Immuno-Globulin on the Population of Lymphoid . . . Cells".
Coico Richard F.
Thorbecke G. J.
New York University
Teskin Robin L.
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