Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1995-11-09
2003-06-10
Nolan, Patrick J. (Department: 1644)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S023100
Reexamination Certificate
active
06576754
ABSTRACT:
BACKGROUND OF THE INVENTION
Induction of a humoral response is important in host defense, for example, in fighting infections by pathogens. A humoral response is mediated by B cells, but requires the help of other cells, such as T cells. Development of a humoral response is a multistage process which occurs primarily in secondary lymphoid tissues.
Resting B cells circulate in the blood, pass through secondary lymphoid tissues, such as lymph nodes, Peyer's patches, spleen and tonsils, where they come into contact with trapped antigens. B cells recognizing a specific antigen through their surface immunoglobulins process the antigen and enter the T cell rich paracortical regions below the outer layer, or cortex, of lymphoid tissues. Some of the T cells in this region have been activated through contact with antigen presenting cells. These T cells in turn promote B cell activation by direct contact with the B cells via interaction of cell surface molecules and by the secretion of T cell-specific cytokines, such as IL-2, IL-4, and IL-5. This cell-cell interaction between T and B cells or production of T cell specific cytokines induces B cells to migrate into B cell follicles. In these follicles, the B cells interact with follicular dendritic cells having antigen-antibody complexes on their surface resulting in the formation of a germinal center. B cells in germinal centers undergo active proliferation, affinity maturation, and differentiation into memory B cells or antibody secreting plasma cells. Thus, whereas antibody-secreting plasma cells produce antibodies to fight infections, memory B cells assure a more rapid response to subsequent exposure to the same antigen.
Some molecules involved in the induction of B-cell proliferation and differentiation have been identified. In addition to cytokines produced in large part by activated T cells, crosslinking of specific B cell surface molecules also provide such signals (Clark E. A. et al, (1994),
Nature
367, 425). One such B cell surface molecule is CD40. CD40 is a 45-50 kD protein expressed on activated B cells. Valle et al., (1989),
Eur. J Immunol,
19:1463-1467; Gordon et al., (1988),
J Immunol.,
140:1425-1430; Gruber et al., (1989),
J Immunol,
142: 4144-4152. Crosslinking of CD40 with antibodies or with its natural ligand, CD40L, also termed gp39, together with other stimulatory signals induces B cell proliferation and antibody production. Armitage et al., (1992),
Nature,
357:80-82 ; Hollenbaugh et al., (1992),
EMBO J,
11:4313-4319.
T cells are not only required for providing help to B cells, but also play a major role in cellular immune responses, such as in delayed type hypersensitivity reactions and in cytotoxicity. To exert their activity, T cells must be activated. To induce antigen-specific T cell activation and clonal expansion, two signals provided by antigen-presenting cells (APCs) must be delivered to the surface of resting T lymphocytes (Jenkins, M. and Schwartz, R. (1987)
J. Exp. Med
165, 302-319; Mueller, D. L., et al. (1990)
J Immunol.
144, 3701-3709; Williams, I. R. and Unanue, E. R. (1990)
J Immunol.
145, 85-93). The first signal, which confers specificity to the immune response, is mediated via the T cell receptor (TCR) following recognition of foreign antigenic peptide presented in the context of the major histocompatibility complex (MHC). The second signal, termed costimulation, induces T cells to proliferate and become functional (Schwartz, R. H. (1990)
Science
248, 1349-1356). Costimulation is neither antigen-specific, nor MHC restricted and is thought to be provided by one or more distinct cell surface molecules expressed by APCs (Jenkins, M. K., et al. (1988)
J Immunol.
140, 3324-3330; Linsley, P. S., et al. (1991)
J. Exp. Med
173, 721-730; Gimmi, C. D., et al., (1991)
Proc. Natl. Acad Sci. USA.
88, 6575-6579; Young, J. W., et al. (1 992)
J Clin. Invest.
90, 229-237; Koulova, L., et al. (I 991)
J. Exp. Med
173, 759-762; Reiser, H., et al. (1992)
Proc. Natl. Acad. Sci. USA.
89, 271-275; van-Seventer, G. A., et al. (1990)
J. Immunol.
144, 4579-4586; LaSalle, J. M., et al., (I 991)
J Immunol.
147, 774-80; Dustin, M. I., et al., (1989)
J Exp. Med
169, 503; Armitage, R. J., et al. (1992)
Nature
357, 80-82; Liu, Y., et al. (1992)
J. Exp. Med.
175, 437-445). B7- 1 and B7-2 are two such costimulatory molecules which interact with CD28 and CTLA4 on T cells (Linsley, P. S., et al., (1991)
J. Exp. Med.
173, 721-730; Gimmi, C. D., et al., (1991)
Proc. Natl. Acad. Sci. USA.
88, 6575-6579; Koulova, L., et al., (1991)
J Exp. Med.
173, 759-762; Reiser, H., et al. (1992)
Proc. Natl. Acad. Sci. USA.
89, 271-275; Linsley, P. S. et al. (1990)
Proc. Natl. Acad. Sci. USA.
87, 5031-5035; Freeman, G. J. et al. (1991)
J Exp. Med
174,625-631; Freeman, G. J. et al. (1993)
Science
262:909-911; Azuma, M. et al. (1993) Nature 366:76-79; and Freeman, G. J. et al. (993)
J Exp. Med
178:2185-2192). Though the molecules B7-1 and B7-2 play a critical role in costimulation of T cell, there is some evidence that additional molecules can provide a costimulatory singnal to T cells.
Previous studies demonstrated that several antibodies recognized a 150kD cell-surface homodimer, termed CD100, that is expressed on a number of hematopoietic cells including B and T lymphocytes, granulocytes, monocytes and natural killer cells but not on eosinophils, platelets, erythrocytes or hematopoietic progenitor cells (Bougeret, C. et al., (1992),
J Immunol.
148, 318; Herold, C., et al., Eds., (Oxford University Press, Oxford, 1995), Leucocyte Typing V., S. F. Schlossman, et al., Eds. vol. 1, pp. 52). These studies indicated that CD100 expression on resting T cells increases on T cells after phytohemagglutinin activation (Bougeret, C. et al., (1992),
J Immunol.
148, 318). In addition, it has been reported that crosslinking of CD 100 provides a costimulatory signal to T cells, indicating that this molecule may be involved in T cell activation and clonal expansion (Herold C. et al., (1994),
Int. Immunol.
7, 1). However, the role of CD 100, in particular its role on B lymphocytes is unknown.
SUMMARY OF THE INVENTION
This invention provides isolated nucleic acid molecules encoding a CD100 antigen. Such nucleic acid molecules (e.g., cDNAs) have a nucleotide sequence encoding a CD100 antigen or biolocially active portions thereof, such as a peptide having a CD100 activity. In a preferred embodiment, the isolated nucleic acid molecule has a nucleotide sequence shown in
FIG. 1
, SEQ ID NO: 1, or a portion thereof such as the coding region of the nucleotide sequence of
FIG. 1
, SEQ ID NO: 1. Other preferred nucleic acid molecules encode a protein having the amino acid sequence of
FIG. 2
, SEQ ID NO: 2. Nucleic acid molecules derived from hematopoietic cells (e.g., a naturally-occurring nucleic acid molecule found in an activated lymphocyte) which hybridize under stringent conditions to the nucleotide sequence shown in
FIG. 1
, SEQ ID NO: 1 are also within the scope of the invention.
In another embodiment, the isolated nucleic acid molecule is a nucleotide sequence encoding a protein having an amino acid sequence which is at least about 80%, preferably at least about 85%, more preferably at least about 90% and most preferably at least about 95-99% overall amino acid sequence identity with an amino acid sequence shown in
FIG. 2
, SEQ ID NO: 2. This invention further pertains to nucleic acid molecules which encode a protein which includes a semaphorin domain having an amino acid sequence at least 80%, preferably at least 90%, more preferably at least 95-99% identical to an amino acid sequence shown in
FIG. 2
, SEQ ID NO: 2. Also within the scope of this invention are nucleic acid molecules which encode a protein which includes an extracellular domain having an amino acid sequence at least 80%, preferably at least 90%, more preferably at least 95-99% identical to an amino acid sequence shown in
FIG. 2
, SEQ ID NO: 2.
Nucleic acid molecules encoding proteins which include a semaphorin domain having an a
Boussiotis Vassiliki A.
Freeman Gordon J.
Hall Kathryn T.
Nadler Lee M.
Schultze Joachim L.
Dana-Farber Cancer Institute
Ewoldt Gerald R.
Lahive & Cockfield LLP
Nolan Patrick J.
Smith, Esq. DeAnn F.
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