Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues
Reexamination Certificate
1997-02-10
2001-11-06
Scheiner, Laurie (Department: 1648)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
C530S350000
Reexamination Certificate
active
06313263
ABSTRACT:
BACKGROUND OF THE INVENTION
Within this application several publications are referenced by Arabic numerals within parentheses. Full citations for these references may be found at the end of the specification immediately preceding the claims. The disclosures of these publications in their entirety are hereby incorporated by reference into this application in order to more fully describe, the state of the art to which this invention pertains.
Understanding T cell recognition of antigen and the restriction of the process by major histocompatibility complex (MHC) encoded antigens has been an important goal in immunology. A major step forward occurred with the immunochemical identification of clone specific disulfide-linked heterodimers on T cells, composed of subunits termed T cell antigen,receptors (TCR) &agr; and &bgr;. The TCR &agr; and &bgr; subunits have a relative molecular mass (M
r
) of approximately 50,000 and 40,000 daltons, respectively (1, 2, 3). Genes that rearrange during T cell ontogeny and encode the TCR &bgr; (4, 5) and TCR &agr; (6, 7, 8) subunits were isolated either by subtractive hybridization or by probing with oligonucleotides.
A unique feature of the human TCR &agr;, &bgr; was the observed comodulation (2), coimmunoprecipitation (9, 10) and required coexpression (11) of the TCR &agr;, &bgr; molecules with the T3 glycoprotein, which suggested that these two structures were related. Subsequently, the direct physical association of the two protein complexes was demonstrated by chemically cross-linking the TCR &agr;, &bgr; molecules to the T3 glycoprotein and identifying the components of the cross-linked complex as the TCR &bgr; subunit and the T3 glycoprotein (M
r
28,000) subunit (12). A T3 counterpart is similarly associated with murine TCR &agr;, &bgr; (13, 14).
A third gene that rearranges in T cells, designated TCR &ggr;, has been identified in mouse (15, 16, 17) and in man (18, 19). However, there are major differences between the human and mouse TCR &ggr; gene in terms of its genetic structure; for example, the cDNA of the human TCR &ggr; gene indicates five potential sites for N-linked glycosylation in the TCR &ggr; gene product, which contrasts with the notable absence of such sites in the murine TCR &ggr; gene. Thus, the human TCR &ggr; gene product will have a high molecular weight which is not predictable from its genetic sequence.
The TCR &ggr; gene rearrangements occur in lymphocytes with suppressor-cytotoxic as well as helper phenotypes and may produce a large number of TCR &ggr; chains (18, 19, 20, 21, 22, 23). However, the function of the TCR &ggr; gene is unknown. Furthermore, neither the protein encoded by the TCR &ggr; gene nor its possible association with other structures (as occurs with TCR &agr;, &bgr; and T3 glycoproteins) have been defined. In humans, the multiple glycosylation sites render it impossible to predict with accuracy the nature and size of the TCR &ggr; polypeptide structure. Additionally, the published literature does not teach or suggest the utility of TCR &ggr; with regard to diagnosing, monitoring or staging human diseases.
It appears increasingly likely that the TCR &agr;, &bgr; molecule alone determines both antigen recognition and MHC restriction on at least some T cells (24, 25). However, it is not clear that TCR &agr;, &bgr; accounts for the process of T cell selection during T cell ontogeny or for all antigen specific recognition by mature T cells. For example, suppressor T lymphocytes remain an enigma; in some cases they delete or fail to rearrange TCR &bgr; genes (26,27). Thus, it is of great importance to determine if a second T cell receptor exists, to define its structure (particularly with regard to the possible use of the TCR &ggr; gene product) and ultimately to understand what function or functions it serves.
SUMMARY OF THE INVENTION
The present invention provides a purified polypeptide which comprises at least a portion of a &dgr; T cell receptor polypeptide. Additionally, a substance capable of specifically forming a complex with at least one &dgr; T cell receptor polypeptide is provided.
Also provided is a method for detecting T cells, each of which has a &dgr; T cell receptor polypeptide. This method comprises contacting a sample which contains T cells with substances capable of forming complexes with &dgr; T cell receptor polypeptides so as to form cellular complexes between the substances and the &dgr; T cell receptor polypeptides. These cellular complexes are detected and thereby T cells, each of which has a &dgr; T cell receptor polypeptide, are detected.
The invention further provides a method for diagnosing an immune system abnormality in a subject. This method comprises determining the number of T cells in a sample from the subject and contacting the sample with substances capable of forming complexes with at least one &dgr; T cell receptor polypeptide so as to form cellular complexes between the substances and the &dgr; T cell receptor polypeptides. The percentage of T cells in the sample which have a &dgr; T cell receptor polypeptide is determined and compared with the percentage of T cells which have a &dgr; T cell receptor polypeptide in a sample from a normal subject who does not have the immune system abnormality. A difference in the percentage of T cells so determined would be indicative of the immune system abnormality. A further method for diagnosing an immune system abnormality in a subject is provided by the present invention. This method comprises determining the number of &dgr; T cell receptor polypeptide bearing T cells in a sample from the subject and determining the amount of &dgr; T cell receptor polypeptides in the &dgr; T cell receptor bearing T cells. The amount of &dgr; T cell receptor polypeptides so determined is compared with the amount of &dgr; T cell receptor polypeptides in an equal number of &dgr; T cell receptor polypeptide bearing T cells in a sample from a normal subject who does not have the immune system abnormality. A difference in the amount so determined would be indicative of the immune system abnormality.
A further method for diagnosing an immune system abnormality in a subject is provided. This method comprises determining in a sample from the subject the number of T cells which have a &dgr; T cell receptor polypeptide and the number of T cells consisting of the group of T cells which have one of the surface markers T4, T8 and a &agr;, &bgr; T cell receptor. The numbers of T cells so determined are compared with the number of T cells which have a &dgr; T cell receptor polypeptide and the number of T cells in the group which have the same surface marker as the group of T cells determined in the sample from the subject, in a sample from a subject who does not have the immune system abnormality. A difference in the number of T cells so determined which have a &dgr; T cell receptor polypeptide relative to the number of T cells in the group so determined would be indicative of the immune system abnormality.
The present invention also provides a purified polypeptide which comprises at least a portion of a T cell receptor polypeptide. Additionally, a substance capable of specifically forming a complex with at least one &ggr; T cell receptor polypeptide is provided. Furthermore, a method for detecting T cells, each of which has a &ggr; T cell receptor polypeptide is provided. This method comprises contacting a sample which contains T cells with substances capable of forming complexes with &ggr; T cell receptor polypeptides so as to form cellular complexes between the substances and the &ggr; T cell receptor polypeptides. These cellular complexes are detected and thereby T cells, each of which has a &ggr; T cell receptor polypeptide, are detected.
A further method for diagnosing an immune system abnormality in a subject is provided by the present invention. This method comprises determining the number of T cells in a sample from the subject and contacting the sample with substances capable of forming complexes with at least one &ggr; T cell receptor polypeptide s
Brenner Michael B.
Ip Stephen H.
Krangel Michael S.
Seidman Johnathan
Strominger Jack L.
Astra AB
Pennie & Edmonds LLP
Scheiner Laurie
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