Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2000-12-06
2003-01-28
Horlick, Kenneth R. (Department: 1637)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091100, C435S091200
Reexamination Certificate
active
06511807
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to the field of immunological disorders and, more specifically, to major histocompatibility complex transplantation molecules.
BACKGROUND INFORMATION
The major histocompatibility complex (MHC) codes for a variety of gene products, many of which play a central role in the body's defense against pathogenic organisms. Such molecules include the classical transplantation antigens and structurally related molecules, proteins for transport of foreign peptides within cells, serum complement proteins, the lymphokines tumor necrosis &agr; and tumor necrosis &bgr;, cytochromes and heat shock proteins.
The classical transplantation antigens, encoded for by genes in the MHC, are a highly polymorphic group of molecules that were originally discovered for their role in determining rejection of foreign transplanted cells and tissue. An extensive body of experimental work has since supported a role for the classical transplantation antigens in self-recognition. In the current paradigm, transplantation antigens serve to present peptides derived from both self and foreign proteins, for recognition by cells of the immune system.
Two distinct groups of antigens, class I and class II antigens, are encoded by genes within the MHC. Class I antigens are expressed on virtually all nucleated cells in the body and play a role in the mediation of immune responses based on cytotoxic thymus-derived (T) lymphocyte mediated cell killing. Cytotoxic T lymphocytes play a role in killing of virus infected cells and tumor cells. The class I MHC molecule is composed of a 45 kiloDalton (kDa) heavy chain associated non-covalently with a 12 kDa protein known as &bgr;
2
microglobulin (&bgr;
2
M). The present paradigm characterizes class I antigens as presenting peptide fragments derived from both self and foreign proteins synthesized endogenously within the cell.
The class I molecules were discovered for their role in transplantation and were termed the “classical” class I molecules, to distinguish them from a later discovered group of class I molecules termed the “nonclassical” class I molecules. Genes encoding the nonclassical class I MHC molecules consist of the majority of genes so far identified in the MHC locus. Nonclassical class I MHC molecules are overall structurally related to the classical class I MHC transplantation antigens in having extensive sequence homology and a heavy chain noncovalently associated with &bgr;
2
M. Nonclassical class I MHC molecules are, in general, less polymorphic than the classical class I MHC molecules and are more circumscribed in their tissue distribution. Several types of nonclassical class I molecules are expressed principally in the gastrointestinal (GI) tract, raising questions regarding their function, if any in the immune system.
MHC class II antigens are expressed principally by specialized antigen presenting cells in the body. Such cells are limited to the antibody producing B lymphocyte as well as macrophages and dendritic cells distributed in various tissues of the body. The class II molecule on the cell-surface is composed of an &agr; chain of 33 kDa and a &bgr; chain of 28 kDa associated noncovalently. Class II molecules as presently understood function principally to present peptides derived from self or foreign proteins to a specialized class of T lymphocyte that supports the development of cytotoxic T lymphocytes, provides immunity to fungal infections and assists B lymphocytes in the generation of protective antibody responses to encapsulated bacterial infections. MHC class II antigens present peptide fragments derived from proteins taken up by cells from the surrounding environment, in contrast to classical class I molecules, which present peptides derived from endogenously synthesized proteins.
A variety of human autoimmune diseases have been shown to be associated more frequently in the population with individuals who inherit certain genes of the MHC. For many of these diseases, the association is localized to the region of the MHC encoding class II histocompatibility antigens. These diseases are not inherited by simple mendelian segregation of MHC genes, since only one sibling of a set of identical twins may have the disease. This feature suggests that other genetic factors or environmental factors have roles in the development of autoimmunity, with genes in the MHC playing a significant part of the process.
The current paradigm for MHC gene function provides several theories to explain a role for MHC genes in autoimmune disease. They include the inappropriate expression of class II MHC molecules in cells eliciting the autoimmune response or aberrant recognition of self-peptides by particular MHC gene products. Such theories, however, remain to be proven. In addition, the current paradigm fails to provide a useful hypothesis to explain the basis for an MHC-associated iron storage disease known as hemochromatosis. This disease is known from animal studies and from the genomic structure of several class I genes to involve an MHC encoded class I molecule since deletion of the &bgr;
2
M gene in these animals results in the disease.
Thus, there exists a need to develop new approaches to the treatment of MHC associated diseases. The present invention is based on a new paradigm for the role of class I and class II antigens and other broadly related molecules in self-recognition and in regulation of the immune system. This paradigm provides that self-recognition molecules have a central function to recognize and modify carbohydrate structures. Thus, the present invention provides new methods for identifying carbohydrate ligands for self-recognition molecules and utilizing such ligands to treat diseases involving aberrant self-recognition such as autoimmune diseases, inflammatory diseases or susceptibility to infections and provides related advantages as well.
SUMMARY OF THE INVENTION
The present invention provides a substantially purified carbohydrate ligand that specifically binds to a leczyme. In addition, the invention provides methods to identify a carbohydrate ligand that specifically binds to a leczyme or a leczyme that specifically binds to a carbohydrate ligand. The invention further provides methods to identify a peptide that binds to the carbohydrate ligand binding-site of a leczyme.
The present invention also provides methods for isolating a carbohydrate ligand that binds to a leczyme or for isolating a leczyme that binds to a carbohydrate ligand. The invention further provides methods to identify a carbohydrate ligand or a leczyme that can modify the function of a cell and to obtain such functionally modified cells.
The invention also provides methods for modifying a cell to produce a carbohydrate ligand by introducing an expression vector encoding a leczyme into the cell, wherein the expression of the leczyme produces the carbohydrate ligand.
The invention also provides methods for modulating an immune response to an antigen by administering the antigen and a carbohydrate ligand.
The invention also provides methods for treating a disease state involving a leczyme by administering an effective amount of a carbohydrate ligand that binds to the leczyme involved in the disease state or by administering an effective amount of a leczyme that has a similar binding specificity to the leczyme involved in the disease state.
The invention further provides methods to diagnose a genetic basis for hemochromatosis by detecting a mutation in a class I MHC molecule that reduces it's ability to associate with &bgr;
2
microglobulin.
DETAILED DESCRIPTION OF THE INVENTION
The present invention results from a profound new paradigm for the function of self-recognition molecules in organisms including mammals. The new paradigm holds that many types of self-recognition molecules heretofore known as peptide recognition and presentation structures have a more central function in the recognition and modification of carbohydrate-based molecules. Although the current paradigm does not exclude recognition of peptide
Beattie, Esq. Ingrid A.
Horlick Kenneth R.
Mintz Levin Cohn Ferris Glovsky & Popeo P.C.
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