Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Reexamination Certificate
2001-01-09
2004-09-07
Ewoldt, G. R. (Department: 1644)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
C424S001210, C424S093100, C424S278100, C424S283100, C424S812000
Reexamination Certificate
active
06787154
ABSTRACT:
FIELD
The field of this invention is immunology, specifically, methods of preparing artificial antigen presenting cells and their application to methods of isolating antigen-specific T cells, methods of modulating the T cell response and methods of treating conditions which would benefit from the modulation of the T cell response, for example, transplantation therapy, autoimmune disorders, allergies, cancers and viral and bacterial infections.
BACKGROUND
The following description provides a summary of information relevant to the present invention. It is not an admission that any of the information provided herein is prior art to the presently claimed invention, nor that any of the publications specifically or implicitly referenced are prior art to the invention.
The immunologic arts have advanced markedly over the past ten years. The complexity of the science explaining aspects of the field is immense. We set forth below in this section a discussion concerning known aspects of various elements involved in immunogenic responses and concepts in the art that are related to the invention disclosed herein.
T Cells
T lymphocytes (i.e., T cells) are part of the immune system, which defends the body against bacterial, viral and protozoal infection, as well as aberrant molecules that contain epitopes recognized as non-self. The recognition of non-self molecules as well as the destruction of infectious agents carrying non-self antigens is a function of T cells. These cells provide for the cell-mediated immune responses of adaptive immunity.
Infecting pathogens are generally accessible to extracellular antibodies found in the blood and the extracellular spaces. However, some infecting agents, and all viruses, replicate inside cells where they are not exposed to, and cannot be detected by, extracellular antibodies. In order for these foreign agents to be accessible to the cell-mediated immune response, the cells harboring such pathogens must either “express” antigenic motifs of the infecting agents on the surface of the cells or the antigenic motifs must be shed from the cells, e.g. by cell death, to be accessable to and subsequently expressed on the cell membrane of phagocytic antigen presenting cells (“APCs”) that participate in the immune process.
Antigens derived from replicating virus for example, are displayed on the surface of infected cells where they may be recognized by “cytotoxic” T cells which may then control the infection by recognizing the viral antigen and killing the cell. The actions of such cytotoxic T cells depends upon direct interaction between the antigenic motif of the infecting agent expressed on the surface of the infected cells and the T cell's receptors having a specificity for the motif.
Although T cells are important in the control of intracellular infections, some foreign agents evade such control because they replicate only in the vesicles of macrophages; an important example is
Mycobacterium tuberculosis
, the pathogen that causes tuberculosis. Whereas bacteria entering macrophages are usually destroyed in the lysosomes, which contain a variety of enzymes and bactericidal substances, infectious agents such as
M. tuberculosis
, survive because the vesicles they occupy cannot fuse with the lysosomes. The immune system provides for fighting such agents by a second type of T cell, known as a T helper cell, which helps to activate macrophages and induce the fusion of lysosomes with the vesicles containing the infecting agents. The helper cells also bring about the stimulation of other immune mechanisms of the phagocyte. T helper cells may further be involved in initiating and/or sustaining the immune system's release of soluble factors that attract macrophages and other professional APCs to the site of infection.
Additionally, specialized “helper” T cells play a central part in the destruction of extracellular pathogens by interacting with B cells. Depending on the type of infection being controlled, participating T helper cells may have an inflammatory or Th1-like phenotype, or a suppressive Th2-like phenotype.
T Cell Receptors
T cell receptors (TCRs) are closely related to antibody molecules in structure and are involved in antigen binding. Variability in the antigen binding site of the TCR is created in a fashion similar to antibodies in that a large capacity for diversity is available. The diversity is found in the CDR3 loops of TCR variable regions which are found in the center of the antigen-binding site of the TCR. The diversity that is obtainable by TCRs for specific antigens is also directly related to an MHC molecule on the APC's surface to which the antigenic motif is bound and presented to the TCR.
One type of MHC that is involved in presenting processed antigen is class II MHC. The antigen or peptide binding site for a peptide on a class II MHC molecule lies in a cleft between the alpha and beta chain helices of the MHC molecule. In another type of MHC, the class I MHC, the binding site for a peptide lies in a cleft between the two alpha helices of the alpha chain. From the arrangement of highly variable antigens complexing with MHC molecule alleles, it is understandable that the mechanism of TCR recognition involves a combined distribution of variability in the TCR which must correlate with a distribution of variability in the ligand (i.e., antigen/MHC molecule complex). (Garboczi, et al.,
Nature
Vol. 384; 134-41; Ward and Quadri,
Curr Op Immunol
. Vol. 9:97-106; Garcia, et al.,
Science
, Vol. 279:1166-72).
MHC Molecules
In general, T cell responses to non-self motifs depend on the interactions of the T cells with other cells containing proteins recognized as non-self. In the case of cytotoxic T cells and Th1 cells, non-self proteins (i.e. antigens) are recognized on the surface of the target cell (such as an infected cell). Th2 cells, on the other hand, recognize and interact with antigen presented by professional antigen presenting cells such as dendritic cells, and B cells. Dendritic cells non-specifically internalize antigen while B cells bind and internalize foreign antigens via their surface immunoglobulin. In any case, T cells recognize their targets by detecting non-self antigenic motifs (e.g., peptide fragments derived from for example, a bacterium or virus) that are expressed either on infected cells or other immune cells, e.g. phagocytic APC. The molecules that associate with these peptide or antigen fragments and present them to T cells are membrane glycoproteins encoded by a cluster of genes bearing the cumbersome name “major histocompatibility complex” (MHC). These glycoproteins were first identified in mice in studies examining the effects on the immune response to transplanted tissues. In humans, the MHC equivalent has been termed HLA for “human leukocyte antigen”. In general, the term MHC is used to describe generally the molecules in the mammalian immune system involved in the presentation of antigenic motifs to T cells. As used specifically in this Letters Patent, MHC means any major histocompatibility complex molecule, either class I or class II, from any mammalian organism including a human, such molecule comprising full-length MHC molecules or sub-units thereof further comprising MHC encoded antigen-presenting glycoproteins having the capacity to bind a peptide representing a fragment of an auto antigen or other non-antigenic or antigenic sequence (e.g., a peptide), said MHC further having an amino acid sequence that is expressed and purified from natural sources, or by any artificial means in prokaryotic or eukaryotic systems having different glycosilations, or of either natural or synthetic origin that contains or comprises a modification of a natural MHC sequence.
The actions of T cells depend on their ability to recognize antigenic motifs on cells (such as cells harboring pathogens or that have internalized pathogen-derived products). T cells recognize peptide fragments (e.g., pathogen-derived proteins) in the form of complexes between such peptides and MHC molecules that are expressed on the surface
Biotechnology Law Group
Chamben Daniel M.
Ewoldt G. R.
Murdook Douglas E.
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