Invented by Anne De Groot, William Martin, Daniel S. Rivera, Epivax Inc
The Epivax Inc invention works as followsThe invention relates to epitopes for T cells, wherein said epitopes comprise a peptide/polypeptide chain consisting at least one portion of an immunoglobulin variable or constant region. The invention also covers methods for using and making epitopes.
Background for Regulatory T Cell Epitopes, Compositions and Uses thereof
Therapy for autoimmunity, transplantation allergies and other diseases aims to induce tolerance to foreign antigens. It is also possible to induce tolerance to autologous and non-autologous proteins. Therapeutic tolerance induction was based on broad-based strategies that led to cellular depletion or cytokine profile modification. These broad-based approaches can weaken the immune system and make many people more vulnerable to autoimmune attacks, cancer, and opportunistic infections. It is important to use targeted and less aggressive approaches to inducing immune tolerance.
Immune tolerance is controlled by complex interactions between T cells and B cells. Initial self/nonself discrimination takes place in the thymus, during neonatal development. Medullary epithelial cell expression of self protein epitopes is able to target immature T-cells. However, T cells that recognize self antigens with high affinity will be deleted. Autoreactive T cells with moderate affinity may not be deleted and can sometimes be transformed to so-called?natural? cells. TReg cells are regulatory T cells. These TReg cells, which are natural cells from the body, are sent to the peripheral and help with constant suppression of autoimmunity.
A second type of tolerance is found in the peripheral where mature T cells become?adaptive?. The TReg phenotype is activated via the T cell receptor and in the presence IL-10 or TGF-?. These?adaptive? cells could play a variety of roles. These TReg cells could play a role in controlling inflammation after the successful elimination of an invading pathogen. They may also be used to promote co-existence of beneficial symbiotic bacteria or viruses. ?Adaptive? TReg could also be a part of managing the life cycle for human antibodies that have been subject to somatic hypermutation.
Natural regulatory cells are an important component of immune regulation in peripheral areas. TCR activated natural Tregs can suppress bystander effector T cells responses to unrelated antigens via contact dependent and independent mechanisms. These cells release cytokines, including IL-10 or TGF-?. This can also induce antigen-specific adaptive Tregs. It is not known if natural Tregs have antigen specificity, or if they circulate in clinically significant quantities despite extensive efforts.
There is a need for the identification of regulatory epitopes in T cells contained in common autologous proteins like IgG (?Tregitopes?) Methods and methods related to their preparation, and their use.
The invention harnesses regulatory T cells’ functions (TReg), especially those cells that regulate immune responses to self and foreign proteins (pre-existing TReg) The invention also provides T-cell epitope polypeptide compounds.
The therapeutic value of selective engagement and activation pre-existing natural Treg using Tregitopes or Tregitope/antigen fusions is in the treatment of any condition that has an unwelcome immune response. These include: Type 1 diabetes, MS and Lupus; Transplant-related disorders like Graft vs. Host disease (GVHD); Allergies; Immune rejection of biologic medications such as monoclonal antibody, replacement proteins like FVIII, Insulin, and the use of therapeutic toxins like Botulinum xin; and management of the immune response to infectious diseases, acute or chronic.
In one embodiment, a composition of T-cell epitopes polypeptide polypeptides comprises at least one polypeptide from the group consisting: SEQ ID NoS:4-58. The invention is directed to a pharmaceutical composition that includes a polypeptide from the invention and a pharmaceutically acceptable transporter.
In one embodiment, the invention is directed at a nucleic acids encoding at minimum one T-cell epitope protein polypeptide from the following group: SEQ ID NoS:4-58. The invention is directed to a vector that contains a nucleic acids of the invention in a particular embodiment. Another embodiment of the invention is directed at a cell containing a vector.
In one embodiment, an invention is directed at a method for treating or preventing medical conditions in subjects in need thereof. This involves administering a therapeutically-effective amount of a T cell epitope polypeptide chosen from the following group: SEQ ID NoS:4-58. A particular embodiment includes a medical condition that can be described as an allergy, an autoimmune disorder, a transplant-related disorder, graft against host disease, an enzyme disorder or protein deficiency disorder or infertility.
In one embodiment, this invention is directed at a kit for treating or preventing a medical condition in a subject. The kit includes at least one T cell epitope polypeptide chosen from the following group: SEQ ID NoS:4-58.
In one embodiment, this invention is directed at a method of expanding a population regulatory T cells. It involves: (a) providing biological samples from subjects; (b) isolating regulatory cells from the biological sample; and (c) contacting regulatory T cell isolated with a Tregitope mixture of the invention under conditions in which the number of T-regulatory genes increases to produce an expanded regulatory composition.
In one embodiment, this invention is directed at a method of stimulating regulatory cells in a biologic sample. It includes: (a) providing biological samples from subjects; (b) isolating regulatory cells from the biological samples; and (c) contacting regulatory cells with an effective amount a Tregitope mixture of the invention under conditions in which the T-regulatory cell are stimulated to alter one of several biological functions, thus stimulating the regulatory cells in the biological sample.
In one embodiment, this invention is directed at a method of suppressing the immune response in a subject. This involves administering a composition consisting of a therapeutically effective amount a peptide comprising an Tregitope to that subject. The composition represses immune response. The peptide suppresses the effector T-cell response in a particular embodiment. The peptide in a particular embodiment suppresses the helper T-cell response. Another embodiment suppresses the B cell response.
In one embodiment, this invention is directed at a method for suppressing antigen-specific immune responses in subjects through administration of a therapeutically efficacious amount of a composition that contains one or more Tregitopes. The composition may be covalently bound, noncovalently bound, or in admixture to a target antigen, resulting in a diminution in immune response to the target antigen. The suppressive effect of natural Treg is used in a specific embodiment. Another embodiment of the suppressive effect involves adaptive Treg. Another embodiment suppresses the effector T cell reaction. Another embodiment suppresses the helper T cell response. Another embodiment suppresses the B cell response. A particular embodiment of the peptide includes a sequence from the following group: SEQ ID NoS:4-58
In one embodiment, this invention is directed at a method to increase the immunogenicity a vaccine delivery vector. This includes identifying and removing regulatory T cell epitopes. A particular embodiment selects T cell epitopes from the following group: SEQ ID NoS:4-58.
The adaptive immune cascade starts when soluble protein-antigens are taken up and processed by Antigen Presenting Cells. The Endoplasmic Reticulum contains many proteases that degrade protein antigens. Some of the protein fragments that result are bound to Class I MHC molecules. Peptide-loaded MHC compounds are transported to the cell surface, where they are interrogated and metabolized by CD4+ T. T cell epitopes are peptidide fragments capable of binding to an MHC molecules and mediating cell to cell interaction between APCs and circulating T cells. These peptide-MHC combinations can be recognized by CD4+ T cell. This depends on the phenotype and local cytokine/chemokine environment. The engagement of the MHC/peptide compound with the T cell receptor TCR of T effector cells results in activation and secretion pro-inflammatory cytokines like IL-4 and IFN-??. The activation of natural T regulatory cell (TReg), on the other hand, results in the expression of immune suppressive cytokines IL-10, and TGF-??, among others (Shevach E., Nat. Rev. Immunol., 2:389-400, 2002). These cytokines can be directly acted upon nearby effector T cell cells, causing anergy and/or apoptosis in certain cases. In some cases, regulatory cytokines or chemokines can convert effector T cell phenotypes to regulatory cytokines. This process is called?induced? Or?adaptive? tolerance. Tregitopes are T cell epitopes capable of binding to MHC molecules, engaging and activating Treg circulating in the body.
Initial self/nonself discrimination occurs during neonatal development in the thymus, where medullary epithelial cell express specific self protein epitopes for immature T-cells. However, T cells that recognize self antigens of high affinity are deleted. Autoreactive T cells with moderate affinity can sometimes be saved and converted into so-called natural regulatory T cell (TReg) cells. These natural TReg cells can be exported to the peripheral and are responsible for continuous suppression of autoimmunity. The natural regulatory T cells are an important component of self tolerance and immune regulation.
Self tolerance is controlled by complex interactions between T cells, B and surface receptors. T regulatory immune reactions counterbalance T effector immune responses to protein antigens (self or foreign). Autoimmunity is a tilt in the balance towards the autoreactive side. This can be achieved by increasing or decreasing the function of T regulatory cell or the number of autoreactive T effectors cells.
A second type of tolerance is found in the peripheral where mature T cells become?adaptive?. TReg phenotype is activated via the T cell receptor and in the presence IL-10 or TGF-?. These are usually supplied by T regulatory cells. These?adaptive? cells could play a variety of roles. These TReg cells could play a role in controlling inflammation after the successful elimination of an invading pathogen. They may also be used to promote co-existence of beneficial symbiotic bacteria or viruses. ?Adaptive? TReg could also be a part of managing the life cycle for human antibodies that have been subject to somatic hypermutation.
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