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Materials and methods for the development of an antigen-specific immune non-responsiveness state

Inactive Publication Date: 2012-08-16
HAYASHI JUN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0006]The present invention provides materials and methods for making a subject (e.g., a mammal such as a human) non-responsive to an antigen. Methods of the invention may comprise contacting the subject with the antigen and a compound that induces anergy. Compounds that induce anergy include those that affect Lck function, Lck activity, Lck binding, Lck mediated signaling and/or Lck SH2 activity, for example, modify (increase or decrease) Lck function, Lck activity, Lck binding, Lck mediated signaling and/or Lck SH2 activity. In some embodiments, the compounds may interfere with the binding of Lck to ζ chain ITAM-2 C terminal phosphotyrosine residues and other ITAM residues of CD3 chains. In some embodiments, compounds that induce anergy may have the structure of compounds 72, 86, or 241. In some embodiments, the antigen may be an autoimmune antigen. Examples of autoimmune antigens include, but are not limited to achetylcholine receptor for myasthenia gravis, glutamic acid decarboxylase for type I diabetes mellitus and rheumatoid factor in rheumatoid arthritis.
[0007]In some embodiments, the present invention provides a method of treating an autoimmune disease in a subject (e.g., a mammal such as a human). Such methods may comprise contacting the subject with an autoimmune antigen and a compound that induces anergy. Compounds that induce anergy include those that affect Lck function, Lck activity, Lck binding, Lck mediated signaling and/or Lck SH2 activity, for example, modify (increase or decrease) Lck function, Lck activity, Lck binding, Lck mediated signaling and/or Lck SH2 activity. In some embodiments, the compounds may interfere with the binding of Lck to ζ cha

Problems solved by technology

Currently, all of the FDA approved immunosuppressor drugs suppress the entire immune response making patient vulnerable to infection.

Method used

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  • Materials and methods for the development of an antigen-specific immune non-responsiveness state
  • Materials and methods for the development of an antigen-specific immune non-responsiveness state

Examples

Experimental program
Comparison scheme
Effect test

example 1

Experimental System

[0027]Popliteal Lymph Node Assay (PLNA):

[0028]PLNA is a quantitative in vivo local graft vs host (GvH) allogeneic reaction that measures T cell activation. A mouse of a first strain (Strain A) is injected in the foot pad with lymphocytes from a mouse of a second stain (strain B). The injected lymphocytes from Stain B will cause a local GvH reaction in the popliteal lymph node of the first mouse (Stain A) causing swelling of the node due to the activation and proliferation of allogeneic T cells. The increase in mass of the popliteal lymph nodes can be measured by weighing the isolated node.

[0029]PLNA takes 1 week where at day 0, 1.5×106 lymph node lymphocytes from strain B mice are injected to the foot pad of strain A mice. Mice are sacrificed on day 7 and popliteal lymph nodes are removed and weighed. Typically, two to three-fold increase in the weight of popliteal lymph node can be observed in this GvH reaction. The immunosuppressive effect of compounds of intere...

example 2

Assessment of Anergy Induction by Compounds Using PLNA

[0030]In order to test the induction of anergy by the compounds, strain A mice can be re-challenged by strain B lymphocytes on day 7. Popliteal lymph nodes are harvested on day 14 and weighed. In the absence of anergy, popliteal lymph node remains swollen due to the re-challenge. If anergy is established by the compound in strain A mice against strain B lymphocytes, popliteal lymph node swelling in strain A mice will be suppressed upon strain B lymphocyte re-challenge, however, popliteal lymph node swelling should be observed if the strain A mice anergic to strain B lymphocytes are re-challenged by lymphocytes from strain C (FIG. 1A).

[0031]Experimental Design.

[0032]Out bred Swiss Webster mice were used as recipient. Lymphocytes from FVB mice were used for PLNA. For assessment of anergy induction by the compounds, Swiss mice were re-challenged using lymphocytes from FVB and SJL mice (FIG. 1B).

[0033]Blank control received PBS injec...

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Abstract

The present invention provides materials and methods for making a subject non-responsive to an antigen. Methods of the invention may comprise contacting the subject with the antigen and a compound that induces anergy. In some embodiments, the antigen may be an autoimmune antigen, examples of which include, but are not limited to acetylcholine receptor for myasthenia gravis, glutamic acid decarboxylase for type I diabetes mellitus and rheumatoid factor in rheumatoid arthritis, hi some embodiments, the present invention provides a method of transplanting an organ, tissue, or cells into a subject (e.g., a mammal such as a human).

Description

BACKGROUND OF THE INVENTION[0001]The immune system recognizes self from non-self. In a healthy individual, the body's immune system is designed to mount immune response to immunogens that enter the body (non-self) but maintain non-responsiveness to the constituents of its own body (self). The immune non-responsiveness (tolerance) to self is established mainly by the elimination of self-reactive T cells (negative selection) during T cell development in the thymus. However, the elimination of self reactive T cells is not entirely dependent on negative selection. Antigen-specific immune non-responsiveness can be established by an alternative mechanism leading to a condition termed anergy.[0002]T cells play a central role in adaptive immune response. The essential role T cells play in the immune response is well illustrated in SCID and nude mice or similar human immunodeficiency diseases where T cell component is absent or dysfunctional. T cells play an essential role in the regulation ...

Claims

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Application Information

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IPC IPC(8): A61K39/00A61P13/12A61P25/00A61P37/06A61K31/455A61P1/00A61P5/14A61P3/00A61K31/195A61K31/502A61P29/00A61P3/10
CPCA61K39/0008A61P1/00A61P13/12A61P19/02A61P25/00A61P29/00A61P3/00A61P37/00A61P37/06A61P5/14A61P3/10A61K31/455A61K31/502A61K31/609
Inventor HAYASHI, JUN
Owner HAYASHI JUN