Generation of antigen specific T suppressor cells for treatment of rejection

Abstract

This invention provides a method of generating antigen specific allospecific human-suppressor CD8+CD28− T cells. This invention also provides a method of generating xenospecific human suppressor CD8+CD28− T cells. This invention further provides a method of generating allopeptide antigen specific human suppressor CD8+CD28− T cells. Methods of treatment for, reduction of risk of rejection of allografts and xenografts and autoimmune diseases using the human suppressor CD8+CD28− T cells so produced are also provides, as are methods of preventing rejection and autoimmune diseases, and vaccines comprising the produced suppressor T cells. Methods of diagnosis to determine whether a level of immuno-suppressant therapy requires a reduction are provided.

Description

[0001] This application is a continuation-in-part application of PCT International Application No. PCT / US00 / 16594, filed Jun. 15, 2000, which claims priority and is a continuation-in-part application of U.S. Ser. No. 09 / 333,809, filed Jun. 15, 1999, the contents of which are hereby incorporated by reference into the present application.[0002] This invention was made with support under Grant Nos. 5-RO1-A125210-11, RO1A125210-10, 5-RO1-A125210-12, and 5-RO1A123210-13 from the National Institutes of Health. Accordingly, the United States Government has certain rights in the invention.[0003] Throughout this application, various references are referred to within parentheses. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains. Full bibliographic citation for these references may be found at the end of this application, preceding the claims. BACKGROUND ...

AI Technical Summary

Benefits of technology

[0018] This invention provides a method of reducing the risk of rejection of an allograft in a subject undergoing immunosuppression therapy which comprises: a) obtaining a blood sample from the subject; b) removing T suppressor cells from the blood sample; c) expanding the T suppressor cells of step (b); and d) reintroducing the expanded T suppressor cells of step (b) into the subject.

[0033] This invention provides a method of reducing the level of rejection of an allograft tissue or organ in a subject who is a transplant recipient of the allograft tissue or organ which comprises administering to the subject tolerogenic antigen presenting cells (APC) which overexpress monocyte inhibitory receptor (MIR), wherein the APC have been incubated with Ts prior to overexpression of MIR, thereby inducing Th anergy so as to prevent rejection of the tissue or organ allograft in the subject.

Problems solved by technology

In spite of considerable effort, however, allospecific human suppressor T cells (Ts) have been difficult to generate.

Immunosuppressive treatments that have been developed so far act non-specifically, placing the recipient at increased risk for infections and malignancies.

This controversy lead to the speculation that no distinctive Ts lineage actually exists.

The generation of Ts lines has proven, however, to be a difficult task rendering the characterization of these cells hard to achieve.

However, the generation and characterization of suppressor T cell lines have met with limited success.

The inhibitory activity of Ts on Th proliferation requires the tripartite interaction between Th, Ts, and APCs and results from inefficient costimulation of Th.

Although the concept that T suppressor cells (Ts) downregulate the immune response has long been accepted, the existence of a distinct population of lymphocytes that mediates suppression has not been convincingly demonstrated.

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