Abstract/Details

Depletion of specific immunity: A novel use of recombinant MHC molecules


2006 2006

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Abstract (summary)

MHC molecules carrying selected peptides will bind specifically to their cognate T cell receptor on individual clones of reactive T cells. Fluorescently labeled, tetrameric MHC-peptide complexes have been widely used to detect and quantitate antigen specific T cell populations via flow cytometry. We hypothesized that such MHC-peptide tetramers could also be used to selectively deplete unique reactive T cell populations, while leaving the remaining T cell repertoire and immune response intact, if the antigen specificity of the T cells were known. Graft-Versus-Host-Disease and other T cell mediated disorders, such as autoimmune diseases, are often the result of clonal or oligoclonal T cell expansion with reactivity against "self" proteins. Current therapies for disorders like these are often broadly immunosuppressive and leave patients at high risk for infection or relapse of malignancy.

In these studies, we successfully demonstrate that an MHC tetramer-based depletion of T cells can be achieved in a murine model of allogeneic bone marrow transplantation. Depletion of a specific alloreactive population of donor splenocytes (<0.5% of CD8+ T cells) prior to transplantation significantly decreased morbidity and mortality from Graft-Versus-Host-Disease. There was no early re-growth of the antigen-specific T cells in the recipient and in vivo CD8+ T cell proliferation was greatly reduced as well. Survival was increased greater than 3-fold over controls, yet the inherent anti-tumor activity of the transplant was retained. This method also provides the proof-of-concept for similar strategies to selectively remove other unwanted T cell clones, which could result in novel therapies for certain autoimmune disorders, T cell malignancies and solid organ graft rejection.

Indexing (details)


Subject
Immunology;
Pharmacology;
Pathology
Classification
0982: Immunology
0419: Pharmacology
0571: Pathology
Identifier / keyword
Health and environmental sciences; Graft-versus-host disease; Immunity; Immunotherapy; MHC
Title
Depletion of specific immunity: A novel use of recombinant MHC molecules
Author
Kappel, Barry J.
Number of pages
108
Publication year
2006
Degree date
2006
School code
0967
Source
DAI-B 67/03, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9780542586002, 0542586002
Advisor
Scheinberg, David A.
University/institution
Weill Medical College of Cornell University
University location
United States -- New York
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3209863
ProQuest document ID
304918667
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/304918667
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