Immunotherapy of autoimmune encephalomyelitis with redirected CD4+CD25+ T lymphocytes.

Abstract

We developed an approach that increases CD4+CD25+ regulatory T-cell potency by antigen-specifically redirecting them against pathologic T lymphocytes. The regulatory cells are transgenically modified with chimeric receptors that link antigen-major histocompatibility complex (MHC) extracellular and transmembrane domains with the cytoplasmic signaling tail of T-cell receptor zeta (TCR-zeta). The receptors' antigen-MHC recognizes the TCR of cognate T lymphocytes. Receptor engagement stimulates the receptor-modified T cell (RMTC) through the linked zeta chain. CD4+CD25+ RMTCs expressing a myelin basic protein (MBP) 89-101-IAs-zeta receptor, unlike unmodified CD4+CD25+ T cells or CD4+CD25- RMTCs, prevented and treated experimental allergic encephalomyelitis (EAE) induced with MBP89-101. The RMTCs were effective even after the autoreactive T-cell repertoire had diversified to include specificities not directly targeted by the chimeric receptor. Remissions were sustained and mortality was decreased from more than 50% to 0%. These results provide proof of principal for a novel approach to enforce the interaction of regulatory and pathologic T lymphocytes, thereby facilitating the treatment of autoimmune disease.

• Authors: Divya J Mekala, Terrence L Geiger
• Journal: Blood (Blood) Vol. 105 Issue 5 Pg. 2090-2 (Mar 01 2005) ISSN: 0006-4971 [Print] United States
• PMID: 15528313 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Membrane Proteins
• Myelin Basic Protein
• Peptide Fragments
• Receptors, Antigen, T-Cell
• Receptors, Interleukin-2
• antigen T cell receptor, zeta chain
• myelin basic protein 89-101

Topics

• Adoptive Transfer (methods)
• Animals
• CD4-Positive T-Lymphocytes (transplantation)
• Cells, Cultured
• Encephalomyelitis, Autoimmune, Experimental (therapy)
• Female
• Membrane Proteins (immunology)
• Mice
• Mice, Transgenic
• Myelin Basic Protein (immunology)
• Peptide Fragments (immunology)
• Receptors, Antigen, T-Cell (immunology)
• Receptors, Interleukin-2
• T-Cell Antigen Receptor Specificity