Immunotherapy of autoimmune encephalomyelitis with redirected CD4+CD25+ T lymphocytes.
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.
Mekala
Divya J
DJ
Department of Pathology, St Jude Children's Research Hospital, 332 N Lauderdale St, D-4047, Memphis, TN 38105, USA.
Geiger
Terrence L
TL
D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000637:transplantation*; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000628:therapy*; D005260:Female; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015375:Receptors, Interleukin-2; D037182:T-Cell Antigen Receptor Specificity
D008565:Membrane Proteins; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; C054979:antigen T cell receptor, zeta chain; C446766:myelin basic protein 89-101