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 ζ (TCR-ζ). The receptors' antigen-MHC recognizes the TCR of cognate T lymphocytes. Receptor engagement stimulates the receptor-modified T cell (RMTC) through the linked ζ chain. CD4 + CD25 + RMTCs expressing a myelin basic protein (MBP) 89-101-IA s -ζ 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.