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

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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 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-IAs-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.