Epstein-Barr virus-specific adoptive immunotherapy for progressive multiple sclerosis

Abstract

Defective control of Epstein-Barr virus (EBV) infection by cytotoxic CD8(+) T cells might predispose to multiple sclerosis (MS) by allowing EBV-infected autoreactive B cells to accumulate in the central nervous system. We have treated a patient with secondary progressive MS with in vitro-expanded autologous EBV-specific CD8(+) T cells directed against viral latent proteins. This adoptive immunotherapy had no adverse effects and the patient showed clinical improvement with reduced disease activity on magnetic resonance imaging and decreased intrathecal immunoglobulin production. This is the first report of the use of EBV-specific adoptive immunotherapy to treat MS or any other autoimmune disease.

Keywords: Adoptive immunotherapy; B cell; CD8+ T cell; Epstein–Barr virus; multiple sclerosis; treatment.

Figure 1.

Laboratory and medical imaging findings before and after EBV-specific adoptive immunotherapy. Panels A and B show the frequencies of T cells in the peripheral blood reactive to an EBV-infected autologous B cell lymphoblastoid cell line (LCL) (Panel A) and to a pool of the LMP1 and LMP2A (LMP) peptides contained within AdE1-LMPpoly (Panel B). T-cell reactivity to EBV was measured by flow cytometry and intracellular interferon-γ staining and is shown as the percentages of reactive cells within the CD8⁺ effector memory (EM; CD45RA^–CD62L^–) T-cell population. Vertical arrows indicate successive T-cell infusions of 5 × 10⁶, 1 × 10⁷, 1.5 × 10⁷ and 2 × 10⁷ cells. Panel C shows the total gadolinium(Gd)-enhancing brain lesion load, as measured by the bidimensional product, which was calculated as the sum of the product (maximum diameter of a lesion multiplied by the largest diameter perpendicular to this maximum diameter) of each lesion. Panel D shows the quantity of intrathecal IgG production (IgG(loc)) which was calculated by the formula of Reiber and Felgenhauer: IgG(loc) (mg/L) = {(CSF IgG ÷ serum IgG) − [0.8 × (√((CSF albumin ÷ serum albumin) + 15))] + 1.8} × serum IgG. Panels E and F show axial plane T1-weighted images at the level of the posterior horns of the lateral ventricles 5 minutes after the IV injection of gadolinium. Panel E demonstrates three periventricular gadolinium-enhancing lesions (arrows) 5 weeks before the commencement of therapy whereas Panel F shows no enhancing lesions 9 weeks after the completion of therapy.