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

Pender MP, Csurhes PA, Smith C, Beagley L, Hooper KD, Raj M, Coulthard A, Burrows SR, Khanna R - Mult. Scler. (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: The University of Queensland, School of Medicine, Brisbane, Queensland, Australia QIMR Centre for Immunotherapy and Vaccine Development and Department of Immunology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia m.pender@uq.edu.au.

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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:10 IgG(loc) (mg/L) = {(CSF IgG ÷ serum IgG) − [0.8 × (√((CSF albumin ÷ serum albumin)2 + 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.
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fig1-1352458514521888: 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:10 IgG(loc) (mg/L) = {(CSF IgG ÷ serum IgG) − [0.8 × (√((CSF albumin ÷ serum albumin)2 + 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.

Mentions: The treatment was successfully completed without significant adverse effects. In particular there were no fevers, flu-like symptoms or malaise. Two to three days after the second and third infusions the patient had tingling and numbness of the lips and tongue for 3–6 h, but in the previous year there had been two attacks of these symptoms, each lasting a week. Following the treatment he experienced a reduction in fatigue and painful lower limb spasms, an improvement in cognition and hand function, and increased productivity at work. These improvements were sustained up to the time of the latest review, 21 weeks after the final T-cell infusion, when neurological examination demonstrated increased voluntary movement of his lower limbs, particularly of the right knee flexors and left knee flexors and extensors to a Medical Research Council grade of 3/5, compared with 1/5 prior to the T-cell therapy. Following treatment the frequency of circulating EBV-specific CD8+ T cells increased (Figure 1(a) and (b)), and there were decreases in the number and size of gadolinium-enhancing MRI brain lesions and in intrathecal IgG production (Figure 1(c–f)). The CSF IgG index decreased from 0.79 (normal <0.70) before treatment to 0.74, 6 weeks after completion of treatment, and then decreased further to 0.63, 21 weeks after completion.


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

Pender MP, Csurhes PA, Smith C, Beagley L, Hooper KD, Raj M, Coulthard A, Burrows SR, Khanna R - Mult. Scler. (2014)

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:10 IgG(loc) (mg/L) = {(CSF IgG ÷ serum IgG) − [0.8 × (√((CSF albumin ÷ serum albumin)2 + 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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2 - License 3
Show All Figures
getmorefigures.php?uid=PMC4230458&req=5

fig1-1352458514521888: 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:10 IgG(loc) (mg/L) = {(CSF IgG ÷ serum IgG) − [0.8 × (√((CSF albumin ÷ serum albumin)2 + 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.
Mentions: The treatment was successfully completed without significant adverse effects. In particular there were no fevers, flu-like symptoms or malaise. Two to three days after the second and third infusions the patient had tingling and numbness of the lips and tongue for 3–6 h, but in the previous year there had been two attacks of these symptoms, each lasting a week. Following the treatment he experienced a reduction in fatigue and painful lower limb spasms, an improvement in cognition and hand function, and increased productivity at work. These improvements were sustained up to the time of the latest review, 21 weeks after the final T-cell infusion, when neurological examination demonstrated increased voluntary movement of his lower limbs, particularly of the right knee flexors and left knee flexors and extensors to a Medical Research Council grade of 3/5, compared with 1/5 prior to the T-cell therapy. Following treatment the frequency of circulating EBV-specific CD8+ T cells increased (Figure 1(a) and (b)), and there were decreases in the number and size of gadolinium-enhancing MRI brain lesions and in intrathecal IgG production (Figure 1(c–f)). The CSF IgG index decreased from 0.79 (normal <0.70) before treatment to 0.74, 6 weeks after completion of treatment, and then decreased further to 0.63, 21 weeks after completion.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: The University of Queensland, School of Medicine, Brisbane, Queensland, Australia QIMR Centre for Immunotherapy and Vaccine Development and Department of Immunology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia m.pender@uq.edu.au.

Show MeSH
Related in: MedlinePlus