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Treatment of experimental autoimmune encephalomyelitis with genetically modified memory T cells.

Mathisen PM, Yu M, Johnson JM, Drazba JA, Tuohy VK - J. Exp. Med. (1997)

Bottom Line: Isolated T cell clones demonstrated antigen-inducible expression of transgene IL-10 and expressed cell surface markers consistent with the phenotype of normal memory T cells.Semiquantitative immunocytochemistry showed a significant correlation between decreased demyelination and treatment with the transfected T cells.Taken together, these data indicate the autoreactive T cells can be genetically designed to produce therapeutic factors in an antigen-inducible manner resulting in a decreased severity of clinical and histological autoimmune demyelinating disease.

View Article: PubMed Central - PubMed

Affiliation: The Cleveland Clinic Foundation, Research Institute, Department of Immunology, FFb-1, Cleveland, Ohio 44195, USA.

ABSTRACT
The migratory properties of memory T cells provide a model vector system for site-specific delivery of therapeutic transgene factors to autoimmune inflammatory lesions. Lymph node cells from (SWRxSJL)F1 mice immunized with the p139-151 determinant of myelin proteolipid protein (PLP) were transfected with a DNA construct that placed the anti-inflammatory cytokine interleukin-10 (IL-10) cDNA under control of an antigen-inducible IL-2 promoter region. Isolated T cell clones demonstrated antigen-inducible expression of transgene IL-10 and expressed cell surface markers consistent with the phenotype of normal memory T cells. Upon adoptive transfer, transfected T cell clones were able to inhibit onset of experimental autoimmune encephalomyelitis (EAE) and to treat EAE animals therapeutically after onset of neurologic signs. Semiquantitative immunocytochemistry showed a significant correlation between decreased demyelination and treatment with the transfected T cells. Taken together, these data indicate the autoreactive T cells can be genetically designed to produce therapeutic factors in an antigen-inducible manner resulting in a decreased severity of clinical and histological autoimmune demyelinating disease.

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Histologic analysis of CNS tissue after adoptive transfer of  transfected T cells. The extent of demyelination was measured by immunocytochemical staining for PLP. (a) Representative section showing demyelination (arrow) in the spinal cord dorsal column of SWXJ control  mouse adoptively transferred with normal splenocytes before EAE onset.  (b) Representative section showing uniform distribution of PLP immunostaining in the spinal cord dorsal column of SWXJ mouse adoptively  transferred before EAE onset with PLP 139–151-specific T cells transfected with the IL-2Prom→ IL-10cDNA construct. Closed Bar, 50 μm.
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Figure 4: Histologic analysis of CNS tissue after adoptive transfer of transfected T cells. The extent of demyelination was measured by immunocytochemical staining for PLP. (a) Representative section showing demyelination (arrow) in the spinal cord dorsal column of SWXJ control mouse adoptively transferred with normal splenocytes before EAE onset. (b) Representative section showing uniform distribution of PLP immunostaining in the spinal cord dorsal column of SWXJ mouse adoptively transferred before EAE onset with PLP 139–151-specific T cells transfected with the IL-2Prom→ IL-10cDNA construct. Closed Bar, 50 μm.

Mentions: To determine the histologic effects after adoptive transfer of transfected T cells, spinal cords from mice receiving either IL-2Prom→ IL-10cDNA–transfected T cells (Fig. 4 b) or normal splenocytes (Fig. 4 a) just before EAE onset were stained immunocytochemically for PLP, and demyelination was quantified by measuring the mean intensity of dorsal column PLP staining. Adoptive transfer of IL-2Prom→ IL-10 cDNA–transfected T cells just before EAE onset resulted in a significant (P = 0.02) mean decrease of 12.2% in CNS demyelination compared with EAE mice receiving normal splenocytes.


Treatment of experimental autoimmune encephalomyelitis with genetically modified memory T cells.

Mathisen PM, Yu M, Johnson JM, Drazba JA, Tuohy VK - J. Exp. Med. (1997)

Histologic analysis of CNS tissue after adoptive transfer of  transfected T cells. The extent of demyelination was measured by immunocytochemical staining for PLP. (a) Representative section showing demyelination (arrow) in the spinal cord dorsal column of SWXJ control  mouse adoptively transferred with normal splenocytes before EAE onset.  (b) Representative section showing uniform distribution of PLP immunostaining in the spinal cord dorsal column of SWXJ mouse adoptively  transferred before EAE onset with PLP 139–151-specific T cells transfected with the IL-2Prom→ IL-10cDNA construct. Closed Bar, 50 μm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2198970&req=5

Figure 4: Histologic analysis of CNS tissue after adoptive transfer of transfected T cells. The extent of demyelination was measured by immunocytochemical staining for PLP. (a) Representative section showing demyelination (arrow) in the spinal cord dorsal column of SWXJ control mouse adoptively transferred with normal splenocytes before EAE onset. (b) Representative section showing uniform distribution of PLP immunostaining in the spinal cord dorsal column of SWXJ mouse adoptively transferred before EAE onset with PLP 139–151-specific T cells transfected with the IL-2Prom→ IL-10cDNA construct. Closed Bar, 50 μm.
Mentions: To determine the histologic effects after adoptive transfer of transfected T cells, spinal cords from mice receiving either IL-2Prom→ IL-10cDNA–transfected T cells (Fig. 4 b) or normal splenocytes (Fig. 4 a) just before EAE onset were stained immunocytochemically for PLP, and demyelination was quantified by measuring the mean intensity of dorsal column PLP staining. Adoptive transfer of IL-2Prom→ IL-10 cDNA–transfected T cells just before EAE onset resulted in a significant (P = 0.02) mean decrease of 12.2% in CNS demyelination compared with EAE mice receiving normal splenocytes.

Bottom Line: Isolated T cell clones demonstrated antigen-inducible expression of transgene IL-10 and expressed cell surface markers consistent with the phenotype of normal memory T cells.Semiquantitative immunocytochemistry showed a significant correlation between decreased demyelination and treatment with the transfected T cells.Taken together, these data indicate the autoreactive T cells can be genetically designed to produce therapeutic factors in an antigen-inducible manner resulting in a decreased severity of clinical and histological autoimmune demyelinating disease.

View Article: PubMed Central - PubMed

Affiliation: The Cleveland Clinic Foundation, Research Institute, Department of Immunology, FFb-1, Cleveland, Ohio 44195, USA.

ABSTRACT
The migratory properties of memory T cells provide a model vector system for site-specific delivery of therapeutic transgene factors to autoimmune inflammatory lesions. Lymph node cells from (SWRxSJL)F1 mice immunized with the p139-151 determinant of myelin proteolipid protein (PLP) were transfected with a DNA construct that placed the anti-inflammatory cytokine interleukin-10 (IL-10) cDNA under control of an antigen-inducible IL-2 promoter region. Isolated T cell clones demonstrated antigen-inducible expression of transgene IL-10 and expressed cell surface markers consistent with the phenotype of normal memory T cells. Upon adoptive transfer, transfected T cell clones were able to inhibit onset of experimental autoimmune encephalomyelitis (EAE) and to treat EAE animals therapeutically after onset of neurologic signs. Semiquantitative immunocytochemistry showed a significant correlation between decreased demyelination and treatment with the transfected T cells. Taken together, these data indicate the autoreactive T cells can be genetically designed to produce therapeutic factors in an antigen-inducible manner resulting in a decreased severity of clinical and histological autoimmune demyelinating disease.

Show MeSH
Related in: MedlinePlus