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Transgenic interleukin 10 prevents induction of experimental autoimmune encephalomyelitis.

Cua DJ, Groux H, Hinton DR, Stohlman SA, Coffman RL - J. Exp. Med. (1999)

Bottom Line: The effectiveness of interleukin 10 (IL-10) in the treatment of autoimmune-mediated central nervous system inflammation is controversial.Antibody depletion confirmed that EAE resistance is dependent on the presence of the transgenic IL-10.This study demonstrates that IL-10 can prevent EAE completely if present at appropriate levels and times during disease induction.

View Article: PubMed Central - PubMed

Affiliation: DNAX Research Institute of Molecular and Cellular Biology, Inc., Palo Alto, California 94304, USA.

ABSTRACT
The effectiveness of interleukin 10 (IL-10) in the treatment of autoimmune-mediated central nervous system inflammation is controversial. Studies of the model system, experimental autoimmune encephalomyelitis (EAE), using various routes, regimens, and delivery methods of IL-10 suggest that these variables may affect its immunoregulatory function. To study the influence of these factors on IL-10 regulation of EAE pathogenesis, we have analyzed transgenic mice expressing human IL-10 (hIL-10) transgene under the control of a class II major histocompatibility complex (MHC) promoter. The hIL-10 transgenic mice are highly resistant to EAE induced by active immunization, and this resistance appears to be mediated by suppression of autoreactive T cell function. Myelin-reactive T helper 1 cells are induced but nonpathogenic in the IL-10 transgenic mice. Antibody depletion confirmed that EAE resistance is dependent on the presence of the transgenic IL-10. Mice expressing the hIL-10 transgene but not the endogenous murine IL-10 gene demonstrated that transgenic IL-10 from MHC class II-expressing cells is sufficient to block induction of EAE. This study demonstrates that IL-10 can prevent EAE completely if present at appropriate levels and times during disease induction.

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Related in: MedlinePlus

Induction of EAE in  hIL-10Tg mice treated with anti– hIL-10 mAb. Days of mAb treatment  are indicated by arrows. (A) Tg mice  were injected with anti–hIL-10 mAb  (1 mg/dose) or isotype-matched mAb  starting at the day of MSCH immunization. One representative experiment out of five is shown. (B) Mice  were injected with the mAb starting  8 d before MSCH immunization.  One representative experiment out  of three is shown.
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Figure 3: Induction of EAE in hIL-10Tg mice treated with anti– hIL-10 mAb. Days of mAb treatment are indicated by arrows. (A) Tg mice were injected with anti–hIL-10 mAb (1 mg/dose) or isotype-matched mAb starting at the day of MSCH immunization. One representative experiment out of five is shown. (B) Mice were injected with the mAb starting 8 d before MSCH immunization. One representative experiment out of three is shown.

Mentions: To show that disease resistance was due to the direct effects of the transgenic IL-10, immunized transgenic SJL/J × BALB/cAnN F1 mice were injected with either JES3-9D7 mAb (hIL-10–specific mAb [16] that does not cross-react with mouse IL-10) or GL113 mAb (an isotype-matched mAb control). Tg mice receiving the first anti–hIL-10 mAb injection on the day of immunization were susceptible to EAE, whereas the isotype control mAb–injected mice were resistant to EAE (Fig. 3 A). This result suggests that EAE resistance of hIL-10Tg mice was the consequence of hIL-10 present during immunization, rather than of developmental effects of the transgene. A consistent delay in the day of disease onset was found in the anti–hIL-10 mAb–treated mice compared to control littermates (Fig. 3 A). To determine the cause of this delay, anti–hIL-10 mAb treatment was initiated 8 d before MSCH immunization. With this treatment regimen, the EAE clinical grade and day of disease onset for hIL-10Tg and control littermate mice were indistinguishable (Fig. 3 B). Similar results were obtained when hIL-10Tg mice on the BALB/cAnN genetic background were treated with the anti–hIL-10 mAb (data not shown).


Transgenic interleukin 10 prevents induction of experimental autoimmune encephalomyelitis.

Cua DJ, Groux H, Hinton DR, Stohlman SA, Coffman RL - J. Exp. Med. (1999)

Induction of EAE in  hIL-10Tg mice treated with anti– hIL-10 mAb. Days of mAb treatment  are indicated by arrows. (A) Tg mice  were injected with anti–hIL-10 mAb  (1 mg/dose) or isotype-matched mAb  starting at the day of MSCH immunization. One representative experiment out of five is shown. (B) Mice  were injected with the mAb starting  8 d before MSCH immunization.  One representative experiment out  of three is shown.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2193046&req=5

Figure 3: Induction of EAE in hIL-10Tg mice treated with anti– hIL-10 mAb. Days of mAb treatment are indicated by arrows. (A) Tg mice were injected with anti–hIL-10 mAb (1 mg/dose) or isotype-matched mAb starting at the day of MSCH immunization. One representative experiment out of five is shown. (B) Mice were injected with the mAb starting 8 d before MSCH immunization. One representative experiment out of three is shown.
Mentions: To show that disease resistance was due to the direct effects of the transgenic IL-10, immunized transgenic SJL/J × BALB/cAnN F1 mice were injected with either JES3-9D7 mAb (hIL-10–specific mAb [16] that does not cross-react with mouse IL-10) or GL113 mAb (an isotype-matched mAb control). Tg mice receiving the first anti–hIL-10 mAb injection on the day of immunization were susceptible to EAE, whereas the isotype control mAb–injected mice were resistant to EAE (Fig. 3 A). This result suggests that EAE resistance of hIL-10Tg mice was the consequence of hIL-10 present during immunization, rather than of developmental effects of the transgene. A consistent delay in the day of disease onset was found in the anti–hIL-10 mAb–treated mice compared to control littermates (Fig. 3 A). To determine the cause of this delay, anti–hIL-10 mAb treatment was initiated 8 d before MSCH immunization. With this treatment regimen, the EAE clinical grade and day of disease onset for hIL-10Tg and control littermate mice were indistinguishable (Fig. 3 B). Similar results were obtained when hIL-10Tg mice on the BALB/cAnN genetic background were treated with the anti–hIL-10 mAb (data not shown).

Bottom Line: The effectiveness of interleukin 10 (IL-10) in the treatment of autoimmune-mediated central nervous system inflammation is controversial.Antibody depletion confirmed that EAE resistance is dependent on the presence of the transgenic IL-10.This study demonstrates that IL-10 can prevent EAE completely if present at appropriate levels and times during disease induction.

View Article: PubMed Central - PubMed

Affiliation: DNAX Research Institute of Molecular and Cellular Biology, Inc., Palo Alto, California 94304, USA.

ABSTRACT
The effectiveness of interleukin 10 (IL-10) in the treatment of autoimmune-mediated central nervous system inflammation is controversial. Studies of the model system, experimental autoimmune encephalomyelitis (EAE), using various routes, regimens, and delivery methods of IL-10 suggest that these variables may affect its immunoregulatory function. To study the influence of these factors on IL-10 regulation of EAE pathogenesis, we have analyzed transgenic mice expressing human IL-10 (hIL-10) transgene under the control of a class II major histocompatibility complex (MHC) promoter. The hIL-10 transgenic mice are highly resistant to EAE induced by active immunization, and this resistance appears to be mediated by suppression of autoreactive T cell function. Myelin-reactive T helper 1 cells are induced but nonpathogenic in the IL-10 transgenic mice. Antibody depletion confirmed that EAE resistance is dependent on the presence of the transgenic IL-10. Mice expressing the hIL-10 transgene but not the endogenous murine IL-10 gene demonstrated that transgenic IL-10 from MHC class II-expressing cells is sufficient to block induction of EAE. This study demonstrates that IL-10 can prevent EAE completely if present at appropriate levels and times during disease induction.

Show MeSH
Related in: MedlinePlus