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Critical points of tumor necrosis factor action in central nervous system autoimmune inflammation defined by gene targeting.

Körner H, Riminton DS, Strickland DH, Lemckert FA, Pollard JD, Sedgwick JD - J. Exp. Med. (1997)

Bottom Line: In this way a single gene effect was studied.These results are consistent with the TNF dependence of processes controlling initial leukocyte movement within the CNS.Nevertheless, potent alternative mechanisms exist to mediate all other phases of EAE.

View Article: PubMed Central - PubMed

Affiliation: Centenary Institute of Cancer Medicine and Cell Biology, Royal Prince Alfred Hospital, Sydney, New South Wales, 2050 Australia.

ABSTRACT
Tumor necrosis factor (TNF)-dependent sites of action in the generation of autoimmune inflammation have been defined by targeted disruption of TNF in the C57BL/6 mouse strain. C57BL/6 mice are susceptible to an inflammatory, demyelinating form of experimental autoimmune encephalomyelitis (EAE) induced by the 35-55 peptide of myelin oligodendrocyte glycoprotein. Direct targeting of a strain in which EAE was inducible was necessary, as the location of the TNF gene renders segregation of the mutated allele from the original major histocompatibility complex by backcrossing virtually impossible. In this way a single gene effect was studied. We show here that TNF is obligatory for normal initiation of the neurological deficit, as demonstrated by a significant (6 d) delay in disease in its absence relative to wild-type (WT) mice. During this delay, comparable numbers of leukocytes were isolated from the perfused central nervous system (CNS) of WT and TNF-/- mice. However, in the TNF-/- mice, immunohistological analysis of CNS tissue indicated that leukocytes failed to form the typical mature perivascular cuffs observed in WT mice at this same time point. Severe EAE, including paralysis and widespread CNS perivascular inflammation, eventually developed without TNF. TNF-/- and WT mice recovered from the acute illness at the same time, such that the overall disease course in TNF-/- mice was only 60% of the course in control mice. Primary demyelination occurred in both WT and TNF-/- mice, although it was of variable magnitude. These results are consistent with the TNF dependence of processes controlling initial leukocyte movement within the CNS. Nevertheless, potent alternative mechanisms exist to mediate all other phases of EAE.

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Natural history of EAE in WT and TNF−/− C57BL/6 mice.  (A) Mean clinical EAE scores (± SEM) of WT mice (•, n = 6) and  TNF−/− mice (○, n = 8) after immunization with MOG/CFA. The  horizontal bar at days 13–15 indicates a time point of closer examination,  referred to in Fig. 2 and in the text. (B) As a measure of the relative susceptibility of WT and TNF−/− mice to neurological deficits induced by  immunization with MOG, areas under the curves in A were determined.  Results are representative of four separate time course studies.
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Figure 1: Natural history of EAE in WT and TNF−/− C57BL/6 mice. (A) Mean clinical EAE scores (± SEM) of WT mice (•, n = 6) and TNF−/− mice (○, n = 8) after immunization with MOG/CFA. The horizontal bar at days 13–15 indicates a time point of closer examination, referred to in Fig. 2 and in the text. (B) As a measure of the relative susceptibility of WT and TNF−/− mice to neurological deficits induced by immunization with MOG, areas under the curves in A were determined. Results are representative of four separate time course studies.

Mentions: Upon challenge with the encephalitogenic MOG 35–55 peptide, WT mice exhibited signs of clinical disease from day 10 (Fig. 1 A), manifest as symmetrical ascending motor deficits. Disease severity then increased rapidly to reach a peak at day 20, followed by gradual recovery over the next 20 d to a relatively mild deficit that persisted for the life of the mouse (data not shown). Although TNF−/− mice did develop EAE after MOG peptide challenge, the onset of clinical disease was substantially and reproducibly delayed (Fig. 1 A). The rate of progression once disease became established and the eventual peak severity of disease in TNF−/− mice were comparable to WT mice. Both WT and TNF−/− mice recovered simultaneously despite the initial delay in disease onset in mice lacking TNF. Thus, the overall disease course was reduced to 60% of the course in control mice in the absence of TNF (Fig. 1 B). Like WT mice, mice lacking TNF maintained a mild level of disability for an extended time after resolution of the initial peak clinical deficit.


Critical points of tumor necrosis factor action in central nervous system autoimmune inflammation defined by gene targeting.

Körner H, Riminton DS, Strickland DH, Lemckert FA, Pollard JD, Sedgwick JD - J. Exp. Med. (1997)

Natural history of EAE in WT and TNF−/− C57BL/6 mice.  (A) Mean clinical EAE scores (± SEM) of WT mice (•, n = 6) and  TNF−/− mice (○, n = 8) after immunization with MOG/CFA. The  horizontal bar at days 13–15 indicates a time point of closer examination,  referred to in Fig. 2 and in the text. (B) As a measure of the relative susceptibility of WT and TNF−/− mice to neurological deficits induced by  immunization with MOG, areas under the curves in A were determined.  Results are representative of four separate time course studies.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199118&req=5

Figure 1: Natural history of EAE in WT and TNF−/− C57BL/6 mice. (A) Mean clinical EAE scores (± SEM) of WT mice (•, n = 6) and TNF−/− mice (○, n = 8) after immunization with MOG/CFA. The horizontal bar at days 13–15 indicates a time point of closer examination, referred to in Fig. 2 and in the text. (B) As a measure of the relative susceptibility of WT and TNF−/− mice to neurological deficits induced by immunization with MOG, areas under the curves in A were determined. Results are representative of four separate time course studies.
Mentions: Upon challenge with the encephalitogenic MOG 35–55 peptide, WT mice exhibited signs of clinical disease from day 10 (Fig. 1 A), manifest as symmetrical ascending motor deficits. Disease severity then increased rapidly to reach a peak at day 20, followed by gradual recovery over the next 20 d to a relatively mild deficit that persisted for the life of the mouse (data not shown). Although TNF−/− mice did develop EAE after MOG peptide challenge, the onset of clinical disease was substantially and reproducibly delayed (Fig. 1 A). The rate of progression once disease became established and the eventual peak severity of disease in TNF−/− mice were comparable to WT mice. Both WT and TNF−/− mice recovered simultaneously despite the initial delay in disease onset in mice lacking TNF. Thus, the overall disease course was reduced to 60% of the course in control mice in the absence of TNF (Fig. 1 B). Like WT mice, mice lacking TNF maintained a mild level of disability for an extended time after resolution of the initial peak clinical deficit.

Bottom Line: In this way a single gene effect was studied.These results are consistent with the TNF dependence of processes controlling initial leukocyte movement within the CNS.Nevertheless, potent alternative mechanisms exist to mediate all other phases of EAE.

View Article: PubMed Central - PubMed

Affiliation: Centenary Institute of Cancer Medicine and Cell Biology, Royal Prince Alfred Hospital, Sydney, New South Wales, 2050 Australia.

ABSTRACT
Tumor necrosis factor (TNF)-dependent sites of action in the generation of autoimmune inflammation have been defined by targeted disruption of TNF in the C57BL/6 mouse strain. C57BL/6 mice are susceptible to an inflammatory, demyelinating form of experimental autoimmune encephalomyelitis (EAE) induced by the 35-55 peptide of myelin oligodendrocyte glycoprotein. Direct targeting of a strain in which EAE was inducible was necessary, as the location of the TNF gene renders segregation of the mutated allele from the original major histocompatibility complex by backcrossing virtually impossible. In this way a single gene effect was studied. We show here that TNF is obligatory for normal initiation of the neurological deficit, as demonstrated by a significant (6 d) delay in disease in its absence relative to wild-type (WT) mice. During this delay, comparable numbers of leukocytes were isolated from the perfused central nervous system (CNS) of WT and TNF-/- mice. However, in the TNF-/- mice, immunohistological analysis of CNS tissue indicated that leukocytes failed to form the typical mature perivascular cuffs observed in WT mice at this same time point. Severe EAE, including paralysis and widespread CNS perivascular inflammation, eventually developed without TNF. TNF-/- and WT mice recovered from the acute illness at the same time, such that the overall disease course in TNF-/- mice was only 60% of the course in control mice. Primary demyelination occurred in both WT and TNF-/- mice, although it was of variable magnitude. These results are consistent with the TNF dependence of processes controlling initial leukocyte movement within the CNS. Nevertheless, potent alternative mechanisms exist to mediate all other phases of EAE.

Show MeSH
Related in: MedlinePlus