Limits...
Uncoupling the proinflammatory from the immunosuppressive properties of tumor necrosis factor (TNF) at the p55 TNF receptor level: implications for pathogenesis and therapy of autoimmune demyelination.

Kassiotis G, Kollias G - J. Exp. Med. (2001)

Bottom Line: In addition to its well-established proinflammatory effects, TNF exhibits potent immunosuppressive properties, providing one possible explanation for the immune and disease activating effect of anti-TNF treatment of MS.Strikingly, immunosuppression by TNF and protection against EAE does not require the p55 TNFR, whereas the same receptor is necessary for the detrimental effects of TNF during the acute phase of the disease.Thus, blocking the function of the p55 TNFR in autoimmune demyelination may inhibit the noxious proinflammatory activities of TNF without compromising its immunosuppressive properties.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens 115-21, Greece.

ABSTRACT
Multiple sclerosis (MS) is a disabling inflammatory demyelinating disease of the central nervous system, considered to result from self-reactivity to myelin antigens. Tumor necrosis factor (TNF) and the p55 TNF receptor (TNFR) have been strongly implicated in MS pathogenesis. We reveal in this study a dual role for TNF in experimental autoimmune encephalomyelitis (EAE), a mouse model for MS. In addition to its well-established proinflammatory effects, TNF exhibits potent immunosuppressive properties, providing one possible explanation for the immune and disease activating effect of anti-TNF treatment of MS. We show that in TNF-deficient mice, myelin-specific T cell reactivity fails to regress and expansion of activated/memory T cells is abnormally prolonged, leading to exacerbated EAE. Strikingly, immunosuppression by TNF and protection against EAE does not require the p55 TNFR, whereas the same receptor is necessary for the detrimental effects of TNF during the acute phase of the disease. Thus, blocking the function of the p55 TNFR in autoimmune demyelination may inhibit the noxious proinflammatory activities of TNF without compromising its immunosuppressive properties.

Show MeSH

Related in: MedlinePlus

Establishment of resistance to MOG-induced EAE in B6.p55−/− and C57BL/6 mice but not in B6.TNF−/− after MOGp35–55 immunization. EAE was induced in mice by MOGp35–55 immunization in CFA containing 1 mg H37Ra per mouse. On the day of immunization and 48 h later, mice received 200 ng PTx intraperitoneally. 50 d later, EAE was reinduced using the same protocol. Each curve represents the mean clinical score ± SD of each group.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2195909&req=5

Figure 7: Establishment of resistance to MOG-induced EAE in B6.p55−/− and C57BL/6 mice but not in B6.TNF−/− after MOGp35–55 immunization. EAE was induced in mice by MOGp35–55 immunization in CFA containing 1 mg H37Ra per mouse. On the day of immunization and 48 h later, mice received 200 ng PTx intraperitoneally. 50 d later, EAE was reinduced using the same protocol. Each curve represents the mean clinical score ± SD of each group.

Mentions: To address the effect of TNF deficiency on the autoimmune disease resulting from MOG immunization of susceptible backgrounds, TNF−/− mice were backcrossed to C57BL/6 mice for at least six generations and EAE was induced by MOGp35–55 immunization and PTx coadministration. In agreement with previous reports 78, onset of clinical symptoms was delayed by several days in B6.TNF−/− mice compared with C57BL/6 mice (Fig. 4 a). Surprisingly, however, despite delayed onset and overall reduced disease, after recovery from the acute episode of disease, B6.TNF−/− mice developed a chronic-progressive form of EAE (Fig. 4 a), in contrast to C57BL/6 mice, which retained only a mild deficit (Fig. 4 a). In separate experiments, EAE was induced by MOGp35–55 immunization without PTx coadministration, a protocol that induces EAE only in C57BL/6 but not in B6.TNF−/− mice (see below, Fig. 7). Although B6.TNF−/− mice were not susceptible to the acute episode of disease, they developed the late chronic-progressive form, as seen in Fig. 4 a (data not shown). Similarly, p55p75−/− mice on a MOG-resistant B6,129 background (resistance conferred by the 129 genetic background [13]), although fully refractory to the acute episode of EAE (Fig. 4 b), developed the late chronic-progressive form of EAE, in contrast to B6,129 F2 control mice (Fig. 4 b). Together, these experiments demonstrate that despite being beneficial during the onset of disease, TNF deficiency is associated with late complication of myelin-directed autoimmune disease.


Uncoupling the proinflammatory from the immunosuppressive properties of tumor necrosis factor (TNF) at the p55 TNF receptor level: implications for pathogenesis and therapy of autoimmune demyelination.

Kassiotis G, Kollias G - J. Exp. Med. (2001)

Establishment of resistance to MOG-induced EAE in B6.p55−/− and C57BL/6 mice but not in B6.TNF−/− after MOGp35–55 immunization. EAE was induced in mice by MOGp35–55 immunization in CFA containing 1 mg H37Ra per mouse. On the day of immunization and 48 h later, mice received 200 ng PTx intraperitoneally. 50 d later, EAE was reinduced using the same protocol. Each curve represents the mean clinical score ± SD of each group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195909&req=5

Figure 7: Establishment of resistance to MOG-induced EAE in B6.p55−/− and C57BL/6 mice but not in B6.TNF−/− after MOGp35–55 immunization. EAE was induced in mice by MOGp35–55 immunization in CFA containing 1 mg H37Ra per mouse. On the day of immunization and 48 h later, mice received 200 ng PTx intraperitoneally. 50 d later, EAE was reinduced using the same protocol. Each curve represents the mean clinical score ± SD of each group.
Mentions: To address the effect of TNF deficiency on the autoimmune disease resulting from MOG immunization of susceptible backgrounds, TNF−/− mice were backcrossed to C57BL/6 mice for at least six generations and EAE was induced by MOGp35–55 immunization and PTx coadministration. In agreement with previous reports 78, onset of clinical symptoms was delayed by several days in B6.TNF−/− mice compared with C57BL/6 mice (Fig. 4 a). Surprisingly, however, despite delayed onset and overall reduced disease, after recovery from the acute episode of disease, B6.TNF−/− mice developed a chronic-progressive form of EAE (Fig. 4 a), in contrast to C57BL/6 mice, which retained only a mild deficit (Fig. 4 a). In separate experiments, EAE was induced by MOGp35–55 immunization without PTx coadministration, a protocol that induces EAE only in C57BL/6 but not in B6.TNF−/− mice (see below, Fig. 7). Although B6.TNF−/− mice were not susceptible to the acute episode of disease, they developed the late chronic-progressive form, as seen in Fig. 4 a (data not shown). Similarly, p55p75−/− mice on a MOG-resistant B6,129 background (resistance conferred by the 129 genetic background [13]), although fully refractory to the acute episode of EAE (Fig. 4 b), developed the late chronic-progressive form of EAE, in contrast to B6,129 F2 control mice (Fig. 4 b). Together, these experiments demonstrate that despite being beneficial during the onset of disease, TNF deficiency is associated with late complication of myelin-directed autoimmune disease.

Bottom Line: In addition to its well-established proinflammatory effects, TNF exhibits potent immunosuppressive properties, providing one possible explanation for the immune and disease activating effect of anti-TNF treatment of MS.Strikingly, immunosuppression by TNF and protection against EAE does not require the p55 TNFR, whereas the same receptor is necessary for the detrimental effects of TNF during the acute phase of the disease.Thus, blocking the function of the p55 TNFR in autoimmune demyelination may inhibit the noxious proinflammatory activities of TNF without compromising its immunosuppressive properties.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens 115-21, Greece.

ABSTRACT
Multiple sclerosis (MS) is a disabling inflammatory demyelinating disease of the central nervous system, considered to result from self-reactivity to myelin antigens. Tumor necrosis factor (TNF) and the p55 TNF receptor (TNFR) have been strongly implicated in MS pathogenesis. We reveal in this study a dual role for TNF in experimental autoimmune encephalomyelitis (EAE), a mouse model for MS. In addition to its well-established proinflammatory effects, TNF exhibits potent immunosuppressive properties, providing one possible explanation for the immune and disease activating effect of anti-TNF treatment of MS. We show that in TNF-deficient mice, myelin-specific T cell reactivity fails to regress and expansion of activated/memory T cells is abnormally prolonged, leading to exacerbated EAE. Strikingly, immunosuppression by TNF and protection against EAE does not require the p55 TNFR, whereas the same receptor is necessary for the detrimental effects of TNF during the acute phase of the disease. Thus, blocking the function of the p55 TNFR in autoimmune demyelination may inhibit the noxious proinflammatory activities of TNF without compromising its immunosuppressive properties.

Show MeSH
Related in: MedlinePlus