Tumor necrosis factor blockade in actively induced experimental autoimmune encephalomyelitis prevents clinical disease despite activated T cell infiltration to the central nervous system

Abstract

Recently, we demonstrated that experimental autoimmune encephalomyelitis (EAE) in the rat, passively transferred using myelin basic protein (MBP)-reactive encephalitogenic CD4+ T cells, was preventable by administration of a p55-tumor necrosis factor-IgG fusion protein (TNFR-IgG). This was despite quantitatively and qualitatively normal movement of these MBP-specific T cells to the central nervous system (CNS). To extend these findings, the effect of TNFR-IgG on EAE actively induced by injection of MBP in complete Freund's adjuvant was examined. This form of EAE in the rat typically involves an acute, self-limiting neurological deficit, substantial CNS inflammation, but minimal demyelination. Here we show that administration of TNFR-IgG prior to onset of disease signs completely prevented the neurological deficit or markedly reduced its severity. This blockade of clinical disease was dissociated from weight loss which occurred at the same tempo and magnitude as in control rats exhibiting neurological signs of disease such as paralysis. The timing of TNF blockade was critical as established clinical disease was relatively refractory to TNFR-IgG treatment. Activated CD4+ T cells expressing normal or elevated levels of VLA4, major histocompatibility complex class II, MRC OX40 and CD25 were isolated from or immunohistochemically localized in the CNS of clinically healthy rats treated before disease onset. There was a reduction of the amount of other inflammatory leukocytes in the CNS of these treated animals but, more importantly, the activation state of inflammatory leukocytes, as well as that of microglia isolated from treated animals, was reduced. Thus, TNFR-IgG, when administered before disease onset, appears to act by inhibiting an effector function of activated T cells and possibly other inflammatory leukocytes necessary to bring about the neurological deficit. However, while TNF is a critically important cytokine for the early events leading to initiation of EAE, it is not a necessary factor in the acute neurological deficit characteristic of this form of EAE, once disease onset has occurred.

Gene Therapy for Chronic Relapsing Experimental Allergic Encephalomyelitis Using Cells Expressing a Novel Soluble p75 Dimeric TNF Receptor

“…Although some dTNFR-tsF-treated mice in this study did develop EAE, there were a number of animals that were completely protected from EAE, showing stable weight progression and no CNS infiltrate. This may indicate a higher degree of TNF neutralization by the dTNFR-tsF cells, inhibiting TNF-induced cachexia, compared with the bolus protein administration in some studies (23). This study also demonstrates that both the development of acute phase EAE and the development of relapse may also be inhibited by dTNFR.…”

“…‫,ء‬ p Ͻ 0.05; ‫,ءء‬ p Ͻ 0.005; ‫,ءءء‬ p Ͻ 0.0002 compared with tsF-treated mice. loss correlates with blood-brain barrier dysfunction and cellular recruitment (24); and in some cases of TNF-specific protein therapy, animals showed weight loss even though disease was reduced (23). Although some dTNFR-tsF-treated mice in this study did develop EAE, there were a number of animals that were completely protected from EAE, showing stable weight progression and no CNS infiltrate.…”

“…However, it has also been suggested that TNF-specific (p55 TNFR-Ig) treatment may decrease the activation state of encephalitogenic T cells rather than inhibiting T cell infiltration into the CNS (23). The onset of weight i.c.…”

Cytokine production profiles in chronic relapsing–remitting experimental autoimmune encephalomyelitis: IFN-γ and TNF-α are important participants in the first attack but not in the relapse

“…TNF-α also has suspected immunoregulatory activities [16,17]. Reports on TNF-α−/− mice with EAE have shown conflicting results: whereas Liu et al [18] reported more severe EAE in TNF-α−/− C57BL/ 6 mice immunized with MOG, Körner et al [19] observed a delayed first attack of EAE using the same mice and antigen. In the present study, we focused on cytokine production to elucidate the mechanisms of relapse in CREAE mice immunized with MOG 35-55 and witnessed that IFN-γ and TNF-α production by spleen cells and mRNA expression in the CNS were elevated only during the first attack.…”

Augmentation of natural immunity to a pro-inflammatory cytokine (TNF-alpha) by targeted DNA vaccine confers long-lasting resistance to experimental autoimmune encephalomyelitis

“…TNF-␣ is produced by activated T cells (mostly Th1) and macrophages, and its elevated expression at the site of inflammation occurs during the critical phase of disease, 11 at the time when the 'secondary influx' of leukocytes is apparent. 3 Except for a single recent study carried out in genetically modified animals, 36 all investigators agree that TNF-␣ contributes to the pro-inflammatory process in EAE, and probably MS. 25,[37][38][39][40][41][42][43][44][45][46][47][48][49][50][51] Thus, inhibition of TNF-␣ activity by either neutralizing antibodies or soluble TNF receptor therapy, effectively prevents, or even reverses EAE. 25,42,45,[47][48][49][50][51] Overexpression of TNF-␣ in the CNS aggravated the dis-ease, 46 whereas genetically impaired expression of this gene inhibited the development and progression of disease.…”