Soluble antigen therapy induces apoptosis of autoreactive T cells preferentially in the target organ rather than in the peripheral lymphoid organs

Abstract

The administration of soluble myelin proteins is an effective way of down-regulating the inflammation in the central nervous system (CNS) in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. To shed more light on the mechanism of this antigen-specific therapy, we determined the effect of the intraperitoneal (i.p.) injection of soluble myelin basic protein (MBP) on Tcell apoptosis in the CNS and peripheral lymphoid organs of Lewis rats with EAE induced by inoculation with MBP and complete Freund's adjuvant. In particular we assessed the level of apoptosis of Vbeta8.2+ Tcells, which constitute the predominant encephalitogenic MBP-reactive T cell population in the Lewis rat. The daily i.p. injection of MBP for 3 days from the onset of neurological signs inhibited the further development of neurological signs of EAE. Using two-color flow cytometry we found that a single i.p. injection of MBP increased the level of apoptosis of the Vbeta8.2+ T cell population in the CNS to 26.2% compared to 7.4% in saline-treated rats and 7.6% in ovalbumin-treated rats. In contrast, treatment with MBP did not increase the level of apoptosis of the Vbeta8.2+ population in the popliteal lymph node draining the inoculation site (1.4%) or in the spleen (1.6%) above that occurring in saline-treated rats (1.6% and 1.1%, respectively). Limiting dilution analysis revealed that the frequency of T cells reactive to the major encephalitogenic epitope, MBP72-89, was decreased in the CNS but not in the popliteal lymph node by this treatment. Three-color flow cytometry in MBP-treated rats demonstrated that CNS Vbeta8.2+ T cells expressing Fas (CD95) and Fas ligand were highly vulnerable to apoptosis compared to Vbeta8.2+ Tcells not expressing these proteins. We conclude that the i.p. injection of MBP increases the spontaneously occurring Fas-mediated activation-induced apoptosis of autoreactive T cells in the CNS in EAE and that this contributes to the therapeutic effect of the injection.

Decreased production of TNF-alpha by lymph node cells indicates experimental autoimmune encephalomyelitis remission in Lewis rats

“…in the CNS at this stage (Ishigami et al 1998). Indeed, quantitative morphometric analysis of these infiltrates confirmed previous reports in the literature; more intense inflammation was found in brain sections from the acute phase.…”

B cell Apoptosis in the Central Nervous System in Experimental Autoimmune Encephalomyelitis: Roles of B cell CD95, CD95L and Bcl-2 Expression

“…Figure 3 and Table 3 show that B cell apoptosis in EAE mainly occurs in the CNS, as has been previously reported for T cells [10,11,27].…”

Systemic Administration of Agonist Peptide Blocks the Progression of Spontaneous CD8-Mediated Autoimmune Diabetes in Transgenic Mice Without Bystander Damage

“…In other systems, autoreactive T cells have been shown to undergo apoptosis in the tissue targeted by the autoimmune process following peptide treatment (47,48). Whether this also applies to the present model could not be assessed, as apoptotic cells were already numerous in the infiltrated pancreas of untreated animals (our unpublished results), precluding the evaluation of an increase in apoptotic cell numbers.…”