CNS gene expression pattern associated with spontaneous experimental autoimmune encephalomyelitis

Self Cite

Our previous studies demonstrated that oligomeric recombinant TCR ligands (RTL) can treat clinical signs of experimental autoimmune encephalomyelitis (EAE) and induce long-term T cell tolerance against encephalitogenic peptides. In the current study, we produced a monomeric I-As/PLP 139-151 peptide construct (RTL401) suitable for use in SJL/J mice that develop relapsing disease after injection of PLP 139-151 peptide in CFA. RTL401 given i.v. or s.c. but not empty RTL400 or free PLP 139-151 peptide prevented relapses and significantly reduced clinical severity of EAE induced by PLP 139-151 peptide in SJL/J or (C57BL/6 × SJL)F1 mice, but did not inhibit EAE induced by PLP 178-191 or MBP 84-104 peptides in SJL/J mice, or MOG 35-55 peptide in (C57BL/6 × SJL/J)F1 mice. RTL treatment of EAE caused stable or enhanced T cell proliferation and secretion of IL-10 in the periphery, but reduced secretion of inflammatory cytokines and chemokines. In CNS, there was a modest reduction of inflammatory cells, reduced expression of very late activation Ag-4, lymphocyte function-associated Ag-1, and inflammatory cytokines, chemokines, and chemokine receptors, but enhanced expression of Th2-related factors, IL-10, TGF-β3, and CCR3. These results suggest that monomeric RTL therapy induces a cytokine switch that curbs the encephalitogenic potential of PLP 139-151-specific T cells without fully preventing their entry into CNS, wherein they reduce the severity of inflammation. This mechanism differs from that observed using oligomeric RTL therapy in other EAE models. These results strongly support the clinical application of this novel class of peptide/MHC class II constructs in patients with multiple sclerosis who have focused T cell responses to known encephalitogenic myelin peptides.

Section: Effects Of Rtl401 Treatment On Cns During Eaesupporting

confidence: 90%

Section: Discussionmentioning

confidence: 90%

Monomeric Recombinant TCR Ligand Reduces Relapse Rate and Severity of Experimental Autoimmune Encephalomyelitis in SJL/J Mice through Cytokine Switch

Huan

Subramanian

Jones

et al. 2004

Self Cite

“…In general, changes in splenic cytokine mRNA levels induced by RTL401 treatment reflected changes in secreted protein levels. There was a significant increase in proinflammatory cytokines, IFN-␥ and TNF-␣, but also a marked increase in Th2 cytokines (IL-4 and IL-13), the Tr1 cytokine (IL-10), and TGF-␤3, which we previously associated with protection against EAE (19) in splenocytes from RTL401 i.v.-treated mice (Fig. 5).…”

Section: Mrna Expression In Spleen and Spinal Cord Of Vehicle-vs Rtl4mentioning

confidence: 60%

“…1), suggesting that there was not a natural progression to the relapsing phase induced by active immunization. This difference was most likely reflected by the fact that there were few similarities in cytokine message profiles observed in spinal cord tissue taken on day 19 from RTL401-treated mice with passive EAE (enhanced levels of IL-13 and IFN-␥) vs spinal cord tissue taken at any time point from RTL401-treated mice with active EAE (decreased levels of inflammatory cytokines, but enhanced levels of Th2-associated CCR3 (29) and TGF-␤3 that we showed previously to be associated with protection against EAE (19)). Expression of other regulatory molecules, including Th3-associated TGF-␤1 (30) and Treg-associated FoxP3 (31), was not elevated in RTL401-treated mice with passive EAE.…”

Section: Discussionmentioning

confidence: 77%

Treatment of Passive Experimental Autoimmune Encephalomyelitis in SJL Mice with a Recombinant TCR Ligand Induces IL-13 and Prevents Axonal Injury

Offner

Subramanian²,

Wang

et al. 2005

Self Cite

The major goal of this study was to evaluate the efficacy and mechanism of a rTCR ligand (RTL) construct (I-As/proteolipid protein (PLP)-139–151 peptide = RTL401) for treatment of SJL/J mice developing passive experimental autoimmune encephalomyelitis (EAE) that did not involve coimmunization with the highly inflammatory CFA. Our results demonstrated clearly that RTL401 was highly effective in treating passive EAE, with kinetics of recovery from disease very similar to treatment of actively induced EAE. The potent RTL401 treatment effect was reflected by a partial reduction of infiltrating mononuclear cells into CNS, minimal inflammatory lesions in spinal cord, and preservation of axons injured in vehicle-treated mice during the progression of EAE. Interestingly, in the absence of CFA, RTL401 treatment strongly enhanced production of the Th2 cytokine, IL-13, in spleen, blood, and spinal cord tissue, with variable effects on other Th1 and Th2 cytokines, and no significant effect on the Th3 cytokine, TGF-β1, or on FoxP3 that is expressed by regulatory T cells. Moreover, pretreatment of PLP-139–151-specific T cells with RTL401 in vitro induced high levels of secreted IL-13, with lesser induction of other pro- and anti-inflammatory cytokines. Given the importance of IL-13 for protection against EAE, these data strongly implicate IL-13 as a dominant regulatory cytokine induced by RTL therapy. Pronounced IL-13 levels coupled with marked reduction in IL-6 levels secreted by PLP-specific T cells from blood after treatment of mice with RTL401 indicate that IL-13 and IL-6 may be useful markers for following effects of RTL therapy in future clinical trials in multiple sclerosis.

“…Several recent reports have attempted to characterize the transcriptional profiles in the CNS or LN of EAE mice, helping to define the molecular fingerprint of the demyelinating process (3,(5)(6)(7)(8). However, most of these studies focused on cross-sectional analyses associated with a concrete EAE status.…”

mentioning

confidence: 99%

Increased Transcriptional Activity of Milk-Related Genes following the Active Phase of Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

Otaegui

Mostafavi

Bernard

et al. 2007

We analyzed global transcriptional changes in the lymph nodes of mice with experimental autoimmune encephalomyelitis in a longitudinal fashion. Most of the transcriptional activity was observed between 3 and 5 days postimmunization. After that period, gene expression changes decayed sharply back to baseline levels. A comparison of transcriptional profiles between immunized and control mice at the time of peak disease activity revealed 266 transcripts, mostly involved in cell-cell interaction and protein synthesis. When the same comparison was performed at the time of recovery from an attack, increased expression of genes coding for milk components were identified. Specifically, casein α (Csn1s1), β (Csn2), γ (Csn1s2a), and κ (Csn3), in addition to lactoalbumin α and extracellular proteinase were elevated >3-fold in immunized animals compared with CFA-injected controls. We confirmed these findings by quantitative RT-PCR and immunostaining of Csn3. Interestingly, the expression of Csn3 was also found elevated in the blood of multiple sclerosis (MS) patients after a relapse. Altogether, our data suggest that increased production of milk-related transcripts in the lymph nodes and blood succeeds an inflammatory event in experimental autoimmune encephalomyelitis and MS. The potential role of lactogenic hormones in MS is discussed.