Differential Susceptibility Of Human Th1 Versus Th 2 Cells To Induction Of Anergy And Apoptosis By ECDI/Antigen-Coupled Antigen Presenting Cells
Vandenbark AA, Barnes D, Finn T, Bourdette DN, Whitham R, Robey I, Kaleeba J, Bebo BF Jr, Miller SD, Offner H, Chou YK
Int Immunol 2000 Jan;12(1):57-66
Veterans Affairs Medical Center, NeuroImmunology Research R & D-31, Portland, OR 97201, USA. Sc
PMID# 10607750; UI# 20076287
Antigen-coupled Antigen Presenting Cells (APC) serve as potent ToleroGens for inhibiting Immune Responses in vivo and in vitro.
Apparently by providing an Antigen-specific signal through the TCR in the absence of co-stimulation. Although this approach has been well studied in rodents, little is known about its effects on human T-Cells.
We evaluated the specificity and mechanisms of Tolerization of human T-Cells in vitro using Monocyte-enriched adherent cells that were pulsed with Antigen and treated with, 1-Ethyl-3-(3-Dimethylaminopropyl)-Carbodiimide (ECDI).
Autologous Antigen-coupled APC selectively Tolerized T-Cells of the T-Helper 1 (Th1) but not Th2 lineage through a mechanism that involved both Antigen-Specific and Antigen-Non-Specific elements.
The Tolerization process was dependent on the ECDI and Antigen concentration, and the coupling time, and was reflected by initial up-regulation of CD25.
However, upon re-stimulation with fresh APC and Antigen, Tolerized Th1 Cells failed to proliferate or to produce Th1 Cytokine message or secreted protein.
They had decreased expression of CD25, CD28 and B7 and increased expression of MHC Class II molecules, and demonstrated an enhanced commitment to Apoptosis.
Th1 Cell Tolerization could be prevented by adding Anti-CD28 AntiBody, IL-2 or untreated APC at the same time as the ECDI/Antigen-coupled APC, or reversed by adding Anti-CD28 AntiBody or IL-2 upon re-stimulation with fresh APC plus Antigen.
Thus, the tolerizing effect of ECDI/Antigen-coupled APC on human Th1 Cells appears to involve a reversible Anergy mechanism leading to Apoptosis, whereby the targeted T-Cells receive full or partial activation through the TCR, without coordinate co-stimulation.
These data suggest DiChotomous signaling requirements for inactivating Cells of the Th1 and Th2 lineages that may have important implications for treatment of Th1-mediated AutoImmune or Inflammatory Diseases.
Effect Of Interferon-ß-1b In MS: Assessment Of Annual Accumulation of PD/T2 Activity On MRI
UBC MS/MRI Analysis Group and the MS Study Group
Zhao GJ, Koopmans RA, Li DK, Bedell L, Paty DW
Neurology 2000 Jan 11;54(1):200-6
Univ of British Columbia, Division of Neurology, Vancouver Hospital and Health Science Center, Canada
PMID# 10636148; UI# 20100103
To determine whether the efficacy of Interferon-beta-1b (IFN-ß-1b) on lesion activity could be shown with annual analysis of MRI.
Clinical outcomes and MRI burden of disease changes in MS patients in a multicenter double-blind placebo-controlled 5-year trial of IFN-ß-1b have been reported, together with an analysis of 6-weekly MRI activity in a small subgroup during 2 years.
MRI activity measurements based on annual scans have not been documented.
Patients were randomized into three treatment arms: placebo, 1.6 mIU, and 8 mIU IFN-ß-1b self-administered subcutaneously every other day. Active lesions were identified as new, enlarging, or recurrent on Proton Density and T2-weighted MRI scans.
Gadolinium was not used. An annual accumulation activity index was developed as an additional analysis of lesion activity.
During the 5 years, both high- and low-dose IFN-ß-1b groups showed a striking reduction in lesion annual accumulation activity on the activity index versus placebo (p = 0.001).
Thirty-five percent of the high-dose patients and 29% of the low-dose patients were MRI inactive by this method of analysis, whereas only 16% of placebo patients were inactive (p = 0.001, placebo versus 8 mIU).
This analysis of the annual accumulation of lesion activity shows that the previously reported treatment effect seen on MRI scanning once every 6 weeks in a subcohort of the patients can also be seen on yearly scans.
This annual accumulation activity analysis provides an independent MRI confirmation of a treatment and dose effect for IFN-ß-1b.
Activation Of Regulatory Cells Suppresses Experimental Allergic EncephaloMyelitis Via Secretion Of IL-10
Stohlman SA, Pei L, Cua DJ, Li Z, Hinton DR
J Immunol 1999 Dec 1;163(11):6338-44
Univ of Southern California School of Medicine, Depts of Molecular Microbiology and Immunology, Neurology, and Pathology, Los Angeles, CA 90033, USA
PMID# 10570329; UI# 20040434
Suppression of CD4+ Th1 Cell-mediated AutoImmune Disease via Immune deviation is an attractive potential therapeutic approach.
CD4+ Th2 T-Cells specific for Myelin Basic Protein, induced by immunization of young adult male SJL mice, suppress or modify the progression of CNS AutoImmune Disease.
This report demonstrates that activation of Non-NeuroAntigen-specific Th2 Cells is sufficient to suppress both clinical and histological Experimental Allergic EncephaloMyelitis (EAE).
Th2 Cells were obtained following immunization of male SJL mice with keyhole Limpet Hemocyanin. Transfer of these cells did not modify EAE, a model of human Multiple Sclerosis, in the absence of cognate Ag.
Disease suppression was obtained following adoptive transfer and subcutaneous immunization.
Suppression was not due to the deletion of Myelin Basic Protein-specific T-Cells, but resulted from the presence of IL-10 as demonstrated by the inhibition of Th2-mediated EAE suppression via passive transfer with either anti-IL-10 or anti-IL-10R mAb.
These data demonstrate that peripheral activation of a CD4+ Th2 population specific for an Ag not expressed in the CNS modifies CNS AutoImmune Disease via IL-10.
These data suggest that either peripheral activation or direct administration of IL-10 may be of benefit in treating Th1-mediated AutoImmune Diseases.