Immunology: Meeting Review^©

Abstracts written for <http://www.multiplesclerosis.com> in 2002 and reprinted here with permission.

Blood tests for disease activity in MS patients appear more and more feasible

Researchers have documented strong positive correlations between interferon (IFN)-, tumor necrosis factor (TNF)- production and MRI parameters of disease activity. There was also an inverse correlation with the suppressive cytokine, tumor growth factor (TGF)- and MRI findings. According to Karim Makhlouf, results of the study confirm that immune changes in the peripheral blood mononuclear cells (PBMC) of MS are measurable and correlate with MRI evidence of disease activity. Thirty patients with multiple sclerosis (15 with relapsing-remitting and 15 with chronic progressive disease) from the placebo arm of a linomide clinical trial participated in the immunologic study. Patients had blood taken for cytokine measurements at baseline, 12, 24, 36, and 48 weeks. MRI scans were done at baseline, then every 4 weeks for 6 months. These data support hopes that one or more blood tests to monitor disease exacerbation may soon be available.

[S33.006/A247]

Differentiating MS subtypes and therapeutic response by dendritic cell-activation status

Dendritic cells (DC), the most potent of all antigen-presenting cells (APC), play a central role in initiating immune response. Aron Karni told the AAN audience: "…the activation status of DC may play a key role in determining the type of immune activity in MS as well as response to therapy in different stages of disease." Karni and fellow researchers investigated DCs taken directly from the blood of MS patients, characterizing both their activation state and functional status. Compared to patients with relapsing-remitting (RR) MS, those with secondary progressive (SP) disease had a significantly increased percentage of activated CD11c+DC. Furthermore, CD11c+DC in patients with stable RRMS express high levels of PDL-1, an inhibitory costimulatory molecule. (Bacterial infection as a trigger for upregulated DC activity was ruled out by the antigen-presenting cells' response to IFN- and bacterial lipopolysaccharide.)

Note: Immune cells are identified by specific cell surface markers termed clusters of differentiation (CD). Among other functions, activation of CD11c enables dendritic cells to adhere to target sites. [www.ncbi.nlm.nih.gov/PROW; NCBI locuslink for CD11c; Sell in Immunology, Immunopathology, and Immunity pp. 17, 18]

[S43.002/A326,A327]

Copaxone mechanism of action tied to specific cytotoxic T cell (CD8+) effect

The first direct evidence for glatiramer acetate (GA)-specific CD8+ responses was reported by Nitin J. Karandikar. In contrast to healthy individuals, these responses are deficient in untreated MS patients. Therapy with GA (Copaxone®) resulted in upregulation of the CD8+ activity in the MS patients, restoring them to levels seen in subjects without MS. According to Karandikar, study findings strongly suggest a role for CD8+ cell modulation in GA's therapeutic effect.

Note: Like all immune cells, T-cell subpopulations are also identified by specific cell surface markers termed clusters of differentiation (CD). Target-cell killing T-cytotoxic [T_TCL] cells are designated as CD8+. [Sell in Immunology, Immunopathology, and Immunity pp. 17, 18]

[S33.004/A246]

Addition of Prednisone to IFN beta-1a may boost anti-inflammatory effect

Adding low daily dose of Prednisone to interferon (IFN)beta-1a may provide additional benefits for MS patients, according to Hassan H. Salama. One group of patients with clinically definite MS was treated with IFN beta-1a at 20 mcg by weekly intramuscular injection (n=22) and another with INF beta-1a combined with Prednisone at a daily oral dose of 15 mg (n=33). Results of serum testing revealed that treatment with interferon alone significantly reduced TNF- and ICAM-1 (vascular adhesion molecules for lymphocytes) but not IL-2R and IL-12. Inhibition of IL-12, IL-2R, TNF- and ICAM-1 was more profound in patients treated with IFN beta-1a plus Prednisone. Salama concludes that combination therapy may further lower production of pro-inflammatory cytokines and T-cell activation. Notably however, the relapse rate was virtually identical, 14% (3/22) of patients on IFN beta-1a alone and 15% (5/33) of those on combination treatment had single relapses during the 12 months of the trial.

[PO.123/A307]

IL-18 a potential new target for MS therapy?

Findings that provide a better understanding of the mechanisms leading raised interferon (IFN)- levels in MS patients were reported by Arnon Karni . Karni and colleagues measured IL-18 and IFN- levels after stimulation of peripheral blood mononuclear cells from 58 untreated MS patients. (Additionally, the role of endogenous IL-12 and IL-18 on IFN- production was studied by adding neutralizing IL-12 and IL-18 antibodies into the cell culture.) These experiments revealed the following immune cascade: CD4+ T cell activation upregulates CD40 ligand expression interacts with CD40 on antigen presenting cells leads to secretion of interleukin (IL)-12 and IL-18. IL-12 and IL-18 secretion increases IFN- in a linked fashion in relapsing-remitting MS but independently in secondary-progressive disease. These results, say Karni, identify IL-18 as a potential new target for immune therapy of MS. (see addendum below)

Note: T-helper [T_H] cells are identified as CD4+ and help in antibody formation . [Sell in Immunology, Immunopathology, and Immunity pp. 17, 18]

[PO4.114/A303, A304]

End of the TRAIL for a neuroinflammatory TNF?

The tumor necrosing factor (TNF)-related apoptosis inducing ligand (TRAIL) appears to have other immunoregulatory functions. Jan D. Lunemann reported his group's investigation of TRAIL expression in the brain. In contrast to other known death ligands, TRAIL was not found to be constitutively expressed in the human brain. However, its apoptosis mediating receptors were detected on neurons and oligodendrocytes. Luneman told the audience that: "A blockade of TRAIL mediated brain tissue damage might therefore be of therapeutic benefit." (See addendum below.)

[PO4.122/A307]

Immune suppression yielding to immune tolerance agents but with caution

Researchers continue to try and coax subtle shifts in the immune system (immune tolerance) rather that hit it with a sledge-hammer (immune suppression). Triggered by work in transplant medicine, the approach is also used to modulate autoimmune illnesses such as multiple sclerosis. While interferons have proved both beneficial and safe, other attempts at subtle immune modulation have caused enough harm to have clinical studies halted. For example, clinical studies of an altered peptide ligand (APL) ended disastrously in 2000. Three of 8 volunteers suffered exacerbations of MS symptoms linked to peptide-targeting drug supposed to temper immune attacks. It's not clear what went wrong said Roland Martin chief of the cellular immunology section at the National Institute of Neurological Disorders and Stroke who was conducting the trial. He theorizes that dosing may have been too high, somehow triggering an immune overdrive instead of quelling their activity. He does say that the potential efficacy of APL in autoimmune diseases should be pursued, but how this should be done and which APL should be used is unclear at the moment. [Science, 19 April 2002, pp. 456-458; Science 7 June 2002, pp. 1801, 1802]

Immunology and Genetics

B-Cell Clonal Expansion in CNS A Promising Tool For MS Diagnosis

Clonal expansion of B lymphocytes and differentiation into antibody secreting plasma cells is an early inflammatory event in MS and their presence may prove diagnostic.

Yufen Quin and colleagues analyzed cerebrospinal fluid cells from 30 patients with clinically isolated syndrome (CIS) suggestive of MS using 1) RT-PCR to amplify immunoglobulin variable heavy chain (Ig-VH) genes and 2) gene sequencing to detect B-cell clonality and VH gene somatic hypermutation. Results revealed abnormalities in CIS patients with few or no MRI lesions and without intrathecal IgG oligoclonal bands (OCB). Thus, techniques to detect B-cell clonal expansion and antibody production in the CNS may provide important diagnostic alternatives to MRI and OCB. [P04.003]

Long-lived Disease-Relevant Plasma Cells Can Infiltrate the Brain From the CSF

A research group from Munich, Germany represented by Norbert Goebels, investigated brain tissue and cerebrospinal fluid of MS patients to determine: 1) whether they contain distinct or identical B-cell repertoires and 2) if the persisting pool is predominately populated by memory B cells or long-lived plasma cells. They used PCR to identify and characterize clonally expanded B-cell populations, analyzing matched pairs of cDNA from cells in the cerebrospinal fluid (CSF) and brain tissue of two MS patients undergoing diagnostic cerebral biopsies. Cloned DNA from two additional MS patients were also analyzed.

These researchers showed for the first time that both brain tissue and CSF of MS patients contain partly identical repertoires of expanded B-cell clones. This was "especially remarkable" because the brain biopsy and spinal tap were done as far as 5 years apart. They also demonstrated that the extraordinary persistence is provided by long-lived plasma cells. This strongly indicates that at least some disease-relevant plasma cells infiltrating the brain of MS patients originate in the spinal fluid. [S55.005]

CD8+ T Cells Potential Target for Immunotherapy

T-cells have always been considered essential to MS pathogenesis although up to now it has not been possible to link a defined T-cell population with disease activity. Using a very elegant technique, Dun Zhou and fellow researchers in Marburg Germany were able to detect significant repertoire changes in DE8+ (but not CD4+) T cells in the CNS of patients with MS.

After identifying clonotypic T cells in the cerebrospinal fluid (CSF) of patients with recent-onset disease the group continued to monitor patients' peripheral blood for T-cell activity for the first few years of illness. The investigators discovered that clonotypic CD8+ T cells strongly expanded in the blood during clinical relapses and transiently changed their phenotype with upregulation of HLA-DR and LFA-1 and down regulation of CD28. During remission the CD8+ T-cell clonotypes contracted in peripheral blood but persisted in the CSF.

These results, says Dr. Zhou: "…imply an important role [for] CD8+ cells in the pathogenesis [of MS] providing a novel target for immune intervention…." [S55.006]

African Americans Appear to Have More Aggressive MS Than Caucasian Americans

Preliminary results from an ongoing study suggest that African Americans (AA) are at higher risk for 1) disability, 2) developing secondary progressive MS and 3) presenting with opticospinal disease more often than their Caucasian American (CA) counterparts. These surprising findings are emerging from a comprehensive, retrospective investigation conducted by the Multiple Sclerosis Genetics Group (MSGG). Notably, AA patients had a 1.74-fold greater risk for progression to EDSS=4.0 (p=0.740) and a 2.3-fold greater risk for SPMS (p= 0.001) than CA patients (AA n= 207, CA n=314). Bruce C. Cree, reporting for the group, also said that a preliminary analysis of HLA class I and class II polymorphisms confirmed a well-documented association between HLA DR2 halotype with MS in both groups of patients. These data will be extended into a confirmatory dataset. Additional analyses of genotype-phenotype correlations are also in progress. [PO1.122]