Changes in Activated T Cells in the Blood Correlate With Disease Activity in Multiple Sclerosis

Khoury, Samia J.; Guttmann, Charles R.G.; Orav, E. John; Kikinis, R.; Jólesz, Ferenc A.; Weiner, Howard L.

doi:10.1001/archneur.57.8.1183

Cited by 103 publications

(67 citation statements)

References 48 publications

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“…It has been previously reported that the presence of activated T cells in the BM may affect the growth and survival characteristics of BM hematopoietic progenitor cells or even the hematopoiesis supporting capacity of BM stromal cells by inducing intricate cell-tocell interactions and proinflammatory cytokine production. 26,[29][30][31][32][33][34][35] In agreement with previous reports, we found increased numbers of activated T cells in PB of our MS patients, 15,[36][37][38] and also increased proportions of activated T cells in patients' BM. Interestingly, the proportion of HLA-DR þ and CD38 þ cells in patient BM CD3 þ cells inversely correlated with the number of CFCs in the BMMC fraction, suggesting that activated T cells may be implicated in the defective clonogenic potential of hematopoietic progenitor cells in MS.…”

Section: Cytokines In Ltbmc Supernatantssupporting

confidence: 91%

Normal bone marrow hematopoietic stem cell reserves and normal stromal cell function support the use of autologous stem cell transplantation in patients with multiple sclerosis

Papadaki

Tsagournisakis

Mastorodemos

et al. 2005

Bone Marrow Transplant

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Summary:Bone marrow (BM) stem cell reserves and function and stromal cell hematopoiesis supporting capacity were evaluated in 15 patients with multiple sclerosis (MS) and 61 normal controls using flow cytometry, clonogenic assays, long-term BM cultures (LTBMCs) and enzymelinked immunosorbent assays. MS patients displayed normal CD34 þ cell numbers but a low frequency of colony-forming cells (CFCs) in both BM mononuclear and purified CD34 þ cell fractions, compared to controls. Patients had increased proportions of activated BM CD3 þ /HLA-DR þ and CD3 þ /CD38 þ T cells that correlated inversely with CFC numbers. Patient BM CD3 þ T cells inhibited colony formation by normal CD34 þ cells and patient CFC numbers increased significantly following immunomagnetic removal of T cells from BMMCs, suggesting that activated T cells may be involved in the defective clonogenic potential of hematopoietic progenitors. Patient BM stromal cells displayed normal hematopoiesis supporting capacity indicated by the CFC number in the nonadherent cell fraction of LTBMCs recharged with normal CD34 þ cells. Culture supernatants displayed normal stromal derived factor-1 and stem cell factor/kit ligand but increased flt-3 ligand levels. These findings provide support for the use of autologous stem cell transplantation in MS patients. The low clonogenic potential of BM hematopoietic progenitors probably reflects the presence of activated T cells rather than an intrinsic defect.

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Section: Cytokines In Ltbmc Supernatantssupporting

confidence: 91%

Normal bone marrow hematopoietic stem cell reserves and normal stromal cell function support the use of autologous stem cell transplantation in patients with multiple sclerosis

Papadaki

Tsagournisakis

Mastorodemos

et al. 2005

Bone Marrow Transplant

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“…24 However, subjects with active autoimmune disease are more likely to have a higher frequency of activated T cells than healthy control subjects. [25][26][27] Therefore, we designed a FACS isolation strategy in which non-CD4 þ T cells were eliminated and only the top 1% of CD4 þ CD25 þ high T cells were collected as the regulatory T-cell subset. We have reported elevated apoptosis levels and decreased function of the CD4 þ CD25 þ high T-cell subset isolated from subjects with recent-onset T1D and from multiple autoantibody-positive subjects.…”

Section: Discussionmentioning

confidence: 99%

Genetic association of HLA DQB1 with CD4+CD25+high T-cell apoptosis in type 1 diabetes

et al. 2009

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Type 1 diabetes (T1D) has a strong genetic component and the major locus lies in the HLA DQB1 region. We found earlier an increased apoptosis with decreased viability and function of the CD4 þ CD25 þ high T-cell subset (Treg) in human subjects with recent-onset T1D and in multiple autoantibody-positive, high at-risk individuals. Tregs normally inhibit or delay onset of T1D in animal models and increased Treg apoptosis could bring on or accelerate disease from effector T-cell-mediated destruction of insulin-producing beta cells. In this study, we test the hypothesis that HLA DQB1 genotypes are associated with increased CD4 þ CD25 þ high T-cell apoptosis. HLA DQ-based genetic risk status was significantly associated with CD4 þ CD25 þ high T-cell apoptosis, after adjustment for age, gender and phenotypic status (n ¼ 83, F ¼ 4.04 (d.f. ¼ 3), P ¼ 0.01). Unaffected, autoantibody-negative high risk HLA DQB1 control subjects showed increased CD4 þ CD25 þ high apoptosis levels compared with low risk HLA DQB1 control subjects (n ¼ 26, P ¼ 0.002), confirming that the association precedes disease. The association of specific HLA DQB1 genotypes with Treg apoptosis was also tested, showing significance for HLA DQB1*0302, DQB1*0201 and HLA DQB1*0602 alleles. Our study shows an association of HLA DQB1 genotypes with CD4 þ CD25 þ high T-cell apoptosis, which implicates CD4 þ CD25 þ high T-cell apoptosis as a new intermediate trait for T1D.

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“…For example, changes in enhancing lesion number and T 2 lesion volume correlate with clinical activity (i.e., attacks) 39 and clinical progression, 37 as well as with markers of immunologic activity. 40 Different levels not only of hypointensity but also of the rate of temporal change were observed when comparing remyelinating and inactive demyelinating T 1 lesions. 41 The need for more accurate assessment is enough to warrant a closer look at the dynamics of new lesion formation in the context of the underlying pathological processes of inflammation, degeneration, and repairespecially in the context of finding early markers of progression.…”

Section: T 2 Lesion Evolutionmentioning

confidence: 99%

Time-Series Modeling of Multiple Sclerosis Disease Activity: A Promising Window on Disease Progression and Repair Potential?

Meier

Weiner

2007

Neurotherapeutics

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Summary:This article discusses and reviews advanced forms of serial morphometry in the context of a disease progression model in multiple sclerosis (MS). This model of disease activity distinguishes between overall disease activity and the proportion thereof that becomes permanent damage. This translates into a progression model that features a repair potential, which, when exhausted, marks the conversion or progression from relapsing to progressive disease. The level of repair capacity at a given time determines the rate of progression. Both clinical and MRI variables appear to be in support of such a model. We examine possible MRI markers for this repair capacity, particularly the short-term behavior of new MRI lesions, quantified by methods of time-series analysis-that is, capturing lesion dynamics in the form of MRI intensity change directly, rather than shape or volume change. Lower rates of individual lesion recovery may represent lower repair and greater proximity to a progressive stage. Individuals with low transient lesion turnover appear to undergo more rapid progression and atrophy. Because disease-modifying therapies aim to alter the pathophysiological chain of inflammation, demyelination, and axonal loss, a therapeutic effect may therefore be more readily apparent as a change in lesion dynamics and recovery rate and level, rather than a change in total lesion burden or enhancing lesion number. Key Words: Multiple sclerosis, disease modeling, serial MRI, morphometry, lesion evolution, repair. THE REPAIR POTENTIAL HYPOTHESISMore than 80% of newly diagnosed cases of clinically definite multiple sclerosis (MS) fall into the relapsingremitting (RRMS) category. A large proportion of RRMS patients eventually convert to a secondary progressive stage (SPMS) within 6 -10 years. 1,2 The hallmark of this stage is a progressive worsening of disability in the absence of relapses, and a shift from inflammatory to degenerative activity, apparent on MRI as fewer contrast-enhancing lesions and accelerated brain parenchymal atrophy (FIG. 1). The etiology of this progression is not known, but a premise commonly offered is that of a threshold effect and the exhaustion of structural and functional redundancy, leading from inflammatory and relapsing to more diffuse and accelerated accrual of damage.Here we review and discuss this progression model, focusing on the concept of a hypothesized repair potential as a marker for progression. Of particular interest is the possibility of obtaining early MRI markers of this repair potential from advanced forms of serial quantitativ MRI. As new therapies with alternative mechanisms (other than broad or targeted immune suppression) become available to MS patients, specific markers that reliably predict long-term progression early in the disease are becoming increasingly critical.A growing body of evidence is congruent with a repair potential model: histopathological analyses have revealed a shift from focal inflammatory activity in RRMS to diffuse damage in SPMS 3 and overall reduced...

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Changes in Activated T Cells in the Blood Correlate With Disease Activity in Multiple Sclerosis

Abstract: There is a linkage between peripheral T-lymphocyte activation as measured by cell surface markers and disease activity in patients with multiple sclerosis. Arch Neurol. 2000;57:1183-1189

Cited by 103 publications

References 48 publications

Normal bone marrow hematopoietic stem cell reserves and normal stromal cell function support the use of autologous stem cell transplantation in patients with multiple sclerosis

Normal bone marrow hematopoietic stem cell reserves and normal stromal cell function support the use of autologous stem cell transplantation in patients with multiple sclerosis

Genetic association of HLA DQB1 with CD4+CD25+high T-cell apoptosis in type 1 diabetes

Time-Series Modeling of Multiple Sclerosis Disease Activity: A Promising Window on Disease Progression and Repair Potential?

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