R. Q. Hintzen

Interferon (IFN)-beta treatment enhances CD95 and interleukin 10 expression but reduces interferon-gamma producing T cells in MS patients

Abstract Interferon (IFN)-β has been shown to favorably alter the disease course of relapsing-remitting multiple sclerosis (RRMS) patients. Although its mode of action is still unclear, there is ample evidence from in vitro studies that IFN-β directly modulates the function of immune cells. We analyzed here the effects of IFN-β treatment on immune functions in vivo in a group of 25 RRMS patients who received IFN-β (8 MIU) on alternate days. At baseline and at 1, 3 and 6 months from the start of the treatment, parameters for differentiation and activation states of both monocytes and T lymphocytes were assessed. A transient increase was seen in plasma (p) interleukin (IL)-10 level whereas pIL-12 (p40) was not affected. A similar change was found in the ability of monocytes to secrete these cytokines in vitro. Notably, patients who in vitro readily responded to IFN-β with enhanced IL-10 production had the highest pIL-10 levels. Concerning T-cell differentiation, flowcytometric analysis of cytokine production showed that treatment with IFN-β moderately decreased the mean percentages of CD8pos T cells producing IL-2 and IFN-γ and CD8neg T cells producing IL-4 (p

Baseline T cell reactivity in multiple sclerosis is correlated to efficacy of interferon-β

BACKGROUND Measuring proliferative responses of T lymphocytes is a simple, reproducible and widely used assay of immune competence. Evidence suggests a role of T cell reactivity in autoimmune diseases. Interferon (IFN)-beta blocks in vitro proliferation of human T cells. OBJECTIVES To assess (i) the relation between T cell proliferation and disease characteristics of MS patients, (ii) differences in T cell proliferation between subgroups and HC, and (iii) the predictive value of T cell proliferation for efficacy of IFN-beta. METHODS Proliferative responses were measured in phytohaemagglutinin (PHA), anti-CD2/CD28 and anti-CD3 stimulated whole blood of 189 MS patients and 249 healthy controls (HC). Forty-eight patients started treatment with IFN-beta. Based on EDSS progression, number of relapses and steroid interventions, patients were classified as either clinical responder or nonresponder to IFN-beta. RESULTS Significant differences between MS subgroups and HC were found in T cell responses upon both PHA stimulation (RR>HC: p=0.001 and SP>HC: p=0.001) and CD2/CD28 stimulation (RR>HC, SP>HC and PP>HC: all p values <0.001). No significant differences were found between the MS subgroups. A probability of 88% (95% CI, 71-95%) for a favorable response to IFN-beta was found with increased baseline proliferative T cell responses to PHA; a probability of only 16% (95% CI, 7-33%) with decreased values. CONCLUSION Our results suggest that the level of T cell proliferation in whole blood predicts efficacy of IFN-beta in MS.

Analysis of CD27 surface expression on T-cell subsets in MS patients

Within the peripheral blood, CD4+CD27- T cells only reside within the CD45RA- (memory or primed) T cell subset. Cells with this phenotype have characteristics of specialized effector T cells according to their cytokine secretion profiles and the expression of tissue-specific adhesion molecules. This subset was previously found to be increased in certain diseases that are associated with immune activation. Therefore we analyzed CD27 expression of peripheral blood and CSF T cells in MS patients. Within the CD4+ T cell subset no differences were seen between MS patients and controls in proportions of CD45RA-CD27- cells. However, when the CD3+ T cell compartment was analyzed, CD27- cells were also found within the CD45RA+ subset. These cells, most likely CD8+, are significantly reduced in PBL and CSF of MS patients as compared with OND patients. In MS and OND groups the level of CD27- cells in peripheral blood correlated significantly with that in CSF, indicating a balanced migration of CD27- cells between the two compartments. In OIND patients, however, this equilibrium was lost. The correlation of the level of CD27+ cells with the amount of intrathecally produced IgG in MS patients may suggest that CD27+ cells are responsible for B cell help in this disease.