Treatment Of Multiple Sclerosis With Interferon-ß Primes Monocyte-Derived Macrophages For Apoptotic Cell Death
Van Weyenbergh J, Wietzerbin J, Rouillard D, Barral-Netto M, Liblau R
J Leukoc Biol 2001 Nov;70(5):745-8
U365 INSERM, Section de Recherche, Institut Curie; U546 INSERM, Hopital La Pitie-Salpetriere, Paris, France; Goncalo Moniz Research Center, Oswaldo Cruz Foundation, Salvador-Bahia, Brazil
PMID# 11698494; UI# 21555228
Although Interferon-beta (IFN-ß) has shown a significant clinical benefit in Multiple Sclerosis (MS), its mechanism of action remains unclear.
We found that IFN-ß treatment of patients with MS resulted in a significant increase in Apoptotic Cell Death (measured by Annexin V staining and nuclear fragmentation) of Monocyte-derived Macrophages.
As compared with cells derived from patients before treatment. Stimulation of the cells with IFN-ß in vitro resulted in an even further increase of Annexin V binding, as well as increased Fas (CD95+, APO-1) expression.
However, no increased Fas expression, Apoptotic Monocytes, or MonoCytopenia were observed upon in vivo treatment.
This indicates that IFN-ß does not deliver a death signal to Monocytes but rather primes for subsequent Macrophage Apoptosis upon activation or differentiation.
Niino M, Kikuchi S, Fukazawa T, Yabe I, Sasaki H, Tashiro K
Tissue Antigens 2001 Aug;58(2):93-6
Hokkaido Univ Graduate School of Medicine, Dept of Neurology, Sapporo, Japan
PMID# 11696222; UI# 21553642
Despite the strength of the association of Multiple Sclerosis (MS) and Human Leukocyte Antigen (HLA)-DR2, other Genetic elements could have a role in the pathophysiology of MS.
We investigated possible associations with PolyMorphic susceptibility Genes located within the HLA complex, i.e., Heat-Shock Protein (HSP) 70-1, HSP70-2, and HSP70-hom in Japanese patients with MS.
Furthermore, we analyzed the influence of HSP70 gene PolyMorphisms on the severity of the disease, clinical course, Magnetic Resonance Imaging findings, and OligoClonal Bands in the CerebroSpinal Fluid, and HLA in MS patients.
The results of the present study indicated that there were no significant differences in the distribution of all HSP70 Genotypes and Allele frequencies between Japanese MS patients and controls.
In MS patients, there were no associations between HSP70 Gene PolyMorphisms and the clinical data.
Moreover, there were no significant differences in HSP70 Genotype or Allele frequencies between MS patients positive for HLA-DRB1*1501 Alleles and matched controls.
Our data indicate that HSP70 Gene PolyMorphisms are not relevant in the susceptibility to or the severity of Japanese MS patients.
Interferon-ß Therapy Downregulates The Anti-Apoptosis Protein FLIP In Multiple Sclerosis T-Cells
Sharief MK, Semra YK, Seidi OA, Zoukos Y
Interferon-ß reduces clinical exacerbations in Multiple Sclerosis (MS) through several ImmunoModulatory mechanisms that may involve augmentation of programmed cell death (Apoptosis) of T-Lymphocytes.
J NeuroImmunol 2001 Jan 11;120(1-2):199-207
Guy's, King's and St Thomas' School of Medicine, Guy's Hospital, Dept of NeuroImmunology, Hodgkin Building, SE1 9RT, London, UK
PMID# 11694335; UI# 21551362
The AntiApoptosis protein FLIP (Fas-associated death domain-like InterLeukin-1ß-converting enzyme inhibitory protein) has been recently identified as a potent regulator of T-Lymphocyte susceptibility to Apoptosis.
In a prospective study, we evaluated the expression of FLIP and other Apoptosis regulatory proteins in ex vivo activated T-Lymphocytes from MS patients, before and serially after treatment with Interferon-ß.
We also investigated the long-term effects of Interferon-ß on T-Cell Apoptosis in a cross-sectional study of MS patients receiving chronic drug therapy.
Treatment with Interferon-ß reduced the expression of FLIP isoforms in activated T-Lymphocytes. This reduced expression correlated with augmented T-Cell susceptibility to Apoptosis and with clinical response to treatment.
In contrast, Interferon-ß therapy did not alter cellular expression of the AntiApoptotic protein Bcl-2. This downregulatory effect of Interferon-ß on cellular FLIP expression was maintained following long-term therapy.
Our findings suggest that Interferon-ß therapy exerts a regulatory effect on peripheral T-Lymphocytes through a ProApoptosis mechanism that involves the downregulation of cellular FLIP expression.
Cytokine And IL-12 Receptor mRNA Discriminate Between Different Clinical Subtypes In Multiple Sclerosis
van Boxel-Dezaire AH, Smits M, van Trigt-Hoff SC, Killestein J, van Houwelingen JC, Polman CH, Nagelkerken L
J NeuroImmunol 2001 Jan 11;120(1-2):152-60
TNO Prevention and Health, Division of Immunological and Infectious Diseases, PO Box 2215, 2301 CE, Leiden, The Netherlands
PMID# 11694330; UI# 21551357
Little is known about the involvement of Cytokines in the pathogenesis of Primary/Progressive (PP) Multiple Sclerosis (MS).
We evaluated in this cross-sectional study whether IL-18, IL-12p35, IL-12p40, TNF- IFN-, IL-10, IL-4, TGF-ß, IL-12Rbeta1, and IL-12Rß2 mRNA expression in unstimulated white blood cells showed significant differences.
Between, Relapsing/Remitting (RR), Secondary/Progressive (SP) and PP MS patients, and healthy controls.
All clinical subtypes showed unique mRNA expression patterns as compared to the controls.
Both RR and SP patients displayed increased levels of IL-12p40, IL-18, and TGF-ß mRNA compared to controls, whereas PP patients showed only increased IL-18 mRNA levels.
Both in PP and SP patients, IFN- and IL-10 mRNA were decreased compared to RR patients and controls.
PP patients were unique in that they showed decreased IL-12Rß1 mRNA.
In conclusion, our data show that the assessment of Cytokine (Receptor) mRNA profiles is useful to discriminate between the different clinical subtypes.
And, suggest that different Cytokines are involved in the pathogenesis of PP MS as compared to RR and SP MS.
Aktas O, Ari N, Rieks M, Hoffmann V, Schimrigk S, Przuntek H, Pohlau D
Acta Neurol Scand 2001 Nov;104(5):266-270
Ruhr Univ, Division of NeuroImmunology, Dept of Neurology, Charite, Berlin; Dept of Microbiology, Bochum; Dept of Neurology, Kamillusklinik, Asbach, Germany; St Josef-Hospital, Bochum, Germany;
We investigated whether therapy of Multiple Sclerosis (MS) with Glatiramer Acetate (GA) involves the modulation of programmed cell death (Apoptosis) in disease-relevant T-Helper Lymphocytes.
Material And Methods
Blood was drawn from 15 Relapsing/Remitting MS patients both before (baseline) as well as 6, 12, and 18 weeks after GA therapy and from 15 healthy controls.
Detection of Apoptosis was performed in response to in vitro stimulation with GA, Myelin Basic Protein or medium alone.
T-Helper Lymphocytes from untreated MS patients displayed an overall increased Apoptosis susceptibility in vitro, compared to controls.
During subsequent GA therapy, Apoptosis vulnerability of these T-Cells in MS patients significantly declined under the initial baseline before treatment, and was finally equal in treated patients and controls.
GA itself had no direct Apoptosis-modulatory properties in vitro.
Our findings indicate that therapy of Multiple Sclerosis with Glatiramer Acetate presumably involves the compensation of altered Apoptosis in T-Helper Lymphocytes.