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1.
Cells ; 12(9)2023 04 25.
Article in English | MEDLINE | ID: mdl-37174643

ABSTRACT

Cladribine has been approved for the treatment of multiple sclerosis (MS) and its administration results in a long-lasting depletion of lymphocytes. As lymphopenia is known to hamper immune responses to vaccination, we evaluated the immunogenicity of the influenza vaccine in patients undergoing cladribine treatment at different stages vs. controls. The antibody response in 90 cladribine-treated MS patients was prospectively compared with 10 control subjects receiving platform immunotherapy (NCT05019248). Serum samples were collected before and six months after vaccination. Response to vaccination was determined by the hemagglutination-inhibition test. Postvaccination seroprotection rates against influenza A were comparable in cladribine-treated patients and controls (H1N1: 94.4% vs. 100%; H3N2: 92.2% vs. 90.0%). Influenza B response was lower in the cladribine cohort (61.1% vs. 80%). The increase in geometric mean titers was lower in the cladribine group vs. controls (H1N1: +98.5 vs. +188.1; H3N2: +225.3 vs. +300.0; influenza B: +40.0 vs. +78.4); however, titers increased in both groups for all strains. Seroprotection was achieved irrespective of vaccination timing and lymphocyte subset counts at the time of vaccination in the cladribine cohort. To conclude, cladribine-treated MS patients can mount an adequate immune response to influenza independently of treatment duration and time interval to the last cladribine administration.


Subject(s)
Influenza A Virus, H1N1 Subtype , Influenza Vaccines , Influenza, Human , Multiple Sclerosis , Humans , Influenza, Human/drug therapy , Influenza, Human/prevention & control , Cladribine/therapeutic use , Multiple Sclerosis/drug therapy , Influenza A Virus, H3N2 Subtype , Seasons , Antibody Formation , Vaccination
2.
Mult Scler Relat Disord ; 64: 103931, 2022 Aug.
Article in English | MEDLINE | ID: mdl-35690010

ABSTRACT

BACKGROUND: Cladribine is a synthetic deoxyadenosine analogue approved for the treatment of highly active relapsing multiple sclerosis (RMS). Cladribine is considered to be a semi-selective immune-reconstitution therapy (IRT) that induces long-term remission following short course of treatment. Here, we evaluated the effect of cladribine on immune cell reduction and reconstitution during the first two years of treatment. METHODS: We analyzed our longitudinal, prospective, real-world cohort of 80 cladribine-treated RMS patients from two tertiary centers in Germany. Laboratory testing was conducted monthly and included evaluation of cellular as well as soluble parameters. Laboratory outcomes were correlated with infectious adverse events (AEs) and clinical or paraclinical disease activity. RESULTS: Selective alterations in immune cell populations occurred following cladribine treatment, with the most marked effects observed in year two of treatment. Specifically, a rapid reduction in CD56+ natural killer cells (nadir: month 1 (year 1) and 14 (year 2); -37 and -41% from baseline) was followed by a greater reduction in CD19+ B cells (nadir: month 2 and 14; -81 and -82%); a moderate effect on CD4+ (nadir: month 3 and 15; -48 and -61%) and CD8+ T cells (nadir: month 5 and 18; -40 and -48%). Despite the marked effect on B cells, immunoglobulin levels were unaffected. There was no or minimal effect on thrombocytes and innate immune cells. Clinical and paraclinical disease activity was unrelated to the observed immune alterations. Lymphopenia was the most commonly observed AE (86.3% of patients; grade III-IV lymphopenia: 38.8%). The cumulative incidence of infections was 55% with cladribine treatment, which were mostly mild or moderate. In total, 19 herpes infections developed in 8 (10%) cladribine-treated patients; all cases were dermatomal and 94.7% of the herpetic infections occurred during a period of lymphopenia. CONCLUSIONS: The immunophenotyping data obtained in our real-world setting are comparable to those demonstrated in pivotal clinical trials and provide further evidence that cladribine may represent a form of IRT. However, regarding the side-effect profile of cladribine, severe lymphopenia (exceeding grade II CTCAE) was more frequent, which may have prompted the development of herpes infections. Of note, lymphocyte dynamics did not correlate with clinical and paraclinical measures of disease activity in the two-year follow-up period.


Subject(s)
Lymphopenia , Multiple Sclerosis, Relapsing-Remitting , Multiple Sclerosis , CD8-Positive T-Lymphocytes , Cladribine/adverse effects , Humans , Immunosuppressive Agents/adverse effects , Lymphopenia/chemically induced , Multiple Sclerosis/chemically induced , Multiple Sclerosis/drug therapy , Multiple Sclerosis, Relapsing-Remitting/chemically induced , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Prospective Studies , Recurrence
3.
Int J Mol Med ; 47(6)2021 06.
Article in English | MEDLINE | ID: mdl-33846799

ABSTRACT

Present in more than one billion adults, hypertension is the most significant modifiable risk factor for mortality resulting from cardiovascular disease. Although its pathogenesis is not yet fully understood, the disruption of the renin­angiotensin system (RAS), consisting of the systemic and brain RAS, has been recognized as one of the primary reasons for several types of hypertension. Therefore, acquiring sound knowledge of the basic science of RAS and the underlying mechanisms of the signaling pathways associated with RAS may facilitate the discovery of novel therapeutic targets with which to promote the management of patients with cardiovascular and kidney disease. In total, 4 types of angiotensin II receptors have been identified (AT1R­AT4R), of which AT1R plays the most important role in vasoconstriction and has been most extensively studied. It has been found in several regions of the brain, and its distribution is highly associated with that of angiotensin­like immunoreactivity in nerve terminals. The effect of AT1R involves the activation of multiple media and signaling pathways, among which the most important signaling pathways are considered to be AT1R/JAK/STAT and Ras/Raf/MAPK pathways. In addition, the regulation of the nuclear factor κ­light­chain­enhancer of activated B cells (NF­κB) and cyclic AMP response element­binding (CREB) pathways is also closely related to the effect of ATR1. Their mechanisms of action are related to pro­inflammatory and sympathetic excitatory effects. Central AT1R is involved in almost all types of hypertension, including spontaneous hypertension, salt­sensitive hypertension, obesity­induced hypertension, renovascular hypertension, diabetic hypertension, L­NAME­induced hypertension, stress­induced hypertension, angiotensin II­induced hypertension and aldosterone­induced hypertension. There are 2 types of central AT1R blockade, acute blockade and chronic blockade. The latter can be achieved by chemical blockade or genetic engineering. The present review article aimed to highlight the prevalence, functions, interactions and modulation means of central AT­1R in an effort to assist in the treatment of several pathological conditions. The identification of angiotensin­derived peptides and the development of AT­2R agonists may provide a wider perspective on RAS, as well as novel therapeutic strategies.


Subject(s)
Hypertension/metabolism , Renin-Angiotensin System , Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Animals , Drug Discovery , Humans , Hypertension/drug therapy , Hypertension/physiopathology , Receptor, Angiotensin, Type 1/metabolism , Receptor, Angiotensin, Type 2/agonists , Receptor, Angiotensin, Type 2/metabolism , Renin-Angiotensin System/drug effects
4.
J Clin Periodontol ; 38(2): 122-30, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21062340

ABSTRACT

OBJECTIVE: the aim of this study was to understand the cellular/molecular mechanisms of periodontal breakdown in a collagen-induced arthritis (CIA) model in mice to enhance the understanding of rheumatoid arthritis (RA)-associated alveolar bone loss in humans. MATERIALS AND METHODS: all analyses were performed on paired samples from CIA and control group mice. Mandibles were retrieved for micro-computed tomography (micro-CT), histomorphometric analysis, and isolation of alveolar bone cells (ABCs). In vitro osteoclastogenic/osteogenic/adipogenic potentials of ABCs were evaluated and the mRNA expression of downstream effector genes was assessed. Bone formation of ABCs was assessed using an ectopic transplantation model. RESULTS: histomorphometric and micro-CT data showed that alveolar bone loss was significantly increased in the CIA group (p<0.05). Osteoclastogenesis was significantly increased in the CIA group in vivo (p<0.05), with upregulated mRNA expressions of osteoclastogenesis-associated genes. Osteoblasts appeared to undergo increased apoptosis, and the bone-forming activity of ABCs concomitantly decreased with in vitro osteogenic differentiation and in vivo ectopic transplantation (p<0.05). Also, adipogenesis-associated mRNA expression was highly expressed in the CIA group, resulting in significantly enhanced adipocyte differentiation in vitro (p<0.05). CONCLUSIONS: these data demonstrate that increased osteoclastic activity, decreased bone-forming activity and enhanced adipogenesis promote alveolar bone loss in a CIA model in mice, and they suggest that these mechanisms could account for the same outcome in human RA.


Subject(s)
Alveolar Bone Loss/complications , Arthritis, Rheumatoid/complications , Osteoclasts/pathology , Osteogenesis/physiology , Adipogenesis/physiology , Alveolar Bone Loss/pathology , Animals , Arthritis, Experimental/chemically induced , Arthritis, Experimental/complications , Arthritis, Experimental/pathology , Arthritis, Rheumatoid/pathology , Cells, Cultured , Collagen , Disease Models, Animal , Mandible/diagnostic imaging , Mandible/pathology , Matched-Pair Analysis , Mice , X-Ray Microtomography/veterinary
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