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Reinhard Hohlfeld

Publications and source records attributed to Reinhard Hohlfeld.

At least 19 recordsLinked to original sources
PubMed2026

Long-term safety and efficacy of ponesimod, an oral S1P1 receptor modulator, in relapsing-remitting multiple sclerosis (RRMS): Results from randomized phase 2b core and extension studies spanning up to 13 years.

BACKGROUND: Ponesimod demonstrated efficacy and safety in relapsing-remitting multiple sclerosis (RRMS) in 24-week phase-2 core study, further confirmed by an interim combined analysis of the core and open-label long-term extension (LTE) studies (NCT01093326; up to 8 years). Current study evaluated safety and efficacy of ponesimod using combined core and LTE studies data for up to 13 years. METHODS: Of 393 participants completing the core study, 353 (90%) entered LTE, having 3 treatment periods (TP). In TP1 (∼1.85 years), participants continued core treatment (ponesimod: 10, 20, or 40 mg QD) whereas placebo-treated participants were re-randomized (1:1:1) to respective ponesimod doses. In TP2 (TP2 and TP3 combined duration: ∼10.4 years), participants on 40 mg were re-randomized (1:1) to 10/20 mg, while others continued same dose; in TP3 all participants received 20 mg. Study outcomes included safety and efficacy (ARR, time-to 24-week confirmed-disability-accumulation [24-week CDA], total T1-weighted Gadolinium-enhanced (T1 Gd+) lesions, new/enlarging T2 lesions and Combined Unique Active Lesions [CUALs]). RESULTS: For 20 mg dose, total 92.4% participants experienced ≥1 TEAEs (73.1% mild/moderate severity) and 19 (13%) participants discontinued study. Mean (95% CI) ARR=0.14 (0.10-0.20); Kaplan-Meier estimate (95% CI) of confirmed relapse and 24-week CDA=52.5% (42.3-63.5) and 31.3% (22.6-42.3). Mean [SD] T1 Gd+ lesions decreased from ponesimod baseline (2.62 [7.06]) to 12.4 years (0.26 [1.48]), mean (95% CI) CUALs per participant/year=3.97 (2.75-5.73). CONCLUSION: Ponesimod treatment for up to 13 years was not associated with new safety concerns. Participants continued to experience low levels of disease activity consistently across clinical and MRI outcomes.

Humans↗
PubMed2006

Reconstitution of paired T cell receptor alpha- and beta-chains from microdissected single cells of human inflammatory tissues.

We describe a strategy to "revive" putatively pathogenic T cells from frozen specimens of human inflammatory target organs. To distinguish pathogenic from irrelevant bystander T cells, we focused on cells that were (i) clonally expanded and (ii) in direct morphological contact with a target cell. Using CDR3 spectratyping, we identified clonally expanded T cell receptor (TCR) beta-chains in muscle sections of patients with inflammatory muscle diseases. By immunohistochemistry, we identified those Vbeta-positive T cells that fulfilled the morphological criteria of myocytotoxicity and isolated them by laser microdissection. Next, we identified coexpressed pairs of TCR alpha- and beta-chains by a multiplex PCR protocol, which allows the concomitant amplification of both chains from single cells. This concomitant amplification had not been achieved previously in histological sections, mainly because of the paucity of available anti-alpha-chain antibodies and the great heterogeneity of the alpha-chain genes. From muscle tissue of a patient with polymyositis, we isolated 64 T cells that expressed an expanded Vbeta1 chain. In 23 of these cells, we identified the corresponding alpha-chain. Twenty of these 23 alpha-chains were identical, suggesting antigen-driven selection. After functional reconstitution of the alphabeta-pairs, their antigen-recognition properties could be studied. Our results open avenues for combined analysis of the full TCR alpha- and beta-chain repertoire in human inflammatory tissues.

Autoimmunity↗
PubMed2006

B lineage cells in the inflammatory central nervous system environment: migration, maintenance, local antibody production, and therapeutic modulation.

B cells have long played an enigmatic role in the scenario of multiple sclerosis pathogenesis. This review summarizes recent progress in our understanding of B-cell trafficking, survival, and differentiation in the central nervous system (CNS). We propose four possible routes of intrathecal immunoglobulin-producing cells. The inflammatory CNS provides a unique, B-cell-friendly environment, in which B lineage cells, notably long-lived plasma cells, can survive for many years, perhaps even for a lifetime. These new findings offer a plausible explanation for the notorious persistence and stability of cerebrospinal fluid oligoclonal bands. Furthermore, we highlight similarities and differences of intrathecal immunoglobulin production in multiple sclerosis patients and patients with other CNS inflammatory conditions. Finally, we outline the possibly double-edged effects of B cells and immunoglobulin in the CNS and discuss various therapeutic strategies for targeting the B-cell response.

Animals↗
PubMed2006

The role of neurotrophins in muscle under physiological and pathological conditions.

This review summarizes the various effects of neurotrophins in skeletal muscle and how these proteins act as potential regulators of development, maintenance, function, and regeneration of skeletal muscle fibers. Increasing evidence suggests that this family of neurotrophic factors not only modulates survival and function of innervating motoneurons and proprioceptive neurons but also development and differentiation of myoblasts and muscle fibers. Neurotrophins and neurotrophin receptors play a role in the coordination of muscle innervation and functional differentiation of neuromuscular junctions. However, neurotrophin receptors are also expressed in differentiating muscle cells, in particular at early developmental stages in myoblasts before they fuse. In adults with pathological conditions such as human degenerative and inflammatory muscle disorders, variations of neurotrophin expression are found, but the role of neurotrophins under such conditions is still not clear. The goal of this review is to provide a basis for a better understanding and future studies on the role of these factors under such pathological conditions and for treatment of human muscle diseases.

Animals↗
PubMed2006

MS treatment optimization: report from the 21st ETRIMS/10th ACTRIMS Congress, 28 September-1 October 2005, Thessaloniki, Greece.

Around 3500 international delegates were presented with a broad scientific programme at the joint meeting of the 21st ECTRIMS and 10th ACTRIMS congress held last September. The meeting focused on the heterogeneity of MS and optimizing MS treatment--from the earliest stages to the long-term management of this chronic disease--with the goal of improving patient outcome.

Humans↗
PubMed2005

Chemokines in multiple sclerosis: CXCL12 and CXCL13 up-regulation is differentially linked to CNS immune cell recruitment.

Understanding the mechanisms of immune cell migration to multiple sclerosis lesions offers significant therapeutic potential. This study focused on the chemokines CXCL12 (SDF-1) and CXCL13 (BCA-1), both of which regulate B cell migration in lymphoid tissues. We report that immunohistologically CXCL12 was constitutively expressed in CNS parenchyma on blood vessel walls. In both active and chronic inactive multiple sclerosis lesions CXCL12 protein was elevated and detected on astrocytes and blood vessels. Quantitative PCR demonstrated that CXCL13 was produced in actively demyelinating multiple sclerosis lesions, but not in chronic inactive lesions or in the CNS of subjects who had no neurological disease. CXCL13 protein was localized in perivascular infiltrates and scattered infiltrating cells in lesion parenchyma. In the CSF of relapsing-remitting multiple sclerosis patients, both CXCL12 and CXCL13 were elevated. CXCL13, but not CXCL12, levels correlated strongly with intrathecal immunoglobulin production as well as the presence of B cells, plasma blasts and T cells. About 20% of CSF CD4+ cells and almost all B cells expressed the CXCL13 receptor CXCR5. In vitro, CXCL13 was produced by monocytes and at much higher levels by macrophages. CXCL13 mRNA and protein expression was induced by TNFalpha and IL-1beta but inhibited by IL-4 and IFNgamma. Together, CXCL12 and CXCL13 are elevated in active multiple sclerosis lesions and CXCL12 also in inactive lesions. The consequences of CXCL12 up-regulation could be manifold. CXCL12 localization on blood vessels indicates a possible role in leucocyte extravasation, and CXCL12 may contribute to plasma cell persistence since its receptor CXCR4 is retained during plasma cell differentiation. CXCL12 may contribute to axonal damage as it can become a neurotoxic mediator of cleavage by metalloproteases, which are present in multiple sclerosis lesions. The strong linkage of CXCL13 to immune cells and immunoglobulin levels in CSF suggests that this is one of the factors that attract and maintain B and T cells in inflamed CNS lesions. Therefore, both CXCL13 and CXCR5 may be promising therapeutic targets in multiple sclerosis.

Acute Disease↗
PubMed2005

Expression and function of glial cell line-derived neurotrophic factor family ligands and their receptors on human immune cells.

There is increasing evidence that factors originally identified due to their neurotrophic activity also function within the immune system. This study focused on the related molecules glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) as well as their receptors. GDNF and NTN signaling is mediated by a two-component receptor: a signal-transducing component, RET, which is shared by both ligands, and a ligand-specific binding component, GFR alpha-1 (higher GDNF affinity) or GFR alpha-2 (higher NTN affinity). We report that human T cells, B cells, and monocytes produce NTN but not GDNF, as seen by RT-PCR and immunocytochemistry. RET was expressed by B cells, T cells, and monocytes. Exons 2-5 of RET encoding the cadherin-like domains 1-3 in the extracellular part and exons 16-19 encoding a section of the second tyrosine kinase domain were transcribed in CD4+ T cells, CD8+ T cells, B cells, and monocytes. Different splice variants encoding the C-terminal intracellular part (exons 19-21) of RET were detected. The ligand-binding receptors GFR alpha-1 and GFR alpha-2 were transcribed in all immune cell subsets. Quantitative PCR showed that GFR alpha-2 is by far the dominant ligand binding chain in T cells, B cells, and monocytes. Addition of GDNF or NTN to activated PBMCs reduced the amount of detectable TNF protein without altering its transcription. Together, this suggests that immune cells communicate with each other via NTN. Production of NTN by immune cells might also contribute to the neuroprotective immunity in the CNS observed in different model systems.

3T3 Cells↗
PubMed2005

Assessment of potential cardiotoxic side effects of mitoxantrone in patients with multiple sclerosis.

Previous studies showed that mitoxantrone can reduce disability progression in patients with multiple sclerosis (MS). There is, however, concern that it may cause irreversible cardiomyopathy with reduced left ventricular (LV) ejection fraction (EF) and congestive heart failure. The aim of this prospective study was to investigate cardiac side effects of mitoxantrone by repetitive cardiac monitoring in MS patients. The treatment protocol called for ten courses of a combined mitoxantrone (10 mg/m(2) body surface) and methylprednisolone therapy. Before each course, a transthoracic echocardiogram was performed to determine the LV end-diastolic diameter, the end-systolic diameter and the fractional shortening; the LV-EF was calculated. Seventy-three patients participated (32 males; age 48 +/- 12 years, range 20-75 years; 25 with primary progressive, 47 with secondary progressive and 1 with relapsing-remitting MS) who received at least four courses of mitoxantrone. Three of the 73 patients were excluded during the study (2 patients discontinued therapy; 1 patient with a previous history of ischemic heart disease developed atrial fibrillation after the second course of mitoxantrone). The mean cumulative dose of mitoxantrone was 114.0 +/- 33.8 mg. The mean follow-up time was 23.4 months (range 10-57 months). So far, there has been no significant change in any of the determined parameters (end-diastolic diameter, end-systolic diameter, fractional shortening, EF) over time during all follow-up investigations. Mitoxantrone did not cause signs of congestive heart failure in any of the patients. Further cardiac monitoring is, however, needed to determine the safety of mitoxantrone after longer follow-up times and at higher cumulative doses.

Adult↗
PubMed2005

Secretion of brain-derived neurotrophic factor by glatiramer acetate-reactive T-helper cell lines: Implications for multiple sclerosis therapy.

Treatment with glatiramer acetate (GA) is thought to induce an in vivo change of the cytokine secretion pattern and the effector function of GA-reactive T helper (TH) cells (TH1-TH2-shift). Current theories propose that GA-reactive TH2 cells can penetrate the CNS, since they are activated by daily immunization. Inside the CNS, GA-reactive T cells may cross-react with products of the local myelin turnover presented by local antigen-presenting cells (APCs). Thus, some of the GA-specific TH2 cells may be stimulated to release anti-inflammatory cytokines inhibiting neighbouring inflammatory cells by a mechanism called bystander suppression. We demonstrate that both GA-specific TH2 and TH1 cells produce the neurotrophin brain-derived neurotrophic factor (BDNF). To demonstrate that GA-reactive T cells produce BDNF, we analyzed GA-specific, long-term T-cell lines (TCLs) and used a combination of reverse-transcription PCR and two specially designed techniques for BDNF protein detection: one was based on ELISA of supernatants from co-cultures of GA-specific TCLs plus GA-pulsed antigen-presenting cells, and the other, on the direct intracellular staining of BDNF in individual T cells and flow-cytometric analysis. The different assays and different TCLs yielded similar, consistent results. All GA-specific TH1, TH2 and TH0 lines could be stimulated to produce BDNF.

Blotting, Northern↗
PubMed2005

Intrathecal antibody (IgG) production against human herpesvirus type 6 occurs in about 20% of multiple sclerosis patients and might be linked to a polyspecific B-cell response.

Human herpesvirus 6 (HHV-6) is one of many infectious agents that have been implicated in the pathogenesis of multiple sclerosis (MS). Intrathecal immunoglobulin (Ig) production with oligoclonal CSF bands are hallmarks of both MS and infections of the CNS. In neuroinfections the intrathecal Ig production is directed largely against the respective agent, while MS patients mount an intrathecal Ig production against different pathogens. In this study a total of 77 serum/CSF pairs were first analyzed for an intrathecal immune response against HHV-6. We found that 21% of the MS patients, but none of the control donors showed an intrathecal immunoglobulin (Ig) response against HHV-6 (p = 0.017). Patients with such an intrathecal Ig production had a significantly higher total amount of Ig (p = 0.007) and a higher cell number in the CSF (p = 0.03). In a second step, four of the MS-patients who showed a strong intrathecal Ig production against HHV-6 were examined for immune reactivity against other viruses (human herpesvirus type 1, measles virus, human cytomegalovirus, rubella virus, varicella zoster virus). All of these patients had an intrathecal Ig production against at least one other, unrelated virus. Together, our findings strongly argue that in the majority of MS patients without an intrathecal Ig response to HHV-6 (about 80 % in our study), this virus is not involved in the pathogenesis. In the other 20% the intrathecal Ig production to HHV-6 might reflect reactivation of HHV-6 or could be part of a polyspecific B cell activation.

Adolescent↗
PubMed2005

BAFF is produced by astrocytes and up-regulated in multiple sclerosis lesions and primary central nervous system lymphoma.

We report that B cell-activating factor of the tumor necrosis factor (TNF) family (BAFF) is expressed in the normal human brain at approximately 10% of that in lymphatic tissues (tonsils and adenoids) and is produced by astrocytes. BAFF was regularly detected by enzyme-linked immunosorbent assay in brain tissue lysates and in normal spinal fluid, and in astrocytes by double fluorescence microscopy. Cultured human astrocytes secreted functionally active BAFF after stimulation with interferon-gamma and TNF-alpha via a furin-like protease-dependent pathway. BAFF secretion per cell was manifold higher in activated astrocytes than in monocytes and macrophages. We studied brain lesions with B cell components, and found that in multiple sclerosis plaques, BAFF expression was strongly up-regulated to levels observed in lymphatic tissues. BAFF was localized in astrocytes close to BAFF-R-expressing immune cells. BAFF receptors were strongly expressed in situ in primary central nervous system (CNS) lymphomas. This paper identifies astrocytes as a nonimmune source of BAFF. CNS-produced BAFF may support B cell survival in inflammatory diseases and primary B cell lymphoma.

Astrocytes↗
PubMed2005

Immunobiology of muscle: advances in understanding an immunological microenvironment.

Skeletal muscle, which is the largest cellular compartment of the body, lacks detectable MHC expression under physiological conditions. Therefore, immune reactions triggered by, or directed against, muscle cells proceed along specific pathways. Recently, the expression and functioning of classical MHC, non-classical MHC, adhesion and co-stimulatory molecules have been shown to support the concept that muscle cells can act as facultative antigen-presenting cells and should be considered as active participants, rather than passive targets, of immune reactions. Here, we summarize current knowledge on the immunological capabilities of skeletal muscle cells and discuss how these characteristics might contribute to inflammatory muscle disorders, as well as therapeutic strategies, such as gene or myoblast transfer.

Antigen Presentation↗
PubMed2005

Glatiramer acetate in multiple sclerosis: update on potential mechanisms of action.

Glatiramer acetate is a synthetic random copolymer approved for the immunomodulatory therapy of relapsing-type multiple sclerosis (MS). Previous work has focused on the effects of this drug on T cells, especially the glatiramer-acetate-induced shift of the cytokine profile towards those characteristic of T-helper-2 (Th2) cells. Glatiramer acetate was thought to bring about this Th2 shift by acting like an altered peptide ligand but more recent work has shown that the drug notably affects the properties of antigen-presenting cells, such as monocytes and dendritic cells. These new observations might offer an explanation for the previously observed Th2 shift. In this review, we focus on these new findings. We address several controversial issues, including the possible neurotrophic effects of glatiramer acetate, the potential role of neutralising antibodies to the drug, and attempts to develop biomarkers of the treatment response. Finally, we will think about how a better understanding of glatiramer acetate might help the development of new immunomodulatory agents for MS.

Antibodies↗
PubMed2005

Drug insight: using monoclonal antibodies to treat multiple sclerosis.

Multiple sclerosis (MS) is an immunopathological, presumably autoimmune, disease of the CNS. Several immunomodulatory treatments, including various preparations of interferon-beta, glatiramer acetate and mitoxantrone, have been approved for MS therapy. Because these agents are only partially effective, the search for better therapies continues. Therapeutic monoclonal antibodies (mAbs), a class of biotechnological agents, allow the precise targeting of molecules involved in pathological processes. Therapeutic mAbs have shown much promise in the treatment of many disorders, including inflammatory and putative autoimmune diseases such as MS. These agents have intrinsic limitations, however, such as induction of neutralizing 'anti-antibodies', systemic inflammatory reactions and severe adverse effects, some of which remain to be explained. Most notably, natalizumab (Tysabri), a mAb against alpha4 integrin, was very effective in suppressing MS activity, but had to be withdrawn from the market because several treated patients developed progressive multifocal leukoencephalopathy. This article reviews the state of development of various therapeutic mAbs for MS treatment.

Animals↗
PubMed2005

Muscle-derived positive and negative regulators of the immune response.

PURPOSE OF REVIEW: Recent characterization of the expression and functioning of muscle-derived positive and negative regulators of the immune response will be highlighted in view of the concept that muscle cells can act as facultative antigen-presenting cells and should be considered as active participants rather than passive targets of immune reactions. RECENT FINDINGS: Although lacking detectable major histocompatibility complex expression under physiologic conditions, under pathologic conditions muscle cells can express a variety of immunologically important molecules. Advances were made in characterizing the expression and functioning of classical and nonclassical major histocompatibility complex, adhesion, and costimulatory molecules. Muscle-related expression of the B7-family member called the inducible costimulatory signal ligand was identified as an important costimulatory signal for muscle immune interactions. In contrast, inducible expression of B7-H1 (PD-L1) and the nonclassical major histocompatibility complex molecule human leukocyte antigen-G were identified as relevant immune-inhibitory pathways. SUMMARY: The recent identification of muscle-derived positive and negative signals has broad implications for understanding the active role of muscle in modulating muscle-immune interactions: these signals could modify the immune response against muscle fibers in cell-mediated injury in autoimmune muscle disorders or in various muscle infections. Furthermore, they could modulate the immune responses after protein-based or DNA-based vaccinations and influence muscle-directed antigen-specific and nonantigen-specific immune responses in either condition.

Antigens, CD↗