Antibody-mediated depletion of select T cell subsets in blood and tissue of nonhuman primates DOI Open Access

Matthew S. Sutton,

Allison N. Bucşan, Chelsea C. Lehman

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 23, 2023

Abstract Understanding the immunological control of pathogens requires a detailed evaluation mechanistic contributions individual cell types within immune system. While knockout mouse models that lack certain have been used to help define role those cells, biological and physiological characteristics mice do not necessarily recapitulate human. To overcome some these differences, studies often look towards nonhuman primates (NHPs) due their close phylogenetic relationship humans. evaluate select types, NHP model provides distinct advantages since more closely mirror disease manifestations However, many experimental manipulations routinely in (e.g., gene knock-out) cannot be with model. As an alternative, vivo infusion monoclonal antibodies target surface proteins on specific cells either functionally inhibit or deplete can useful tool. Such depleting address mechanisms action. In studies, extent depletion has generally reported for blood, but thoroughly assessed tissues. Here, we evaluated four regimens primarily T NHP: anti-CD4, anti-CD8α, anti-CD8β, immunotoxin-conjugated anti-CD3. We treatments healthy unvaccinated IV BCG-vaccinated measure vaccine-elicited – which may activated, increased number, resident tissues are depleted compared resting populations NHPs. report quantitative measurements at multiple tissue sites providing insight into range by given mAb. found substantial blood animals, residual remained, residing tissue. Notably, find animal-to-animal variation is consequently use reagents should powered accordingly.

Language: Английский

Re-establishing immune tolerance in multiple sclerosis: focusing on novel mechanisms of mesenchymal stem cell regulation of Th17/Treg balance DOI Creative Commons

Huiru Hu,

Hui Li, Ruoyu Li

et al.

Journal of Translational Medicine, Journal Year: 2024, Volume and Issue: 22(1)

Published: July 15, 2024

The T-helper 17 (Th17) cell and regulatory T (Treg) axis plays a crucial role in the development of multiple sclerosis (MS), which is regarded as an immune imbalance between pro-inflammatory cytokines maintenance tolerance. Mesenchymal stem (MSC)-mediated therapies have received increasing attention MS research. In its animal model experimental autoimmune encephalomyelitis, MSC injection was shown to alter differentiation CD4

Language: Английский

Citations

5
Repeated iv anti‐CD20 treatment in multiple sclerosis: Long‐term effects on peripheral immune cell subsets DOI Creative Commons

Julia Feige,

Tobias Moser, Katja Akgün

et al.

Annals of Clinical and Translational Neurology, Journal Year: 2024, Volume and Issue: 11(2), P. 450 - 465

Published: Jan. 10, 2024

Abstract Objective Repeated intravenous administration of anti‐CD20 depleting monoclonal antibodies 6 months apart is among the highly effective treatment options in multiple sclerosis (MS). Here, we aimed to investigate peripheral immune cell subset depletion kinetics following either rituximab (RTX) or ocrelizumab (OCR) infusions people with MS (pwMS). Methods We studied pwMS treated de‐novo RTX ( n = 7) OCR 8). The examinations were scheduled before initiation therapy and every 12 weeks for up 15 months. Immunophenotyping subsets blood was performed by multiparametric fluorescence cytometry. Results A significant, persistent decrease CD19 + B cells observed already first infusion p < 0.0001). significant proportional reduction memory within B‐cell pool achieved only after two cycles 0.005). a increase immature 0.04) naive 0.004), again second cycle. As T‐cell pool, continuous T helper (TH) cells/central TH 0.02/ 0.008), while number regulatory (Treg) decreased 0.007). percentage dependent TH17.1 central dropped cycle 0.02). No differences between found. Interpretation Peripheral profiling revealed more differentiated insights into prompt delayed immunological effects repeated treatment. observation changes some pathogenetically relevant deserves further attention.

Language: Английский

Citations

3
Cutting-edge approaches to B-cell depletion in autoimmune diseases DOI Creative Commons
William H. Robinson, David Fiorentino, Leland W.K. Chung

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Oct. 9, 2024

B-cell depletion therapy (BCDT) has been employed to treat autoimmune disease for ~20 years. Immunoglobulin G1 (IgG1) monoclonal antibodies targeting CD20 and utilizing effector function (eg, antibody-dependent cellular cytotoxicity, complement-dependent phagocytosis) eliminate B cells have historically the predominant therapeutic approaches. More recently, diverse BCDT approaches a variety of surface antigens developed use in hematologic malignancies, including effector-function–enhanced antibodies, chimeric antigen receptor T-cell (CAR-T) treatment, bispecific engagers (TCEs). The latter category employs CD3 engagement augment killing target cells. Given improvement observed with CAR-T TCEs compared conventional monospecific treatment malignancies recent case reports demonstrating benefit disease, there is potential these mechanisms be effective B-cell–mediated disease. In this review, we discuss various BCDTs that are being diseases, describing molecule designs, mechanisms, advantages disadvantages each approach as they pertain safety, efficacy, patient experience. Additionally, advances strategies presented help broaden understanding safely effectively engage T deep diseases.

Language: Английский

Citations

3
Synthetic Cell-Based Immunotherapies for Neurologic Diseases DOI Creative Commons
Louisa von Baumgarten, Hans J. Stauss, Jan D. Lünemann

et al.

Neurology Neuroimmunology & Neuroinflammation, Journal Year: 2023, Volume and Issue: 10(5)

Published: June 29, 2023

The therapeutic success and widespread approval of genetically engineered T cells for a variety hematologic malignancies spurred the development synthetic cell-based immunotherapies CNS lymphoma, primary brain tumors, growing spectrum nononcologic disease conditions nervous system. Chimeric antigen receptor effector bear potential to deplete target with higher efficacy, better tissue penetration, greater depth than antibody-based cell depletion therapies. In multiple sclerosis other autoimmune disorders, T-cell therapies are being designed currently tested in clinical trials their safety efficacy eliminate pathogenic B-lineage cells. autoantibody expressing disease-relevant autoantigen as surface domains selectively autoreactive B Alternative depletion, antigen-specific regulatory can be locally restrain inflammation, support immune tolerance, or efficiently deliver neuroprotective factors diseases which current options very limited. this article, we illustrate prospects bottlenecks implementation cellular neurologic diseases.

Language: Английский

Citations

7
Antibody-mediated depletion of select leukocyte subsets in blood and tissue of nonhuman primates DOI Creative Commons

Matthew S. Sutton,

Allison N. Bucşan, Chelsea C. Lehman

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: March 11, 2024

Understanding the immunological control of pathogens requires a detailed evaluation mechanistic contributions individual cell types within immune system. While knockout mouse models that lack certain have been used to help define role those cells, biological and physiological characteristics mice do not necessarily recapitulate human. To overcome some these differences, studies often look towards nonhuman primates (NHPs) due their close phylogenetic relationship humans. evaluate select types, NHP model provides distinct advantages since more closely mirror disease manifestations However, many experimental manipulations routinely in (e.g., gene knock-out) cannot be with model. As an alternative, vivo infusion monoclonal antibodies target surface proteins on specific cells either functionally inhibit or deplete can useful tool. Such depleting address mechanisms action. In studies, extent depletion has generally reported for blood, but thoroughly assessed tissues. Here, we evaluated four regimens primarily T NHP: anti-CD4, anti-CD8α, anti-CD8β, immunotoxin-conjugated anti-CD3. We treatments healthy unvaccinated IV BCG-vaccinated measure vaccine-elicited - which may activated, increased number, resident tissues are depleted compared resting populations NHPs. report quantitative measurements at multiple tissue sites providing insight into range by given mAb. found substantial blood animals, residual remained, residing tissue. Notably, find animal-to-animal variation is consequently use reagents should powered accordingly.

Language: Английский

Citations

2
Molecular and neuroimmune pharmacology of S1P receptor modulators and other disease-modifying therapies for multiple sclerosis DOI
Yasuyuki Kihara, Jerold Chun

Pharmacology & Therapeutics, Journal Year: 2023, Volume and Issue: 246, P. 108432 - 108432

Published: May 4, 2023

Language: Английский

Citations

5
Evaluating the Therapeutic Potential of Ublituximab in the Treatment of MS: Design, Development and Place in Therapy DOI Creative Commons
Sarah‐Jane Martin, Melanie Guenette, Jiwon Oh

et al.

Drug Design Development and Therapy, Journal Year: 2024, Volume and Issue: Volume 18, P. 3025 - 3042

Published: July 1, 2024

B cells are critical to the pathogenesis of multiple sclerosis (MS), an autoimmune disease central nervous system. cell depletion using anti-CD20 monoclonal antibodies (mAbs) has proven be extremely successful treatment strategy, with profound suppression both clinical and radiological evidence focal inflammatory disease. Several mAbs now licensed for use in MS, ublituximab being latest gain regulatory approval. The unique properties each mAb may result nuanced differences timing, duration depth depletion, potential such have a relevance drug efficacy adverse effects. In this review, we summarize design, development, current place MS therapy ublituximab.

Language: Английский

Citations

1
Telomere length as a biomarker in multiple sclerosis DOI
María Agustina Piedrabuena, Jorge Correale, Mauricio Farez

et al.

Multiple Sclerosis Journal, Journal Year: 2024, Volume and Issue: 30(10), P. 1258 - 1267

Published: Sept. 1, 2024

Leukocyte telomere length (LTL) shortens with age and may be related to multiple sclerosis (MS).

Language: Английский

Citations

0
Longitudinal analysis of peripheral immune cells in patients with multiple sclerosis treated with anti‐CD20 therapy DOI Creative Commons
Mie Rye Wæde, Lasse F. Voss,

Christina Kingo

et al.

Annals of Clinical and Translational Neurology, Journal Year: 2024, Volume and Issue: 11(10), P. 2657 - 2672

Published: Sept. 15, 2024

Abstract Objective Anti‐CD20 therapy is a highly effective treatment for multiple sclerosis (MS). In this study, we investigated MS‐related changes in peripheral blood mononuclear cell (PBMC) subsets compared to healthy controls and longitudinal related the treatment. Methods Multicolor spectral flow cytometry analysis was performed on 78 samples characterize disease‐ treatment‐related PBMC clusters. Blood from MS patients were collected at baseline up 8 months post‐treatment, with three collection points after initiation. Unsupervised clustering tools manual gating applied identify subclusters of interest quantify changes. Results B cells depleted periphery anti‐CD20 as expected, observed an isolated acute, transitory drop proportion natural killer (NK) NKT among main populations ( P = 0.03, 0.004). Major affected subpopulations cytotoxic immune (NK, NKT, CD8 + T cells), higher reduced brain‐homing ability regulatory function long‐term anti‐CD20‐related effect. Additionally, altered distributions memory exhaustion markers both CD4 cells. Interpretation The findings study elucidate phenotypic clusters NK cells, which have previously been underexplored context therapy. Phenotypic modifications towards more controlled phenotype suggest that these may play critical unrecognized role mediating therapeutic efficacy treatments.

Language: Английский

Citations

0
Beyond the Stroke: A Case Report of Multiple Sclerosis DOI Open Access

Anjali N Karri,

Aizuddin Khalid,

Krishna Iyer

et al.

Cureus, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 18, 2024

Multiple sclerosis is an inflammatory, autoimmune demyelinating condition and poses diagnostic challenges due to varied presentations. This case report presents a divergence from typical clinical presentations of multiple (MS), as the initial presentation resembled symptoms brain stem stroke. Conventionally, MS suspicion arises in presence previous neurological deficits or signs optic neuritis. emphasises need for high suspected stroke transient ischaemic attack (TIA). A 29-year-old woman presented with characterised by crossed hemiparesis, reduced coarse touch sensation, paraesthesia face upper limb, which initially mimicked normal CT head. MRI revealed hyperintense lesions indicative disease, likely MS. contrast did not identify active lesions. Further investigations included vasculitis screen, MOG antibodies, serum angiotensin-converting enzyme (ACE) levels. Treatment intravenous methylprednisolone working diagnosis clinically isolated syndrome (CIS), classification subset MS, resulted symptomatic improvement. The patient responded well had lumbar puncture neurology follow-up, confirming relapsing remitting (RRMS) was started on disease-modifying treatment (DMT). Diagnosis relies McDonald criteria, emphasising dissemination time space. Early intervention familiarity criteria are crucial when dealing highlights complexities importance comprehensive approach evaluation. young presenting progressive affecting activities daily living should prompt urgent early initiation treatment. Familiarity options optimises care management.

Language: Английский

Citations

0