PD-1 Receptor (+) T cells are associated with the efficacy of the combined treatment with regulatory t cells and rituximab in type 1 diabetes children via regulatory t cells suppressive activity amelioration

Article

Author: Sakowska, Justyna ; Chobot, Agata ; Jaźwińska-Curyłło, Anna ; Gliwiński, Mateusz ; Kamińska, Halla ; Hennig, Matylda ; Szadkowska, Agnieszka ; Siebert, Janusz ; Iwaszkiewicz-Grześ, Dorota ; Jarosz-Chobot, Przemysława ; Beń-Skowronek, Iwona ; Bossowski, Artur ; Owczuk, Radosław ; Żalińska, Magdalena ; Trzonkowski, Piotr ; Fendler, Wojciech ; Wołoszyn-Durkiewicz, Anna ; Myśliwiec, Małgorzata ; Marek-Trzonkowska, Natalia ; Zieliński, Maciej ; Młynarski, Wojciech

An imbalance between exaggerated autoaggressive T cell responses, primarily CD8 + T cells, and impaired tolerogenic mechanisms underlie the development of type 1 diabetes mellitus. Disease-modifying strategies, particularly immunotherapy focusing on FoxP3 + T regulatory cells (Treg), and B cells facilitating antigen presentation for T cells, show promise. Selective depletion of B cells may be achieved with an anti-CD20 monoclonal antibody (mAb). In a 2-year-long flow cytometry follow-up, involving 32 peripheral blood T and B cell markers across three trial arms (Treg + rituximab N = 12, Treg + placebo N = 13, control N = 11), we observed significant changes. PD-1 receptor (+) CD4 + Treg, CD4 + effector T cells (Teffs), and CD8 + T cell percentages increased in the combined regimen group by the end of follow-up. Conversely, the control group exhibited a notable reduction in PD-1 receptor (+) CD4 + Teff percentages. Considering clinical endpoints, higher PD-1 receptor (+) expression on T cells correlated with positive responses, including a higher mixed meal tolerance test AUC, and reduced daily insulin dosage. PD-1 receptor (+) T cells emerged as a potential therapy outcome biomarker. In vitro validation confirmed that successful Teff suppression was associated with elevated PD-1 receptor (+) Treg levels. These findings support PD-1 receptor (+) T cells as a reliable indicator of treatment with combined immunotherapy consisting of Tregs and anti-CD20 mAb efficacy in type 1 diabetes mellitus.

01 Dec 2023·American Journal of Transplantation

Donor antigen-specific regulatory T cell administration to recipients of live donor kidneys: A ONE Study consortium pilot trial

Article

Author: Rickert, Charles ; Sawitzki, Birgit ; Contreras-Ruiz, Laura ; Markmann, James F ; Guinan, Eva C ; Tang, Qizhi ; Rosales, Ivy ; Blancho, Giles ; Turka, Laurence A ; Colvin, Robert ; Makar, Robert ; Crisalli, Kerry ; Geissler, Edward K ; Harden, Paul

Regulatory T cells (Tregs) can inhibit cellular immunity in diverse experimental models and have entered early phase clinical trials in autoimmunity and transplantation to assess safety and efficacy. As part of the ONE Study consortium, we conducted a phase I-II clinical trial in which purified donor antigen reactive (dar)-Tregs (CD4⁺CD25⁺CD127^lo) were administered to 3 patients, 7 to 11 days after live donor renal transplant. Recipients received a modified immunosuppression regimen, without induction therapy, consisting of maintenance tacrolimus, mycophenolate mofetil, and steroids. Steroids were weaned off over 14 weeks. No rejection was seen on any protocol biopsy. Therefore, all patients discontinued mycophenolate mofetil 11 to 13 months posttransplant, per protocol. An early for-cause biopsy in 1 patient, 5 days after dar-Treg infusion, revealed absence of rejection and accumulation of Tregs in the kidney allograft. All patients had Treg-containing lymphoid aggregates evident on protocol biopsies performed 8 months posttransplant. The patients are now all >6 years posttransplant on tacrolimus monotherapy with excellent graft function. None experienced rejection episodes. No serious adverse events were attributable to Treg administration. These results support a favorable safety profile of dar-Tregs administered early after renal transplant, suggest early biopsy might be an instructive research endpoint and provide preliminary evidence of potential immunomodulatory activity.

20 Sep 2023·Cells

Differential Effects of Regulatory T Cells in the Meninges and Spinal Cord of Male and Female Mice with Neuropathic Pain.

Article

Author: Fiore, Nathan T ; Keating, Brooke A ; Chen, Yuting ; Williams, Sarah I ; Moalem-Taylor, Gila

Immune cells play a critical role in promoting neuroinflammation and the development of neuropathic pain. However, some subsets of immune cells are essential for pain resolution. Among them are regulatory T cells (Tregs), a specialised subpopulation of T cells that limit excessive immune responses and preserve immune homeostasis. In this study, we utilised intrathecal adoptive transfer of activated Tregs in male and female mice after peripheral nerve injury to investigate Treg migration and whether Treg-mediated suppression of pain behaviours is associated with changes in peripheral immune cell populations in lymphoid and meningeal tissues and spinal microglial and astrocyte reactivity and phenotypes. Treatment with Tregs suppressed mechanical pain hypersensitivity and improved changes in exploratory behaviours after chronic constriction injury (CCI) of the sciatic nerve in both male and female mice. The injected Treg cells were detected in the choroid plexus and the pia mater and in peripheral lymphoid organs in both male and female recipient mice. Nonetheless, Treg treatment resulted in differential changes in meningeal and lymph node immune cell profiles in male and female mice. Moreover, in male mice, adoptive transfer of Tregs ameliorated the CCI-induced increase in microglia reactivity and inflammatory phenotypic shift, increasing M2-like phenotypic markers and attenuating astrocyte reactivity and neurotoxic astrocytes. Contrastingly, in CCI female mice, Treg injection increased astrocyte reactivity and neuroprotective astrocytes. These findings show that the adoptive transfer of Tregs modulates meningeal and peripheral immunity, as well as spinal glial populations, and alleviates neuropathic pain, potentially through different mechanisms in males and females.

News (Medical) associated with Anti-TNFR2 VHH Agonistic Antibodies (Odyssey)

09 Nov 2023

·www.biospace.com

Odyssey Therapeutics to Present Data for Three Immunology Programs at American College of Rheumatology Convergence 2023

BOSTON--(BUSINESS WIRE)-- Odyssey Therapeutics, Inc., a biotechnology company pioneering next-generation precision immunomodulators and oncology medicines, will present data highlighting three of its immunology programs at the American College of Rheumatology (ACR) Convergence 2023 meeting in San Diego, California, November 10-15, 2023. Odyssey’s oral and poster presentations will unveil the first public data for three novel therapeutic approaches to treat large populations with underserved inflammatory and autoimmune diseases. The receptor interacting protein kinase 2 (RIPK2) and interleukin-1 receptor-associated kinase 4 (IRAK4) scaffolding inhibitors, as well as tumor necrosis factor receptor-2 (TNFR2) agonist for regulatory T (Treg) cell modulation, represent targets and approaches of high interest in the pharmaceutical industry, given their broad potential to treat inflammatory disease. “Odyssey’s team of expert drug hunters are tirelessly working to pioneer groundbreaking therapeutic strategies for the management of autoimmune disease,” said Gary D. Glick, Ph.D., founder and CEO of Odyssey Therapeutics. “At ACR, we’ll give patients, researchers and investors the first look at our RIPK2 and IRAK4 scaffolding inhibitors, as well as TNFR2 agonist for Treg cell modulation. These therapies can offer transformative benefits for patients, and the findings shared at ACR reflect significant scientific progress and achievement by our team to understand and solve complex biology with small molecule and protein therapeutics.” Oral Presentation Title: Discovery of First-in-Class IRAK4 Scaffolding Inhibitors for the Treatment of Inflammatory Disorders Abstract number: 2505 Session type: Abstract Session Date and time: Tuesday, November 14, from 4-5:30 p.m. PST Poster Presentations Title: Discovery of a RIPK2 Scaffolding Inhibitor for the Treatment of Joint Autoimmune Diseases Abstract number: 0061 Session type: Poster Session A Date and time: Sunday, November 12, from 9-11 a.m. PST Title: Anti-TNFR2 VHH Agonistic Antibodies Promote and Stabilize Treg Immunosuppressive Activity Abstract number: 0068 Session type: Poster Session A Date and time: Sunday, November 12, from 9-11 a.m. PST About Odyssey Therapeutics Odyssey Therapeutics is a biotechnology company focused on discovering, developing and commercializing the next generation of immunomodulators and oncology medicines. Composed of an expert team of drug hunters, scientists and industry leaders in foundational biology, chemistry and data sciences, Odyssey is transforming drug discovery to accelerate and drive the creation and efficient delivery of life-enhancing precision medicines to patients. For more information, please visit odysseytx.com and follow Odyssey Therapeutics on X (formerly Twitter) and LinkedIn.

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Indication	Highest Phase	Country/Location	Organization	Date
Immune System Diseases	Preclinical	US	Odyssey Therapeutics, Inc.Startup	04 Apr 2023

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