Regulatorische T-Zellen als neues Therapiekonzept in der Transplantationsmedizin

Die Transplantation von soliden Organen oder hämatopoetischen Stammzellen hat sich über die letzten Jahrzehnte für viele Patienten zu einer kurativen Therapieoption entwickelt. Der langfristige Transplantationserfolg ist jedoch wesentlich von der Kontrolle chronischer Abstoßungsreaktionen abhängig. Die Behandlungserfolge im Falle einer chronischen Abstoßungsreaktion sind trotz des Einsatzes moderner immunsuppressiver Medikamente bis heute leider nicht zufriedenstellend. Der therapeutische Einsatz von regulatorischen T-Zellen, welche anti-inflammatorisch wirken und die Immunhomöostase erhalten oder nach Inflammationsprozessen wiederherstellen, entwickelte sich in den letzten Jahren zu einem vielversprechenden Therapiekonzept. Hierbei werden regulatorische T-Zellen (Tregs) dem Patienten selbst oder dem ursprünglichen Stammzellspender entnommen, angereichert und anschließen intravenös verabreicht. Trotz der technischen Möglichkeiten und der klinischen Erfahrungen, die sowohl die Sicherheit als auch die Wirksamkeit von Tregs belegen, stagnieren die Entwicklungen in frühen Phasen klinischer Studien. Im Rahmen unserer Arbeiten haben wir in den letzten Jahren ein eigenes Protokoll entwickelt, das es uns ermöglicht, mittels ex-vivo-Expansion von Tregs aus 50 ml peripherem Vollblut – ohne die Notwendigkeit einer Leukozytapherese – ein sehr reines und funktionell wirksames Treg-Produkt zu generieren und dafür die Herstellungserlaubnis zu erlangen. Wir untersuchten zudem den Einfluss von konventionellen immunsuppressiven Medikamenten auf adoptiv transferierte Tregs, um Synergien zu nutzen und antagonistische Effekte zu vermeiden. Hierbei zeigte sich, dass Calcineurin-Inhibitoren wie Cyclosporin A und Mycophenolat Mofetil das Überleben und die Funktion adoptiv transferierter Tregs unterstützen, während Glukokortikoide in hoher Dosierung vermieden werden sollten. Mit diesem Wissen gelang uns die Translation ex vivo expandierter Tregs: im Rahmen einer Phase I/IIa-Studie konnten bereits Patienten, die eine Lebendspende-Nierentransplantation erhalten haben erfolgreich behandelt werden. Zusätzlich behandelten wir erstmalig drei Kinder, die nach allogener Stammzelltransplantation eine schwere, therapie-refraktäre chronische Abstoßungsreaktion erlitten hatten. Bei allen drei Patienten zeigte sich eine deutliche Besserung des klinischen Bildes und wir konnten zudem ein immunologisches Engraftment von naiven T-Zellen, naiven B-Zellen und dendritischen Zellen nachweisen. Angesichts dieser Ergebnisse und der übereinstimmend vielversprechenden Erfahrungen anderer Gruppen weltweit bleibt es unsere gemeinsame Aufgabe, die Sicherheit und Wirksamkeit von Treg-Therapien zeitnah im Rahmen größerer klinischer Studien weiter untersuchen. Gleichzeitig ist es essentiell, neue Erkenntnisse und innovative technische Möglichkeiten der Produktmodifikation fortlaufend in die Weiterentwicklung von Treg-Produkten einfließen zu lassen. Damit ist die Treg-Therapie auf absehbare Zeit zwar noch immer Einzelfällen vorbehalten, aber weitere wesentliche Meilensteine auf dem Weg in die breite klinische Anwendung werden nach und nach erreicht werden

Comprehensive Characterization of a Next-Generation Antiviral T-Cell Product and Feasibility for Application in Immunosuppressed Transplant Patients

Viral infections have a major impact on morbidity and mortality of immunosuppressed solid organ transplant (SOT) patients because of missing or failure of adequate pharmacologic antiviral treatment. Adoptive antiviral T-cell therapy (AVTT), regenerating disturbed endogenous T-cell immunity, emerged as an attractive alternative approach to combat severe viral complications in immunocompromised patients. AVTT is successful in patients after hematopoietic stem cell transplantation where T-cell products (TCPs) are manufactured from healthy donors. In contrast, in the SOT setting TCPs are derived from/applied back to immunosuppressed patients.We and others demonstrated feasibility of TCP generation from SOT patients and first clinical proof-of-concept trials revealing promising data. However, the initial efficacy is frequently lost longterm, because of limited survival of transferred short-lived T-cells indicating a need for next-generation TCPs. Our recent data suggest that Rapamycin treatment during TCP manufacture, conferring partial inhibition of mTOR, might improve its composition. The aim of this study was to confirm these promising observations in a setting closer to clinical challenges and to deeply characterize the next-generation TCPs. Using cytomegalovirus (CMV) as model, our next-generation Rapamycin-treated (Rapa-)TCP showed consistently increased proportions of CD4+ T-cells as well as CD4+ and CD8+ central-memory T-cells (TCM). In addition, Rapamycin sustained T-cell function despite withdrawal of Rapamycin, showed superior T-cell viability and resistance to apoptosis, stable metabolism upon activation, preferential expansion of TCM, partial conversion of other memory T-cell subsets to TCM and increased clonal diversity. On transcriptome level, we observed a gene expression profile denoting long-lived early memory T-cells with potent effector functions. Furthermore, we successfully applied the novel protocol for the generation of Rapa-TCPs to 19/19 SOT patients in a comparative study, irrespective Amini et al. Advanced CMV-Specific T-Cell Therapy for SOT of their history of CMV reactivation. Moreover, comparison of paired TCPs generated before/after transplantation did not reveal inferiority of the latter despite exposition to maintenance immunosuppression post-SOT. Our data imply that the Rapa-TCPs, exhibiting longevity and sustained T-cell memory, are a reasonable treatment option for SOT patients. Based on our success to manufacture Rapa-TCPs from SOT patients under maintenance immunosuppression, now, we seek ultimate clinical proof of efficacy in a clinical study

Tipping the balance in autoimmunity: are regulatory t cells the cause, the cure, or both?

Abstract Regulatory T cells (Tregs) are a specialized subgroup of T-cell lymphocytes that is crucial for maintaining immune homeostasis and preventing excessive immune responses. Depending on their differentiation route, Tregs can be subdivided into thymically derived Tregs (tTregs) and peripherally induced Tregs (pTregs), which originate from conventional T cells after extrathymic differentiation at peripheral sites. Although the regulatory attributes of tTregs and pTregs partially overlap, their modes of action, protein expression profiles, and functional stability exhibit specific characteristics unique to each subset. Over the last few years, our knowledge of Treg differentiation, maturation, plasticity, and correlations between their phenotypes and functions has increased. Genetic and functional studies in patients with numeric and functional Treg deficiencies have contributed to our mechanistic understanding of immune dysregulation and autoimmune pathologies. This review provides an overview of our current knowledge of Treg biology, discusses monogenetic Treg pathologies and explores the role of Tregs in various other autoimmune disorders. Additionally, we discuss novel approaches that explore Tregs as targets or agents of innovative treatment options

Initial presenting manifestations in 16,486 patients with inborn errors of immunity include infections and noninfectious manifestations

Background: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations. Objective: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts. Methods: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered. Results: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years. Conclusions: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations. (J Allergy Clin Immunol 2021;148:1332-41.