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Tolerizing Effects of Soluble CD137 on the CD137-CD137L Signaling Axis for Exploitation as a Therapeutic in Type 1 Diabetes

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dc.contributor.advisorRidgway, William M.
dc.contributor.advisorRamírez Santana, Heily Carolina
dc.contributor.gruplacCentro de Estudio de Enfermedades Autoinmunes (CREA)
dc.creatorRojas Quintana, Manuel Eduardo
dc.creator.degreeDoctor en Ciencias Biomédicas y Biológicas
dc.creator.degreeLevelDoctorado
dc.date.accessioned2026-07-21T21:38:43Z
dc.date.available2026-07-21T21:38:43Z
dc.date.created2026-07-16
dc.descriptionLas enfermedades autoinmunes (EAI) representan un desafío mayor y creciente para la salud global, siendo la diabetes tipo 1 (DT1) un ejemplo destacado. Estas enfermedades se caracterizan por una falla en la tolerancia inmunológica, lo que da lugar a la activación de células T patógenas que atacan a los propios tejidos del cuerpo. En esta tesis, describimos la epidemiología de la DT1, la incidencia de la poliautoinmunidad (PolyA) y el papel del CD137 soluble (sCD137) como un biomarcador confiable para el diagnóstico y seguimiento de la autoinmunidad. Además, presentamos el diseño y la validación de una nueva inmunoterapia para la autoinmunidad que busca evitar la inmunosupresión global. El primer capítulo describe la epidemiología global de la DT1 y cómo los pacientes con esta condición corren el riesgo de desarrollar EAI adicionales a lo largo de sus vidas. A través de un metaanálisis de 158 estudios, identificamos un patrón sorprendente de PolyA. Los datos revelaron que el 8.50 % de las personas con DT1 tienen al menos otra EAI manifiesta, mientras que aproximadamente el 14.45 % presentan autoinmunidad latente, lo que podría predisponer a los individuos a desarrollar EAI adicionales en el futuro. Esto fue confirmado por el análisis de metarregresión, el cual mostró que la incidencia de PolyA aumenta con cada año vivido con la enfermedad. Posteriormente, exploramos los principales factores asociados a este fenómeno y nos adentramos en los mecanismos moleculares que pueden explicar la aparición de la DT1, incluida la PolyA. Proponemos que esta vulnerabilidad suele desencadenarse por factores ambientales, con el mimetismo molecular actuando como un motor clave. En esta sección, profundizamos en cómo el mimetismo molecular, en el que el sistema inmunológico, mientras ataca a un microbio extraño, despliega una respuesta contra una proteína propia estructuralmente simila, puede encender la chispa inicial de la cascada autoinmune observada a nivel poblacional. A continuación, nos enfocamos en las células centrales en la autoinmunidad: las células T antígeno-específicas. En el capítulo 2, seguimos la trayectoria de estas células, desde su escape de los puntos de control de tolerancia (checkpoints) hasta su activación y posterior diversificación a través de la expansión de epítopos (epitope spreading). Describimos el dogma tradicional de la inmunología, el cual sostiene que la expansión clonal impulsa la selección de clones de células T de mayor afinidad. Sin embargo, evidencia reciente respalda que las células T de baja afinidad perpetúan la autoinmunidad, mientras que las células T de mayor afinidad son predominantemente relevantes en las etapas tempranas de la enfermedad, lo que subraya la necesidad de nuevos biomarcadores que permitan el rastreo de la activación de las células T. El CD137 es un marcador fuerte de la actividad de las células T y, recientemente, múltiples estudios incluyeron la medición sérica de sCD137 en varias condiciones inflamatorias. Para confirmar la utilidad de este biomarcador, realizamos un segundo metaanálisis de 47 estudios. Nuestros hallazgos mostraron que el sCD137, una isoforma de ayuste alternativo (splicing) de la molécula coestimuladora CD137 producida por células T reguladoras (Tregs), se encuentra elevado en la autoinmunidad y puede servir como un marcador indirecto (proxy) del intento del sistema inmunológico por contener una respuesta inmunológica exacerbada. Sin embargo, las terapias inmunosupresoras también conducen a una marcada caída en los niveles de sCD137, estableciéndolo como un indicador sensible del desequilibrio interno entre los mecanismos reguladores e inflamatorios. Finalmente, el Capítulo 3 tiene como objetivo traducir los datos genéticos y clínicos en una estrategia terapéutica tangible. Rastrearemos el origen de esta historia hasta el locus genético Idd9.3, el cual confiere protección contra la DT1 en el ratón NOD, identificando a CD137 como el gen clave. Encontramos que el papel protector de este locus está mediado por un aumento en la producción de la isoforma inmunosupresora sCD137. Esta visión fundamental obtenida de nuestros modelos de ratón se extendió luego al contexto humano. Diseñamos y validamos con éxito proteínas de fusión recombinantes humanas Fc-sCD137, confirmando que el sCD137 humano es un potente punto de control inmunológico. Nuestros estudios mecanicistas revelaron que el sCD137 regula a la baja la vía metabólica mTORC1, un motor central del crecimiento y la función de las células T. Este trabajo proporciona una base sólida para un nuevo enfoque terapéutico que fortalece una de las rutas antiinflamatorias inherentes del sistema inmunológico, en lugar de depender de una inmunosupresión global. En esencia, este trabajo teje un hilo único y coherente desde un problema clínico a gran escala hasta una solución molecular específica. Comienza con la escala epidemiológica de la PolyA en la DT1, luego reduce su enfoque hacia los impulsores celulares y moleculares, valida un biomarcador que rastrea la actividad de las células T y culmina en una inmunoterapia dirigida y guiada por mecanismos específicos. Esperamos que este trabajo ilumine el camino para futuros estudios traslacionales en humanos y, en última instancia, respalde la evaluación de la seguridad y eficacia de esta terapia en la DT1.
dc.description.abstractAutoimmune diseases (ADs) represent a major and growing challenge for global health, with Type 1 Diabetes (T1D) serving as a prominent example. These diseases are characterized by a failure of immunological tolerance, resulting in the activation of pathogenic T cells that attack the body's own tissues. In this thesis, we describe the epidemiology of T1D, the incidence of polyautoimmunity (PolyA), and the role of soluble CD137 (sCD137) as a reliable biomarker for diagnosing and monitoring autoimmunity. In addition, we present the design and validation of a novel immunotherapy for autoimmunity that aims to avoid immunosuppression. The first chapter describes the global epidemiology of T1D and how patients with this condition are at risk of developing additional ADs throughout their lives. Through a meta-analysis of 158 studies, we identified a striking pattern of PolyA. The data revealed that 8.50% of individuals with T1D have at least one other overt AD, while approximately 14.45% present with latent autoimmunity, which could predispose individuals to additional ADs in the future. This was confirmed by the meta-regression analysis, showing that the incidence of new-onset PolyA increases with each year lived with the disease. We then explored the main factors associated with this phenomenon and dived into the molecular mechanisms that may explain the onset of T1D, including PolyA. We propose that this vulnerability is often triggered by environmental factors, with molecular mimicry acting as a key driver. Here, we delve into how a case of mistaken identity, in which the immune system, while targeting a foreign microbe, mounts a response against a structurally similar self-protein, can ignite the initial spark of the autoimmune cascade observed at the population level. Next, we focus on the central effector cell in autoimmunity: the antigen-specific T cell. In chapter 2, we follow the trajectory of these cells, from their escape from tolerance checkpoints to their activation and subsequent diversification through epitope spreading. We describe the traditional dogma of immunology, which holds that clonal expansion drives the selection of higher-affinity T-cell clones. However, novel evidence supports that low-affinity T cells perpetuate autoimmunity, whereas higher-affinity T cells are predominantly relevant in the early stages of disease, underscoring the critical need for novel biomarkers that allow the tracking of T cell activation. The CD137 is a strong marker of T cell activity, and recently, multiple studies included the serum measurement of sCD137 in several inflammatory conditions. To confirm the utility of this biomarker, we conducted a second meta-analysis of 47 studies. Our findings showed that sCD137, a splicing isoform of the costimulatory molecule CD137 produced by regulatory T cells (Tregs), is elevated in autoimmunity and may serve as a proxy marker for the immune system's attempt to restrain an enhanced immunological response. However, immunosuppressive therapies also lead to a marked drop in sCD137 levels, establishing sCD137 as a sensitive indicator of the internal imbalance between regulatory and inflammatory mechanisms. Finally, Chapter 3 aims to translate the genetic and clinical data into a tangible therapeutic strategy. We trace this story back to the T1D-protective Idd9.3 genetic locus in the NOD mouse, pinpointing Cd137 as the key gene. We found that the protective role of this locus is mediated by an increased production of the immunosuppressive sCD137 isoform. This pivotal insight from our mouse models was then extended to the human context. We successfully engineered and validated recombinant human Fc-sCD137 fusion proteins, confirming that human sCD137 is a potent immune checkpoint. Our mechanistic studies revealed that sCD137 downregulates the mTORC1 metabolic pathway, a central engine of T-cell growth and function. This work provides a robust foundation for a new therapeutic approach that strengthens one of the immune system's inherent anti-inflammatory routes rather than relying on global immunosuppression. In essence, this work weaves a single, coherent thread from the large-scale clinical problem to a specific, molecular solution. It begins with the epidemiological scale of PolyA in T1D, then narrows its focus to the cellular and molecular drivers, validates a biomarker that traces T-cell activity, and culminates in a targeted, mechanism-driven immunotherapy. We expect that this work will lighten the path for future translational studies in humans and ultimately support the evaluation of the safety and efficacy of this therapy in T1D.
dc.description.sponsorshipNational Institutes of Health, Grant/Award Number: 1R01DK107541-01A1; National Institute of Diabetes and Digestive and Kidney Diseases
dc.format.extent55 pp
dc.format.mimetypeapplication/pdf
dc.identifier.doihttps://doi.org/10.48713/10336_48073
dc.identifier.urihttps://repository.urosario.edu.co/handle/10336/48073
dc.language.isoeng
dc.publisherUniversidad del Rosario
dc.publisher.departmentEscuela de Medicina y Ciencias de la Salud
dc.publisher.programDoctorado en Ciencias Biomédicas y Biológicas
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.accesRightsinfo:eu-repo/semantics/openAccess
dc.rights.accesoAbierto (Texto Completo)
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dc.source.instnameinstname:Universidad del Rosario
dc.source.reponamereponame:Repositorio Institucional EdocUR
dc.subjectCD137 soluble
dc.subjectCD137
dc.subjectCD137L
dc.subject4-1BB
dc.subject4-1BBL
dc.subjectTnfsf9
dc.subjectTnfrsf9
dc.subjectTregs
dc.subjectTolerancia
dc.subjectAutoinmunidad
dc.subject.keywordSoluble CD137
dc.subject.keywordCD137
dc.subject.keywordCD137L
dc.subject.keyword4-1BB
dc.subject.keyword4-1BBL
dc.subject.keywordTnfsf9
dc.subject.keywordTnfrsf9
dc.subject.keywordTregs
dc.subject.keywordTolerance
dc.subject.keywordAutoimmunity
dc.titleTolerizing Effects of Soluble CD137 on the CD137-CD137L Signaling Axis for Exploitation as a Therapeutic in Type 1 Diabetes
dc.title.TranslatedTitleEfectos Tolerogénicos del CD137 Soluble en el Eje de Señalización CD137-CD137L para su uso Terapéutico en Diabetes Tipo 1
dc.typedoctoralThesis
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local.department.reportEscuela de Medicina y Ciencias de la Salud
local.regionesBogotá
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Doctorado en Ciencias Biomédicas y Biológicas