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2.
Immunobiology ; 228(5): 152720, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37541134

RESUMEN

INTRODUCTION: Treatment of severe COVID-19 disease can be challenging in immunocompromized patients due to newly emerging virus variants of concern (VOC) escaping the humoral response. Thus, T cells recognizing to date unmutated epitopes are not only relevant for patients' immune responses against VOC, but might also serve as a therapeutic option for patients with severe COVID-19 disease in the future, e.g. following allogenic stem cell transplantation. METHODS: To this purpose, the activation, cytokine profile and specificity of T-cell clones against unmutated and omicron Spike (S)-protein was analyzed, HLA restriction was determined and most promising T-cell receptor (TCR) was introduced into allogeneic T cells via CRISPR/Cas9-mediated orthotopic TCR replacement. Finally, T-cell responses of engineered T cells was determined and durability of the TCR replacement measured. PERSPECTIVE: SARS-CoV-2 specific engineered T cells recognizing a genomically stable region of the S-protein of all SARS-CoV 2 variants were successfully generated. Such transgenic T cells exhibit favorable effector functions and provide a treatment option of immunocompromised COVID-19 patients.


Asunto(s)
COVID-19 , SARS-CoV-2 , Humanos , Animales , COVID-19/terapia , Receptores de Antígenos de Linfocitos T/genética , Animales Modificados Genéticamente , Epítopos
3.
Curr Pain Headache Rep ; 26(10): 751-765, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-36074255

RESUMEN

PURPOSE OF REVIEW: Low back pain affects at least 80% of individuals at some point in their lifetime and is the fifth most common reason for physician visits in the USA. Treatment of an acute episode of LBP generally includes rest, activity modification, physical therapy, NSAIDs, and patient education. RECENT FINDINGS: A small percentage of patients will develop chronic pain lasting > 6 months duration. Platelet-rich plasma (PRP) is one of the main pillars of regenerative medicine, as its release of bioactive proteins supports the aim of RM of restoring the anatomical function in degenerative conditions. Mesenchymal stem cells (MSCs) are multipotent stem cells, multipotent progenitor cells, or marrow stromal cells found in various body tissues, including bone marrow, lung, and adipose tissue. Evidence from well-designed case-control or cohort studies for the use of PRP and MSCs in lumbar facet joint, lumbar epidural, and sacroiliac joint injections is currently described as level IV evidence. PRP and MSCs are used autogenously to help facilitate the healing process, and their injection has been studied in the long-term management of discogenic low back pain. PRP has been compared to steroid injections in the sacroiliac joint for chronic low back pain, with favorable results. MSCs have also been shown to be useful in intervertebral disc regeneration and treatment of chronic low back pain associated with degenerative disc disease. Currently, the price for these treatments is extremely high, and thus the standard of care continues to be steroid injections and other treatments. This could change, however, with more robust data and research on the safety and long-term efficacy of biologics compared to other interventional management.


Asunto(s)
Productos Biológicos , Dolor de la Región Lumbar , Humanos , Manejo del Dolor/métodos , Dolor de la Región Lumbar/tratamiento farmacológico , Medicina Regenerativa/métodos , Antiinflamatorios no Esteroideos/uso terapéutico , Esteroides
4.
Eur J Immunol ; 51(10): 2478-2484, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34350584

RESUMEN

Treatment with convalescent plasma has been shown to be safe in coronavirus disease in 2019 (COVID-19) infection, although efficacy reported in immunocompetent patients varies. Nevertheless, neutralizing antibodies are a key requisite in the fight against viral infections. Patients depleted of antibody-producing B cells, such as those treated with rituximab (anti-CD20) for hematological malignancies, lack a fundamental part of their adaptive immunity. Treatment with convalescent plasma appears to be of general benefit in this particularly vulnerable cohort. We analyzed clinical course and inflammation markers of three B-cell-depleted patients suffering from COVID-19 who were treated with convalescent plasma. In addition, we measured serum antibody levels as well as peripheral blood CD38/HLA-DR-positive T-cells ex vivo and CD137-positive T-cells after in vitro stimulation with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-derived peptides in these patients. We observed that therapy with convalescent plasma was effective in all three patients and analysis of CD137-positive T-cells after stimulation with SARS-CoV-2 peptides showed an increase in peptide-specific T-cells after application of convalescent plasma. In conclusion, we here demonstrate efficacy of convalescent plasma therapy in three B-cell-depleted patients and present data that suggest that while application of convalescent plasma elevates systemic antibody levels only transiently, it may also boost specific T-cell responses.


Asunto(s)
Anticuerpos Antivirales/sangre , Linfocitos B/inmunología , COVID-19/terapia , Linfocitos T/inmunología , Adolescente , Anciano , Anticuerpos Neutralizantes/sangre , Linfocitos B/citología , Humanos , Inmunidad Celular/inmunología , Inmunización Pasiva/métodos , Recuento de Linfocitos , Depleción Linfocítica , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células del Manto/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Rituximab/efectos adversos , SARS-CoV-2/inmunología , Resultado del Tratamiento , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo , Sueroterapia para COVID-19
5.
Clin Exp Immunol ; 205(3): 363-378, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34061349

RESUMEN

Since December 2019, Coronavirus disease-19 (COVID-19) has spread rapidly throughout the world, leading to a global effort to develop vaccines and treatments. Despite extensive progress, there remains a need for treatments to bolster the immune responses in infected immunocompromised individuals, such as cancer patients who recently underwent a haematopoietic stem cell transplantation. Immunological protection against COVID-19 is mediated by both short-lived neutralizing antibodies and long-lasting virus-reactive T cells. Therefore, we propose that T cell therapy may augment efficacy of current treatments. For the greatest efficacy with minimal adverse effects, it is important that any cellular therapy is designed to be as specific and directed as possible. Here, we identify T cells from COVID-19 patients with a potentially protective response to two major antigens of the SARS-CoV-2 virus, Spike and Nucleocapsid protein. By generating clones of highly virus-reactive CD4+ T cells, we were able to confirm a set of nine immunodominant epitopes and characterize T cell responses against these. Accordingly, the sensitivity of T cell clones for their specific epitope, as well as the extent and focus of their cytokine response was examined. Moreover, using an advanced T cell receptor (TCR) sequencing approach, we determined the paired TCR-αß sequences of clones of interest. While these data on a limited population require further expansion for universal application, the results presented here form a crucial first step towards TCR-transgenic CD4+ T cell therapy of COVID-19.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , COVID-19/inmunología , COVID-19/terapia , Proteínas de la Nucleocápside de Coronavirus/inmunología , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Aminoácidos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/virología , COVID-19/virología , Células Clonales/inmunología , Células Clonales/virología , Proteínas de la Nucleocápside de Coronavirus/química , Proteínas de la Nucleocápside de Coronavirus/genética , Citocinas/biosíntesis , Epítopos de Linfocito T/química , Epítopos de Linfocito T/genética , Epítopos de Linfocito T/inmunología , Femenino , Humanos , Inmunización Pasiva , Epítopos Inmunodominantes/química , Epítopos Inmunodominantes/genética , Epítopos Inmunodominantes/inmunología , Masculino , Persona de Mediana Edad , Fosfoproteínas/química , Fosfoproteínas/genética , Fosfoproteínas/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , SARS-CoV-2/química , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Sueroterapia para COVID-19
6.
Diabetologia ; 62(12): 2252-2261, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31612266

RESUMEN

AIMS/HYPOTHESIS: The molecular basis for the pathological impact of specific HLA molecules on autoimmune diseases such as type 1 diabetes remains unclear. Recent natural history studies in children have indicated a link between specific HLA genotypes and the first antigenic target against which immune responses develop. We set out to examine this link in vivo by exploring the diabetogenicity of islet antigens on the background of a common diabetes-associated HLA haplotype. METHODS: We generated a novel HLA-transgenic mouse model that expresses high-risk genes for type 1 diabetes (DRB1*03:01-DQA1*05:01-DQB1*02:01) as well as human CD80 under the rat insulin promoter and human CD4, on a C57BL/6 background. Adjuvanted antigen priming was used to reveal the diabetogenicity of candidate antigens and peptides. RESULTS: HLA-DR3-DQ2+huCD4+IA/IE-/-RIP.B7.1+ mice spontaneously developed autoimmune diabetes (incidence 46% by 35 weeks of age), accompanied by numerous hallmarks of human type 1 diabetes (autoantibodies against GAD65 and proinsulin; pancreatic islet infiltration by CD4+, CD8+ B220+, CD11b+ and CD11c+ immune cells). Disease was markedly accelerated and had deeper penetrance after adjuvanted antigen priming with proinsulin (mean onset 11 weeks and incidence 100% by 20 weeks post challenge). Moreover, the diabetogenic effect of proinsulin located to the 15-residue B29-C11 region. CONCLUSIONS/INTERPRETATION: Our study identifies a proinsulin-derived peptide region that is highly diabetogenic on the HLA-DR3-DQ2 background using an in vivo model. This approach and the peptide region identified may have wider implications for future studies of human type 1 diabetes.


Asunto(s)
Diabetes Mellitus Tipo 1/genética , Antígenos HLA-DQ/genética , Antígeno HLA-DR3/genética , Proinsulina/administración & dosificación , Animales , Modelos Animales de Enfermedad , Haplotipos , Ratones , Ratones Transgénicos
7.
Sci Rep ; 8(1): 14106, 2018 09 20.
Artículo en Inglés | MEDLINE | ID: mdl-30237494

RESUMEN

Antigen-specific immunotherapy of autoimmune disease currently remains the only potentially curative approach. However, translation of promising pre-clinical results into successful clinical application has proven challenging. In part, this is because pre-clinical findings in mouse models have to be redesigned for human application due to differences in MHC II. To reduce the gap between pre-clinical and clinical studies, we have created a novel mouse model that expresses human HLA-DR4, but no endogenous MHC on antigen-presenting cells. Moreover, human B7.1 (CD80) is expressed in the pancreatic islets under the control of the rat insulin promoter. Although this model does not develop diabetes spontaneously, it is susceptible to the induction of type 1 diabetes by challenging mice with overlapping peptides derived from murine proinsulin-2 in adjuvant. Unlike the NOD model of spontaneous type 1 diabetes, but akin to the human condition, this model does not have a gender bias. Furthermore, similar to the human condition, the disease is characterised by a diverse leucocyte infiltration of the pancreatic islets and the formation of anti-proinsulin auto-antibodies. The model that we report here offers detailed insights into type-1 diabetes and is expected to prove instrumental when studying the mechanism of action in translational, antigen-specific immunotherapy.


Asunto(s)
Diabetes Mellitus Tipo 1/etiología , Antígeno HLA-DR4/genética , Islotes Pancreáticos/inmunología , Proinsulina , Animales , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Ratones Transgénicos
8.
Acta Neuropathol ; 135(6): 907-921, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29541917

RESUMEN

Bone marrow-derived cells are known to infiltrate the adult brain and fuse with cerebellar Purkinje cells. Histological observations that such heterotypic cell fusion events are substantially more frequent following cerebellar injury suggest they could have a role in the protection of mature brain neurons. To date, the possibility that cell fusion can preserve or restore the structure and function of adult brain neurons has not been directly addressed; indeed, though frequently suggested, the possibility of benefit has always been rather speculative. Here we report, for the first time, that fusion of a bone marrow-derived cell with a neuron in vivo, in the mature brain, results in the formation of a spontaneously firing neuron. Notably, we also provide evidence supporting the concept that heterotypic cell fusion acts as a biological mechanism to repair pathological changes in Purkinje cell structure and electrophysiology. We induced chronic central nervous system inflammation in chimeric mice expressing bone marrow cells tagged with enhanced green fluorescent protein. Subsequent in-depth histological analysis revealed significant Purkinje cell injury. In addition, there was an increased incidence of cell fusion between bone marrow-derived cells and Purkinje cells, revealed as enhanced green fluorescent protein-expressing binucleate heterokaryons. These fused cells resembled healthy Purkinje cells in their morphology, soma size, ability to synthesize the neurotransmitter gamma-aminobutyric acid, and synaptic innervation from neighbouring cells. Extracellular recording of spontaneous firing ex vivo revealed a shift in the predominant mode of firing of non-fused Purkinje cells in the context of cerebellar inflammation. By contrast, the firing patterns of fused Purkinje cells were the same as in healthy control cerebellum, indicating that fusion of bone marrow-derived cells with Purkinje cells mitigated the effects of cell injury on electrical activity. Together, our histological and electrophysiological results provide novel fundamental insights into physiological processes by which nerve cells are protected in adult life.


Asunto(s)
Células de la Médula Ósea/fisiología , Trasplante de Médula Ósea , Encefalomielitis Autoinmune Experimental/fisiopatología , Encefalomielitis Autoinmune Experimental/terapia , Células de Purkinje/fisiología , Potenciales de Acción/fisiología , Animales , Células de la Médula Ósea/patología , Fusión Celular , Quimera , Encefalomielitis Autoinmune Experimental/patología , Femenino , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Inflamación/patología , Inflamación/fisiopatología , Ratones Endogámicos C57BL , Ratones Transgénicos , Vaina de Mielina/patología , Vaina de Mielina/fisiología , Neuroprotección/fisiología , Células de Purkinje/patología , Técnicas de Cultivo de Tejidos
9.
Sci Rep ; 7(1): 11315, 2017 09 12.
Artículo en Inglés | MEDLINE | ID: mdl-28900244

RESUMEN

IL-10 is an immunomodulatory cytokine with a critical role in limiting inflammation in immune-mediated pathologies. The mechanisms leading to IL-10 expression by CD4+ T cells are being elucidated, with several cytokines implicated. We explored the effect of IL-4 on the natural phenomenon of IL-10 production by a chronically stimulated antigen-specific population of differentiated Th1 cells. In vitro, IL-4 blockade inhibited while addition of exogenous IL-4 to Th1 cultures enhanced IL-10 production. In the in vivo setting of peptide immunotherapy leading to a chronically stimulated Th1 phenotype, lack of IL-4Rα inhibited the induction of IL-10. Exploring the interplay of Th1 and Th2 cells through co-culture, Th2-derived IL-4 promoted IL-10 expression by Th1 cultures, reducing their pathogenicity in vivo. Co-culture led to upregulated c-Maf expression with no decrease in the proportion of T-bet+ cells in these cultures. Addition of IL-4 also reduced the encephalitogenic capacity of Th1 cultures. These data demonstrate that IL-4 contributes to IL-10 production and that Th2 cells modulate Th1 cultures towards a self-regulatory phenotype, contributing to the cross-regulation of Th1 and Th2 cells. These findings are important in the context of Th1 driven diseases since they reveal how the Th1 phenotype and function can be modulated by IL-4.


Asunto(s)
Interleucina-10/metabolismo , Interleucina-4/metabolismo , Células TH1/inmunología , Células TH1/metabolismo , Animales , Biomarcadores , Citocinas/metabolismo , Inmunofenotipificación , Activación de Linfocitos , Ratones , Ratones Noqueados , Fenotipo , Receptores de Superficie Celular/genética , Factor de Transcripción STAT6/metabolismo , Células Th2/inmunología , Células Th2/metabolismo
10.
Immunology ; 151(1): 26-42, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28140447

RESUMEN

In multiple sclerosis (MS) T cells aberrantly recognize self-peptides of the myelin sheath and attack the central nervous system (CNS). Antigen-specific peptide immunotherapy, which aims to restore tolerance while avoiding the use of non-specific immunosuppressive drugs, is a promising approach to combat autoimmune disease, but the cellular mechanisms behind successful therapy remain poorly understood. Myeloid-derived suppressor cells (MDSCs) have been studied intensively in the field of cancer and to a lesser extent in autoimmunity. Because of their suppressive effect on the immune system in cancer, we hypothesized that the development of MDSCs and their interaction with CD4+ T cells could be beneficial for antigen-specific immunotherapy. Hence, changes in the quantity, phenotype and function of MDSCs during tolerance induction in our model of MS were evaluated. We reveal, for the first time, an involvement of a subset of MDSCs, known as polymorphonuclear (PMN)-MDSCs, in the process of tolerance induction. PMN-MDSCs were shown to adopt a more suppressive phenotype during peptide immunotherapy and inhibit CD4+ T-cell proliferation in a cell-contact-dependent manner, mediated by arginase-1. Moreover, increased numbers of tolerogenic PMN-MDSCs, such as observed over the course of peptide immunotherapy, were demonstrated to provide protection from disease in a model of experimental autoimmune encephalomyelitis.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Inmunoterapia/métodos , Esclerosis Múltiple/inmunología , Células Supresoras de Origen Mieloide/inmunología , Animales , Arginasa/metabolismo , Linfocitos T CD4-Positivos/trasplante , Diferenciación Celular , Proliferación Celular , Células Cultivadas , Humanos , Tolerancia Inmunológica , Inmunofenotipificación , Activación de Linfocitos , Ratones , Ratones Transgénicos , Proteína Básica de Mielina/inmunología , Fragmentos de Péptidos/inmunología
11.
Immunology ; 145(2): 171-81, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25716063

RESUMEN

Antigen-specific immunotherapy aims to selectively restore tolerance to innocuous antigens in cases of autoimmune or allergic disease, without the need for general immune suppression. Although the principle of antigen-specific immunotherapy was discovered more than a century ago, its clinical application to date is limited, particularly in the control of autoimmunity. This has resulted mainly from a lack of in-depth understanding of the underlying mechanism. More recently, the differentiation of extra-thymically induced T regulatory (Treg) cell subsets has been shown to be instrumental in peripheral tolerance induction. Two main types of inducible Treg cells, interleukin-10-secreting or Foxp3(+) , have now been described, each with distinct characteristics and methods of therapeutic induction. It is crucial, therefore, to identify the suitability of either subset in the control of specific immune disorders. This review explores their natural function, the known mechanisms of therapeutic differentiation of either subset as well as their in vivo functionality and discusses new developments that may aid their use in antigen-specific immunotherapy, with a focus on autoimmune disease.


Asunto(s)
Antígenos/uso terapéutico , Enfermedades Autoinmunes/terapia , Tolerancia Inmunológica , Inmunoterapia/métodos , Linfocitos T Reguladores/inmunología , Animales , Antígenos/inmunología , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Diferenciación Celular/inmunología , Factores de Transcripción Forkhead/inmunología , Humanos , Hipersensibilidad/inmunología , Hipersensibilidad/patología , Hipersensibilidad/terapia , Interleucina-10/inmunología , Linfocitos T Reguladores/patología
12.
PLoS One ; 9(9): e108023, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25238105

RESUMEN

In vitro induced Foxp3+ T regulatory (iTreg) cells form a novel and promising target for therapeutic tolerance induction. However, the potential of these cells as a target for the treatment of various immune diseases, as well as the factors involved in their development and function, remain debated. Here, we demonstrate in a myelin basic protein (MBP)-specific murine model of CNS autoimmune disease that adoptive transfer of antigen-specific iTreg cells ameliorates disease progression. Moreover, we show that the co-stimulatory molecule CTLA-4 mediates in vitro differentiation of iTreg cells. Finally, we demonstrate that the secreted, immunosuppressive cytokine IL-10 controls the ability of antigen-specific iTreg cells to suppress autoimmune disease. Overall, we conclude that antigen-specific iTreg cells, which depend on various immune regulatory molecules for their differentiation and function, represent a major target for effective immunotherapy of autoimmune disease.


Asunto(s)
Antígeno CTLA-4/fisiología , Diferenciación Celular/genética , Encefalomielitis/patología , Interleucina-10/fisiología , Linfocitos T Reguladores/citología , Animales , Antígeno CTLA-4/genética , Antígeno CTLA-4/metabolismo , Encefalomielitis/inmunología , Citometría de Flujo , Factores de Transcripción Forkhead/metabolismo , Interleucina-10/genética , Interleucina-10/metabolismo , Ratones , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo
13.
Nat Commun ; 5: 4741, 2014 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-25182274

RESUMEN

Antigen-specific immunotherapy combats autoimmunity or allergy by reinstating immunological tolerance to target antigens without compromising immune function. Optimization of dosing strategy is critical for effective modulation of pathogenic CD4(+) T-cell activity. Here we report that dose escalation is imperative for safe, subcutaneous delivery of the high self-antigen doses required for effective tolerance induction and elicits anergic, interleukin (IL)-10-secreting regulatory CD4(+) T cells. Analysis of the CD4(+) T-cell transcriptome, at consecutive stages of escalating dose immunotherapy, reveals progressive suppression of transcripts positively regulating inflammatory effector function and repression of cell cycle pathways. We identify transcription factors, c-Maf and NFIL3, and negative co-stimulatory molecules, LAG-3, TIGIT, PD-1 and TIM-3, which characterize this regulatory CD4(+) T-cell population and whose expression correlates with the immunoregulatory cytokine IL-10. These results provide a rationale for dose escalation in T-cell-directed immunotherapy and reveal novel immunological and transcriptional signatures as surrogate markers of successful immunotherapy.


Asunto(s)
Autoantígenos/administración & dosificación , Linfocitos T CD4-Positivos/efectos de los fármacos , Desensibilización Inmunológica/métodos , Encefalomielitis Autoinmune Experimental/terapia , Péptidos/administración & dosificación , Transcriptoma/efectos de los fármacos , Animales , Antígenos CD/genética , Antígenos CD/inmunología , Autoantígenos/química , Autoantígenos/inmunología , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Anergia Clonal/efectos de los fármacos , Mezclas Complejas/administración & dosificación , Mezclas Complejas/inmunología , Relación Dosis-Respuesta Inmunológica , Encefalomielitis Autoinmune Experimental/inducido químicamente , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Femenino , Adyuvante de Freund/administración & dosificación , Adyuvante de Freund/inmunología , Regulación de la Expresión Génica , Receptor 2 Celular del Virus de la Hepatitis A , Inyecciones Subcutáneas , Interleucina-10/genética , Interleucina-10/inmunología , Masculino , Ratones , Ratones Transgénicos , Péptidos/química , Péptidos/inmunología , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología , Proteínas Proto-Oncogénicas c-maf/genética , Proteínas Proto-Oncogénicas c-maf/inmunología , Receptores Inmunológicos/genética , Receptores Inmunológicos/inmunología , Receptores Virales/genética , Receptores Virales/inmunología , Médula Espinal/química , Transcriptoma/inmunología , Proteína del Gen 3 de Activación de Linfocitos
14.
J Immunol Methods ; 414: 58-64, 2014 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-25108241

RESUMEN

Adoptive transfer of antigen-specific, in vitro-induced Foxp3(+) Treg (iTreg) cells protects against autoimmune disease. To generate antigen-specific iTreg cells at high purity, however, remains a challenge. Whereas polyclonal T cell stimulation with anti-CD3 and anti-CD28 antibody yields Foxp3(+) iTreg cells at a purity of 90-95%, antigen-induced iTreg cells typically do not exceed a purity of 65-75%, even in a TCR-transgenic model. In a similar vein to thymic Treg cell selection, iTreg cell differentiation is influenced not only by antigen recognition and the availability of TGF-ß but also by co-factors including costimulation and adhesion molecules. In this study, we demonstrate that blockade of the T cell integrin Leukocyte Function-associated Antigen-1 (LFA-1) during antigen-mediated iTreg cell differentiation augments Foxp3 induction, leading to approximately 90% purity of Foxp3(+) iTreg cells. This increased efficacy not only boosts the yield of Foxp3(+) iTreg cells, it also reduces contamination with activated effector T cells, thus improving the safety of adoptive transfer immunotherapy.


Asunto(s)
Enfermedades Autoinmunes/inmunología , Factores de Transcripción Forkhead/biosíntesis , Antígeno-1 Asociado a Función de Linfocito/inmunología , Linfocitos T Reguladores/citología , Traslado Adoptivo , Animales , Autoinmunidad/inmunología , Antígeno CTLA-4/inmunología , Diferenciación Celular/inmunología , Células Cultivadas , Interleucina-2/inmunología , Ratones , Ratones Transgénicos , Transducción de Señal/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/trasplante , Factor de Crecimiento Transformador beta/inmunología
15.
Front Immunol ; 4: 129, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23755052

RESUMEN

Since the discovery of interleukin-10 (IL-10) in the 1980s, a large body of work has led to its recognition as a pleiotropic immunomodulatory cytokine that affects both the innate and adaptive immune systems. IL-10 is produced by a wide range of cell types, but for the purposes of this review we shall focus on IL-10 secreted by CD4(+) T cells. Here we describe the importance of IL-10 as a mediator of suppression used by both FoxP3(+) and FoxP3(-) T regulatory cells. Moreover, we discuss the molecular events leading to the induction of IL-10 secretion in T helper cell subsets, where it acts as a pivotal negative feedback mechanism. Finally we discuss how a greater understanding of this principle has allowed for the design of more efficient, antigen-specific immunotherapy strategies to exploit this natural phenomenon clinically.

16.
PLoS One ; 8(4): e61334, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23593464

RESUMEN

T regulatory (Treg) cells expressing the transcription factor FoxP3 play a key role in protection against autoimmune disease. GFP-FoxP3 reporter mice have been used widely to study the induction, function and stability of both thymically- and peripherally-induced Treg cells. The N-terminal modification of FoxP3, however, affects its interaction with transcriptional co-factors; this can alter Treg cell development and function in certain self-antigen specific animal models. Interestingly, Treg cell function can be negatively or positively affected, depending on the nature of the model. In this study, we focused on the effect of the GFP-FoxP3 reporter on Treg cell development and function in the Tg4 mouse model. In this model, T cells express a transgenic T cell receptor (TCR) specific for the Myelin Basic Protein (MBP) peptide Ac1-9, making the animals susceptible to experimental autoimmune encephalomyelitis (EAE), a disease akin to multiple sclerosis in humans. Unlike diabetes-susceptible mice, Tg4 FoxP3(gfp) mice did not develop spontaneous autoimmune disease and did not demonstrate augmented susceptibility to induced disease. Concurrently, thymic generation of natural Treg cells was not negatively affected. The induction of FoxP3 expression in naive peripheral T cells was, however, significantly impaired as a result of the transgene. This study shows that the requirements for the interaction of FoxP3 with co-factors, which governs its regulatory ability, differ not only between natural and inducible Treg cells but also between animal models of diseases such as diabetes and EAE.


Asunto(s)
Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/metabolismo , Factores de Transcripción Forkhead/química , Factores de Transcripción Forkhead/metabolismo , Linfocitos T Reguladores/inmunología , Animales , Antígenos/metabolismo , Recuento de Células , Diferenciación Celular , Femenino , Regulación de la Expresión Génica/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Linfocitos T Reguladores/citología
17.
Proc Natl Acad Sci U S A ; 110(3): E221-30, 2013 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-23267099

RESUMEN

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4; CD152) is of pivotal importance for self-tolerance, with deficiency or unfavorable polymorphisms leading to autoimmune disease. Tolerance to self-antigens is achieved through thymic deletion of highly autoreactive conventional T (Tconv) cells and generation of FoxP3(+) regulatory T (Treg) cells. The main costimulatory molecule, CD28, augments the negative selection of Tconv cells and promotes the generation of FoxP3(+) Treg cells. The role of its antagonistic homolog CTLA-4, however, remains a topic of debate. To address this topic, we investigated the thymic development of T cells in the presence and absence of CTLA-4 in a T-cell receptor (TCR) transgenic mouse model specific for the myelin basic protein peptide Ac1-9. We reveal that CTLA-4 is expressed in the corticomedullary region of the thymus. Its absence alters the response of CD4(+)CD8(-) thymocytes to self-antigen recognition, which affects the quantity of the Treg cells generated and broadens the repertoire of peripheral Tconv cells. T-cell repertoire alteration after deletion of CTLA-4 results from changes in TCR Vα and Jα segment selection as well as CDR3α composition in Tconv and Treg cells. CTLA-4, therefore, regulates the early development of self-reactive T cells in the thymus and plays a key role in central tolerance.


Asunto(s)
Antígeno CTLA-4/inmunología , Reordenamiento Génico de Linfocito T , Linfocitos T Reguladores/inmunología , Linfocitos T/inmunología , Secuencia de Aminoácidos , Animales , Variación Antigénica , Antígeno CTLA-4/deficiencia , Antígeno CTLA-4/genética , Diferenciación Celular , Regiones Determinantes de Complementariedad , Citocinas/biosíntesis , Células Dendríticas/citología , Células Dendríticas/inmunología , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/inmunología , Femenino , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Datos de Secuencia Molecular , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Autotolerancia , Linfocitos T/citología , Linfocitos T Reguladores/citología , Timo/citología , Timo/crecimiento & desarrollo , Timo/inmunología
19.
Curr Opin Immunol ; 22(5): 609-15, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20850958

RESUMEN

Nearly a century has passed since the first report describing antigen-specific immunotherapy (antigen-SIT) was published. Research into the use of antigen-SIT in the treatment of both allergic and autoimmune disease has increased dramatically since, although its mechanism of action is only slowly being unravelled. It is clear though, from recent studies, that success of antigen-SIT depends on the induction of regulatory T (T reg) cell subsets that recognise potentially disease-inducing epitopes. The major challenge remaining for the widespread use of antigen-SIT is to safely administer high doses of immunodominant and potentially pathogenic epitopes in a manner that induces T cell tolerance rather than activation. This review illustrates that intelligent design of treatment agents and strategies can lead to the development of safe and effective antigen-SIT.


Asunto(s)
Alérgenos/administración & dosificación , Desensibilización Inmunológica/métodos , Tolerancia Inmunológica/inmunología , Alérgenos/inmunología , Animales , Autoantígenos/inmunología , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/terapia , Humanos
20.
J Exp Med ; 206(8): 1755-67, 2009 Aug 03.
Artículo en Inglés | MEDLINE | ID: mdl-19635862

RESUMEN

Regulation of the immune response to self- and foreign antigens is vitally important for limiting immune pathology associated with both infections and hypersensitivity conditions. Control of autoimmune conditions can be reinforced by tolerance induction with peptide epitopes, but the mechanism is not currently understood. Repetitive intranasal administration of soluble peptide induces peripheral tolerance in myelin basic protein (MBP)-specific TCR transgenic mice. This is characterized by the presence of anergic, interleukin (IL)-10-secreting CD4(+) T cells with regulatory function (IL-10 T reg cells). The differentiation pathway of peptide-induced IL-10 T reg cells was investigated. CD4(+) T cells became anergic after their second encounter with a high-affinity MBP peptide analogue. Loss of proliferative capacity correlated with a switch from the Th1-associated cytokines IL-2 and interferon (IFN)-gamma to the regulatory cytokine IL-10. Nevertheless, IL-10 T reg cells retained the capacity to produce IFN-gamma and concomitantly expressed T-bet, demonstrating their Th1 origin. IL-10 T reg cells suppressed dendritic cell maturation, prevented Th1 cell differentiation, and thereby created a negative feedback loop for Th1-driven immune pathology. These findings demonstrate that Th1 responses can be self-limiting in the context of peripheral tolerance to a self-antigen.


Asunto(s)
Autoinmunidad , Interleucina-10/biosíntesis , Células TH1/citología , Células TH1/inmunología , Animales , Antígenos/administración & dosificación , Autoantígenos/administración & dosificación , Diferenciación Celular , Anergia Clonal , Citocinas/sangre , Células Dendríticas/inmunología , Retroalimentación Fisiológica , Expresión Génica , Interferón gamma/biosíntesis , Ratones , Ratones Transgénicos , Proteína Básica de Mielina , Proteínas del Tejido Nervioso/inmunología , Fragmentos de Péptidos/inmunología , Autotolerancia , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/inmunología , Factores de Transcripción/inmunología
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