RESUMEN
Ag-specific tolerance is a highly desired therapy for immune-mediated diseases. Intravenous infusion of protein/peptide Ags linked to syngeneic splenic leukocytes with ethylene carbodiimide (Ag-coupled splenocytes [Ag-SP]) has been demonstrated to be a highly efficient method for inducing peripheral, Ag-specific T cell tolerance for treatment of autoimmune disease. However, little is understood about the mechanisms underlying this therapy. In this study, we show that apoptotic Ag-SP accumulate in the splenic marginal zone, where their uptake by F4/80(+) macrophages induces production of IL-10, which upregulates the expression of the immunomodulatory costimulatory molecule PD-L1 that is essential for Ag-SP tolerance induction. Ag-SP infusion also induces T regulatory cells that are dispensable for tolerance induction but required for long-term tolerance maintenance. Collectively, these results indicate that Ag-SP tolerance recapitulates how tolerance is normally maintained in the hematopoietic compartment and highlight the interplay between the innate and adaptive immune systems in the induction of Ag-SP tolerance. To our knowledge, we show for the first time that tolerance results from the synergistic effects of two distinct mechanisms, PD-L1-dependent T cell-intrinsic unresponsiveness and the activation of T regulatory cells. These findings are particularly relevant as this tolerance protocol is currently being tested in a Phase I/IIa clinical trial in new-onset relapsing-remitting multiple sclerosis.
Asunto(s)
Tolerancia Inmunológica/inmunología , Macrófagos/inmunología , Proteína Proteolipídica de la Mielina/inmunología , Fragmentos de Péptidos/inmunología , Bazo/inmunología , Linfocitos T Reguladores/inmunología , Animales , Antígenos/inmunología , Apoptosis/inmunología , Antígeno B7-1/biosíntesis , Antígeno B7-1/inmunología , Antígeno B7-H1 , Separación Celular , Encefalomielitis Autoinmune Experimental/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Inmunohistoquímica , Interleucina-10/biosíntesis , Interleucina-10/inmunología , Activación de Linfocitos/inmunología , Linfocitos/inmunología , Activación de Macrófagos/inmunología , Macrófagos/metabolismo , Glicoproteínas de Membrana/biosíntesis , Glicoproteínas de Membrana/inmunología , Ratones , Ratones Endogámicos C57BL , Péptidos/inmunología , Bazo/citologíaRESUMEN
CD4+ T-cell-mediated autoimmune diseases are initiated and maintained by the presentation of self-antigen by antigen-presenting cells (APCs) to self-reactive CD4+ T-cells. According to the two-signal hypothesis, activation of a naive antigen-specific CD4+ T-cell requires stimulation of both the T-cell antigen receptor (signal 1) and costimulatory molecules such as CD28 (signal 2). To date, the majority of therapies for autoimmune diseases approved by the Food and Drug Administration primarily focus on the global inhibition of immune inflammatory activity. The goal of ongoing research in this field is to develop antigen-specific treatments which block the deleterious effects of self-reactive immune cell function while maintaining the ability of the immune system to clear nonself antigens. To this end, the signaling pathways involved in the induction of CD4+ T-cell anergy, as apposed to activation, are a topic of intense interest. This chapter discusses components of the CD4+ T-cell activation pathway that may serve as therapeutic targets for the treatment of autoimmune disease.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/terapia , Activación de Linfocitos/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Transducción de Señal/inmunología , Animales , Humanos , Tolerancia Inmunológica/inmunología , Sinapsis Inmunológicas/inmunologíaRESUMEN
The FDA has co-sponsored three workshops to address minimal residual disease (MRD) detection in acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), and acute myeloid leukemia (AML) as well as an FDA-NCI roundtable symposium on MRD detection and its use as a response biomarker in Multiple Myeloma (MM). As clinical outcomes in MM continue to improve with the introduction of new therapeutics, consideration of biomarkers and their development as validated surrogate endpoints that can be used in the place of traditional clinical trial endpoints of progression-free survival (PFS) will be fundamental to expeditious drug development. This article will describe the FDA drug approval process, the regulatory framework through which a biomarker can be used as a surrogate endpoint for drug approval, and how MRD detection in MM fits within this context. In parallel, this article will also describe the FDA current device clearance process with emphasis on the analytical development as it might apply to an in vitro diagnostic assay for the detection of MRD in MM. It is anticipated that this Special Issue may possibly represent how MRD might serve as a drug development tool in hematological malignancies.
Asunto(s)
Antígenos CD/análisis , Antineoplásicos/uso terapéutico , Aprobación de Drogas/legislación & jurisprudencia , Citometría de Flujo/normas , Mieloma Múltiple/diagnóstico , Neoplasia Residual/diagnóstico , Antígenos CD/genética , Antígenos CD/inmunología , Biomarcadores Farmacológicos/análisis , Aprobación de Recursos/legislación & jurisprudencia , Expresión Génica , Humanos , Inmunofenotipificación , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/inmunología , Mieloma Múltiple/mortalidad , Neoplasia Residual/tratamiento farmacológico , Neoplasia Residual/inmunología , Neoplasia Residual/mortalidad , Células Plasmáticas/efectos de los fármacos , Células Plasmáticas/inmunología , Células Plasmáticas/patología , Pronóstico , Inducción de Remisión , Análisis de Supervivencia , Estados Unidos , United States Food and Drug AdministrationRESUMEN
A principal theme in autoimmunity is the breakdown of central tolerance resulting in the persistence and eventual activation of autoreactive T cells. Because CD4(+) T cells are key contributors to the underlying pathogenic mechanisms responsible for the onset and progression of most autoimmune diseases, they are a logical target for therapeutic interventions. One technique for restoring self-tolerance is to exploit the endogenous regulatory mechanisms that govern CD4(+) T-cell activation. In this review, we discuss promising techniques with the common goal of inducing antigen (Ag)-specific tolerance. Emphasis is given to the use of non-mitogenic anti-CD3 and peptide-specific tolerance strategies that specifically target the T-cell receptor (TCR) in the absence of costimulatory signals. These approaches produce a TCR signal of insufficient strength to cause CD4(+) T-cell activation and instead induce functional T-cell anergy or deletion while avoiding generalized long-term immunosuppression.
Asunto(s)
Enfermedades Autoinmunes del Sistema Nervioso/terapia , Inmunoterapia/métodos , Péptidos/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Autotolerancia/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Complejo CD3/inmunología , Ensayos Clínicos como Asunto , Citocinas/inmunología , Humanos , Terapia de Inmunosupresión/métodos , Modelos Inmunológicos , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/terapia , Péptidos/uso terapéutico , Receptores de Interleucina-2/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunologíaRESUMEN
A primary focus in autoimmunity is the breakdown of central and peripheral tolerance resulting in the survival and eventual activation of autoreactive T cells. As CD4(+) T cells are key contributors to the underlying pathogenic mechanisms responsible for onset and progression of most autoimmune diseases, they are a logical target for therapeutic strategies. One method for restoring self-tolerance is to exploit the endogenous regulatory mechanisms that govern CD4(+) T cell activation. In this review, we discuss tolerance strategies with the common goal of inducing antigen (Ag)-specific tolerance. Emphasis is given to the use of peptide-specific tolerance strategies, focusing on ethylene carbodiimide (ECDI)-peptide-coupled cells (Ag-SP) and nonmitogenic anti-CD3, which specifically target the T cell receptor (TCR) in the absence of costimulatory signals. These approaches induce a TCR signal of insufficient strength to cause CD4(+) T cell activation and instead lead to functional T cell anergy/deletion and activation of Ag-specific induced regulatory T cells (iTregs) while avoiding generalized long-term immunosuppression.
Asunto(s)
Terapia de Inmunosupresión/métodos , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/terapia , Animales , Anticuerpos Monoclonales/uso terapéutico , Autoantígenos , Autoinmunidad , Linfocitos T CD4-Positivos/inmunología , Carbodiimidas , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/terapia , Humanos , Inmunidad Mucosa , Terapia de Inmunosupresión/tendencias , Ratones , Péptidos/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Autotolerancia , Linfocitos T Reguladores/inmunologíaRESUMEN
MHC class II (MHC II)-restricted T cell responses are a common driving force of autoimmune disease. Accordingly, numerous therapeutic strategies target CD4(+) T cells with the hope of attenuating autoimmune responses and restoring self-tolerance. We have previously reported that i.v. treatment with Ag-pulsed, ethylenecarbodiimide (ECDI)-fixed splenocytes (Ag-SPs) is an efficient protocol to induce Ag-specific tolerance for prevention and treatment of experimental autoimmune encephalomyelitis (EAE). Ag-SPs coupled with peptide can directly present peptide:MHC II complexes to target CD4(+) T cells in the absence of costimulation to induce anergy. However, Ag-SPs coupled with whole protein also efficiently attenuates Ag-specific T cell responses suggesting the potential contribution of alternative indirect mechanisms/interactions between the Ag-SPs and target CD4(+) T cells. Thus, we investigated whether MHC II compatibility was essential to the underlying mechanisms by which Ag-SP induces tolerance during autoimmune disease. Using MHC-deficient, allogeneic, and/or syngeneic donor Ag-SPs, we show that MHC compatibility between the Ag-SP donor and the host is not required for tolerance induction. Interestingly, we found that ECDI treatment induces apoptosis of the donor cell population which promotes uptake and reprocessing of donor cell peptides by host APCs resulting in the apparent MHC II-independent induction of tolerance. However, syngeneic donor cells are more efficient at inducing tolerance, suggesting that Ag-SPs induce functional Ag-SP tolerance via both direct and indirect (cross-tolerance) mechanisms leading to prevention and effective treatment of autoimmune disease.
Asunto(s)
Presentación de Antígeno/inmunología , Células Presentadoras de Antígenos/inmunología , Linfocitos T CD4-Positivos/inmunología , Comunicación Celular/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Tolerancia Inmunológica , Animales , Presentación de Antígeno/efectos de los fármacos , Células Presentadoras de Antígenos/trasplante , Apoptosis/inmunología , Autoantígenos/inmunología , Autoantígenos/farmacología , Carbodiimidas/química , Comunicación Celular/efectos de los fármacos , Células Cultivadas , Encefalomielitis Autoinmune Experimental/prevención & control , Fijadores/química , Antígenos de Histocompatibilidad Clase II/inmunología , Tolerancia Inmunológica/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Trasplante Homólogo , Trasplante IsogénicoRESUMEN
The development of safe and effective antigen-specific therapies is needed to treat patients with autoimmune diseases. These therapies must allow for the specific tolerization of self-reactive immune cells without altering host immunity to infectious insults. Experimental models and clinical trials for the treatment of autoimmune disease have identified putative mechanisms by which antigen-specific therapies induce tolerance. Although advances have been made in the development of efficient antigen-specific therapies, translating these therapies from bench to bedside has remained difficult. Here, we discuss the recent advances in our understanding of antigen-specific therapies for the treatment of autoimmune diseases.
Asunto(s)
Autoantígenos/inmunología , Enfermedades Autoinmunes/terapia , Tolerancia Inmunológica , Inmunoterapia/métodos , Péptidos/uso terapéutico , Animales , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/prevención & control , Ensayos Clínicos como Asunto , Modelos Animales de Enfermedad , Humanos , Ratones , Péptidos/inmunologíaRESUMEN
Notch receptors are processed by gamma-secretase acting in synergy with T cell receptor signaling to sustain peripheral T cell activation. Activated CD4+ T cells differentiate into T helper type 1 (TH1) or TH2 subsets. Molecular cues directing TH1 differentiation include expression of the TH1-specific transcription factor T-bet, encoded by Tbx21. However, the regulation of Tbx21 remains incompletely defined. Here we report that Notch1 can directly regulate Tbx21 through complexes formed on the Tbx21 promoter. In vitro, gamma-secretase inhibitors extinguished expression of Notch, interferon-gamma and Tbx21 in TH1-polarized CD4+ cells, whereas ectopic expression of activated Notch1 restored Tbx21 transcription. In vivo, administration of gamma-secretase inhibitors substantially impeded TH1-mediated disease progression in the mouse experimental autoimmune encephalomyelitis model of multiple sclerosis. Thus, using gamma-secretase inhibitors to modulate Notch signaling may prove beneficial in treating TH1-mediated autoimmunity.
Asunto(s)
Proteínas de Unión al ADN/antagonistas & inhibidores , Endopeptidasas/inmunología , Inhibidores de Proteasas/farmacología , Receptores de Superficie Celular/antagonistas & inhibidores , Células TH1/inmunología , Factores de Transcripción/antagonistas & inhibidores , Secretasas de la Proteína Precursora del Amiloide , Animales , Ácido Aspártico Endopeptidasas , Citocinas/inmunología , Proteínas de Unión al ADN/biosíntesis , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/inmunología , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/enzimología , Encefalomielitis Autoinmune Experimental/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Hipersensibilidad Tardía/tratamiento farmacológico , Hipersensibilidad Tardía/inmunología , Immunoblotting , Ratones , Ratones Endogámicos C57BL , Receptor Notch1 , Receptores de Superficie Celular/inmunología , Proteínas de Dominio T Box , Células TH1/efectos de los fármacos , Células TH1/enzimología , Factores de Transcripción/biosíntesis , Factores de Transcripción/genética , Factores de Transcripción/inmunología , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/inmunologíaRESUMEN
Intravenous treatment with Ag (peptide)-coupled, ethylene carbodiimide-fixed syngeneic splenocytes (Ag-SP) is a powerful method to induce anergy in vitro and peripheral T cell tolerance in vivo. In this study, we examined the effects of Ag-SP administration on T cell activity ex vivo and in vivo using OVA-specific DO11.10 TCR transgenic T cells. Although treatment with OVA323-339-SP resulted in a strong inhibition of peptide-specific T cell recall responses in vitro, examination of the immediate effects of Ag-SP treatment on T cells in vivo demonstrated that tolerogen injection resulted in rapid T cell activation and proliferation. Although there was an increase in the number of OVA-specific DO11.10 T cells detected in the lymphoid organs, these previously tolerized T cells were strongly inhibited in mounting proliferative or inflammatory responses upon rechallenge in vivo with peptide in CFA. This unresponsiveness was reversible by treatment with anti-CTLA-4 mAb. These results are consistent with the hypothesis that Ag-SP injection induces a state of T cell anergy that is maintained by CTLA-4 engagement.