RESUMEN
9-kDa granulysin is a protein expressed into the granules of human cytotoxic T lymphocytes (CTL) and natural killer (NK) cells. It has been shown to exert cytolysis on microbes and tumors. We showed previously that 9-kDa granulysin exerted cell death by apoptosis in vitro on hematological tumor cell lines and also on cells from B-cell chronic lymphocytic leukemia (B-CLL) patients. In addition, we have shown the anti-tumor efficiency of granulysin as a single agent in two in vivo models of human tumor development in athymic mice, the MDA-MB-231 mammary adenocarcinoma and the NCI-H929 multiple myeloma, without signs of overt secondary effects by itself. In this work, we have tested recombinant 9-kDa granulysin in an in vivo and especially aggressive model of melanoma development, xenografted UACC62 cells in athymic mice. Recombinant granulysin was administered once UACC62-derived tumors were detectable and it substantially retarded the in vivo development of this aggressive tumor. We could also detect apoptosis induction and increased NK cell infiltration inside granulysin-treated tumor tissues. These observations are especially interesting given the possibility of treating melanoma by intra-tumor injection.
Asunto(s)
Antígenos de Diferenciación de Linfocitos T/uso terapéutico , Melanoma Experimental/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Animales , Antígenos de Diferenciación de Linfocitos T/farmacología , Apoptosis/efectos de los fármacos , Calreticulina/metabolismo , Línea Celular Tumoral , Humanos , Células Asesinas Naturales , Linfocitos Infiltrantes de Tumor , Masculino , Melanoma Experimental/patología , Ratones , Trasplante de Neoplasias , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , Neoplasias Cutáneas/patologíaRESUMEN
CD6 was established as a marker of T cells more than three decades ago, and recent studies have identified CD6 as a risk gene for multiple sclerosis (MS), a disease in which autoreactive T cells are integrally involved. Nevertheless, the precise role of CD6 in regulating T-cell responses is controversial and its significance in the pathogenesis of various diseases remains elusive, partly due to the lack of animals engineered to alter expression of the CD6 gene. In this report, we found that CD6 KO mice showed decreased pathogenic T-cell responses, reduced spinal cord T-cell infiltration, and attenuated disease severity in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. CD6-deficient T cells exhibited augmented activation, but also significantly reduced survival and proliferation after activation, leading to overall decreased Th1 and Th17 polarization. Activated CD6-deficient T cells also showed impaired infiltration through brain microvascular endothelial cell monolayers. Furthermore, by developing CD6 humanized mice, we identified a mouse anti-human CD6 monoclonal antibody that is highly effective in treating established EAE without depleting T cells. These results suggest that (i) CD6 is a negative regulator of T-cell activation, (ii) at the same time, CD6 is a positive regulator of activated T-cell survival/proliferation and infiltration; and (iii) CD6 is a potential new target for treating MS and potentially other T-cell-driven autoimmune conditions.
Asunto(s)
Anticuerpos Monoclonales Humanizados/inmunología , Antígenos CD/inmunología , Antígenos de Diferenciación de Linfocitos T/inmunología , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Esclerosis Múltiple/tratamiento farmacológico , Animales , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antígenos CD/uso terapéutico , Antígenos de Diferenciación de Linfocitos T/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/inmunología , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Humanos , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Ratones , Ratones Noqueados , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Médula Espinal/efectos de los fármacos , Médula Espinal/inmunología , Médula Espinal/patología , Células TH1/inmunología , Células Th17/inmunología , Células Th17/patologíaRESUMEN
CD6, one of the first antigens to be identified on T cells, is a membrane glycoprotein that physically associates with the antigen receptor complex. Because of this, its main function seems to involve the modulation of TCR-mediated signaling pathways. However, growing evidence indicates that this ancient and conserved scavenger-like receptor may also play a role as pattern recognition receptor (PRR), similar to other members of the scavenger receptor cysteine rich superfamily (SRCR-SF). Here, we discuss the functional interactions of CD6 with microbe- and damage-associated signals and the potential use of soluble forms of CD6 in the therapeutic treatment of bacterial infections, in particular multi-drug resistant bacterial strains. Importantly, microbe recognition by CD6 may also have functional consequences on T cell activation and differentiation, which remain to be explored.
Asunto(s)
Antígenos CD/metabolismo , Antígenos de Diferenciación de Linfocitos T/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores Depuradores/metabolismo , Linfocitos T/citología , Animales , Antígenos CD/farmacología , Antígenos CD/uso terapéutico , Antígenos de Diferenciación de Linfocitos T/farmacología , Antígenos de Diferenciación de Linfocitos T/uso terapéutico , Bacterias/inmunología , Infecciones Bacterianas/tratamiento farmacológico , Diferenciación Celular , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Humanos , Activación de Linfocitos , Transducción de Señal , Linfocitos T/inmunologíaRESUMEN
BACKGROUND: Antimicrobial peptides are considered as a potential alternative to antibiotic treatment in acne vulgaris because the development of a resistant strain of Propionibacterium acnes is problematic. Granulysin can be regarded as an ideal substance with which to treat acne because it has antimicrobial and anti-inflammatory effects. OBJECTIVES: This study was performed to explore the effectiveness of granulysin-derived peptides (GDPs) in killing P. acnes in vitro under a standard microbiologic assay and to evaluate their potential use in a topical agent for the treatment of acne vulgaris. METHODS: Twenty different peptides based on the known sequence of a GDP were synthesized and tested in vitro for antimicrobial activity. Thirty patients with facial acne vulgaris were instructed to apply a topical formulation containing synthetic GDP to acne lesions twice per day for 12 weeks. RESULTS: A newly synthesized peptide in which aspartic acid was substituted with arginine, and methionine was substituted with cysteine, showed the highest antimicrobial activity against P. acnes. Moreover, it was effective against both Gram-positive and Gram-negative bacteria in vitro. After treatment with the topical formulation containing 50 ppm of synthetic peptide for 12 weeks, a significant reduction in the number of pustules was observed, regardless of the increase in the number of comedones. In addition, a significant reduction in the clinical grade of acne based on the Korean Acne Grading System (KAGS) was evident. CONCLUSIONS: Synthesized GDP shows strong antimicrobial activity against P. acnes in vitro. The clinical improvement observed suggests a topical formulation containing the GDP has therapeutic potential for the improvement of inflammatory-type acne vulgaris by its antimicrobial activity.
Asunto(s)
Acné Vulgar/tratamiento farmacológico , Antígenos de Diferenciación de Linfocitos T/farmacología , Péptidos Catiónicos Antimicrobianos/farmacología , Dermatosis Facial/tratamiento farmacológico , Propionibacterium acnes/efectos de los fármacos , Administración Cutánea , Adulto , Antiinfecciosos/farmacología , Antiinflamatorios/farmacología , Antígenos de Diferenciación de Linfocitos T/uso terapéutico , Péptidos Catiónicos Antimicrobianos/síntesis química , Péptidos Catiónicos Antimicrobianos/uso terapéutico , Femenino , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
Gram-positive bacteria cause a broad spectrum of infection-related diseases in both immunocompetent and immunocompromised hosts, ranging from localized infections to severe systemic conditions such as septic and toxic shock syndromes. This situation has been aggravated by the recent emergence of multidrug-resistant strains, thus stressing the need for alternative therapeutic approaches. One such possibility would be modulating the host's immune response. Herein, the potential use of a soluble form of the scavenger-like human lymphocyte receptor CD6 (shCD6) belonging to an ancient family of innate immune receptors has been evaluated. shCD6 can bind to a broad spectrum of gram-positive bacteria thanks to the recognition of highly conserved cell wall components (lipoteichoic acid [LTA] and peptidoglycan [PGN]), which are essential for their viability and pathogenicity and are not amenable to antibiotic resistance. shCD6 has in vitro inhibitory effects on both bacterial growth and Toll-like receptor-mediated inflammatory response induced by LTA plus PGN. In vivo infusion of shCD6 improves survival on mouse models of septic shock by Staphylococcus aureus (either multidrug-resistant or -sensitive) or their endotoxins (LTA + PGN) or exotoxins (TSST-1). These results support the use of shCD6 and/or other scavenger-like immune receptors in the treatment of severe gram-positive-induced infectious conditions.
Asunto(s)
Antígenos CD/inmunología , Antígenos de Diferenciación de Linfocitos T/inmunología , Productos Biológicos/inmunología , Peptidoglicano/inmunología , Staphylococcus aureus/inmunología , Ácidos Teicoicos/inmunología , Factores de Virulencia/inmunología , Animales , Antígenos CD/uso terapéutico , Antígenos de Diferenciación de Linfocitos T/uso terapéutico , Productos Biológicos/uso terapéutico , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Peptidoglicano/metabolismo , Unión Proteica , Choque Séptico/tratamiento farmacológico , Infecciones Estafilocócicas/tratamiento farmacológico , Ácidos Teicoicos/metabolismo , Factores de Virulencia/metabolismoRESUMEN
The transmembrane surface glycoprotein CD6 was one of the first antigens identified on T lymphocytes. The recognition of its involvement in T-cell signaling processes heralds the potential of CD6 as a target for therapy in a number of pathologies associated with imbalances in T-cell function. Its tissue distribution, cellular expression, and overall molecular structure are well described, and the interaction with its physiological ligand CD166 has been determined to the amino-acid level. Nevertheless, the involvement of CD6 in signaling pathways remains poorly characterized and its biological function is controversial; still unresolved are whether CD6 is a co-stimulatory molecule in T-cell activation or, similar to the related CD5 antigen, a modulator of intracellular signaling. Here we revisit the earliest attempts of modulating immune function using CD6 monoclonal antibodies, and review the current thinking behind the recent developments in immunotherapy targeting CD6. Notwithstanding the promises and hopes brought by monoclonals already in clinical trials, the fact is that very little is known about the mechanism of action of these reagents, whether they enhance the physiological role of the receptor or whether they may induce a completely novel biochemical response that might, nevertheless, be beneficially used to treat human immune pathology.
Asunto(s)
Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Antígenos CD/inmunología , Antígenos CD/uso terapéutico , Antígenos de Diferenciación de Linfocitos T/inmunología , Antígenos de Diferenciación de Linfocitos T/uso terapéutico , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/terapia , Antígenos CD/metabolismo , Antígenos CD5/inmunología , Antígenos CD5/metabolismo , Moléculas de Adhesión Celular Neuronal/metabolismo , Proliferación Celular , Proteínas Fetales/metabolismo , Humanos , Transducción de Señal , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
La llegada de los fármacos anti-TNF-α (tumor necrosis factor alpha factor de necrosis tumoral alfa) a la clínica ha sido el resultado más exitoso de la investigación traslacional. Sin embargo, la experiencia ha demostrado que estos compuestos no consiguen inducir la remisión clínica en la mitad de los pacientes con artritis reumatoide (AR). Recientemente se han puesto a disposición en el mercado fármacos biológicos no dirigidos contra citocinas que deplecionan las células B o interfieren con la activación de las células T y que también han mostrado eficacia en el control de la actividad de la AR. Una segunda generación de compuestos contra la célula B está en desarrollo de parte de diversas empresas farmacéuticas. Es de esperar que estos productos mejoren la inmunogenicidad y la posología del rituximab, pero es poco probable que incrementen las tasas de remisión alcanzadas por los anti-TNF-α. Actualmente, la regulación de la transducción de señales se ha convertido en un campo muy importante en el desarrollo de los fármacos, y pequeñas moléculas inhibidoras de vías de señalización intracelular se están ensayando como nuevos antiinflamatorios. Para las enfermedades reumáticas, los inhibidores específicos de JAK3 y Syk son, hasta ahora, los compuestos que han mostrado mejores resultados y representan un avance significativo respecto a los inhibidores de la p38 MAPK (mitogen-activated protein kinase ' proteína cinasa activada por mitógeno') (AU)
The arrival of anti-TNF-α to the clinic has been the most successful example of translational research. However, clinical experience has shown that these compounds do not induce clinical remission in half of rheumatoid arthritis (RA) patients. Recently, new biological drugs against non-cytokine targets have been available for RA patients. These compounds deplete B cells or interfere with the activation of T cells and have also shown effectiveness in controlling signs, symptoms and structural damage progression in RA. Second generation B-cell depletion therapies are progressing in the pipeline of several pharmaceutical companies. These compounds will likely improve the immunogenicity and formulation of rituximab, but it is improbable that they will improve the remission rate achieved by the anti-TNF-αδρυγσ. Currently, regulation of signal transduction has evolved into an important field of drug research, and small molecule inhibitors for a number of pathways are tested as new anti-inflammatory agents. For rheumatic diseases, specific Jak3 and Syk inhibitors are, so far, the most successful compounds representing a significant advance over p38 mitogen-activated protein kinase (MAPK) inhibitors (AU)
Asunto(s)
Humanos , Factores de Necrosis Tumoral/antagonistas & inhibidores , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/fisiopatología , Terapia Biológica/métodos , /antagonistas & inhibidores , Antígeno de Maduración de Linfocitos B/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Antígenos de Diferenciación de Linfocitos T/uso terapéutico , Factores de Transcripción/antagonistas & inhibidoresRESUMEN
Chlamydia infections cause substantial morbidity worldwide and effective prevention will depend on a vaccine. Since Chlamydia immunity is T cell-mediated, a major impediment to developing a molecular vaccine has been the difficulty in identifying relevant T cell Ags. In this study, we used a combination of affinity chromatography and tandem mass spectrometry to identify 13 Chlamydia peptides among 331 self-peptides presented by MHC class II (I-A(b)) molecules from bone marrow-derived murine dendritic cells infected with Chlamydia muridarum. These MHC class II-bound peptides were recognized by Chlamydia-specific CD4 T cells harvested from immune mice and adoptive transfer of dendritic cells pulsed ex vivo with the peptides partially protected mice against intranasal and genital tract Chlamydia infection. The results provide evidence for lead vaccine candidates for a T cell-based subunit molecular vaccine against Chlamydia infection suitable for human study.
Asunto(s)
Antígenos Bacterianos/aislamiento & purificación , Antígenos de Diferenciación de Linfocitos T/aislamiento & purificación , Chlamydia muridarum/inmunología , Líquido Intracelular/inmunología , Líquido Intracelular/microbiología , Proteoma/inmunología , Secuencia de Aminoácidos , Animales , Antígenos Bacterianos/metabolismo , Antígenos Bacterianos/uso terapéutico , Antígenos de Diferenciación de Linfocitos T/metabolismo , Antígenos de Diferenciación de Linfocitos T/uso terapéutico , Células Cultivadas , Infecciones por Chlamydia/inmunología , Infecciones por Chlamydia/metabolismo , Infecciones por Chlamydia/prevención & control , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Células Dendríticas/trasplante , Femenino , Antígenos H-2/aislamiento & purificación , Antígenos H-2/metabolismo , Células HeLa , Antígenos de Histocompatibilidad Clase II/aislamiento & purificación , Antígenos de Histocompatibilidad Clase II/metabolismo , Antígenos de Histocompatibilidad Clase II/uso terapéutico , Humanos , Líquido Intracelular/química , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Péptidos/aislamiento & purificación , Péptidos/metabolismo , Péptidos/uso terapéutico , Unión Proteica/inmunología , Proteoma/aislamiento & purificación , Proteoma/metabolismo , Espectrometría de Masas en TándemRESUMEN
BACKGROUND: Activated T cells play a key role in allograft rejection. T cell activation requires signaling via the T cell receptor as well as costimulatory signals. Inducible costimulatory molecule (ICOS), with its ligand B7RP-1, is a recently discovered costimulatory molecule of the CD28 family. The role of this signaling pathway during the early phases of kidney allograft rejection is not clear so far. METHODS: Kidneys were orthotopically transplanted from BALB/c to C57BL/6 mice. Animals were assigned to five experimental groups: blocking anti-ICOS monoclonal antibody, ICOS fusion protein, anti-B7RP1 monoclonal antibody, B7RP-1 fusion protein, and control immunoglobulin G. RESULTS: Survival was significantly reduced in animals treated with ICOS monoclonal antibody (mAb) and B7RP-1 Fc as compared with controls. These animals had also a lower number of apoptotic graft infiltrating T cells, whereas the expression of intracellular interferon-gamma in CD3CD4 T cells was increased. Animals treated with ICOS Fc and B7RP-1 mAb had similar survival and numbers of apoptotic T cells as compared with controls. CONCLUSIONS: In summary, the blockade of ICOS with ICOS mAb or B7RP-1 Fc reduced the amount of apoptosis of infiltrating lymphocytes and resulted in continuous inflammatory processes with progressive tissue damage and graft failure.
Asunto(s)
Antígenos de Diferenciación de Linfocitos T/uso terapéutico , Antígeno B7-1/uso terapéutico , Rechazo de Injerto/tratamiento farmacológico , Trasplante de Riñón/inmunología , Animales , Anticuerpos Monoclonales , Antígenos de Diferenciación de Linfocitos T/inmunología , Apoptosis , Antígeno B7-1/inmunología , Complejo CD3/biosíntesis , Complejo CD3/genética , Inmunoadhesinas CD4/biosíntesis , Inmunoadhesinas CD4/genética , Modelos Animales de Enfermedad , Citometría de Flujo , Expresión Génica , Rechazo de Injerto/inmunología , Rechazo de Injerto/metabolismo , Supervivencia de Injerto , Etiquetado Corte-Fin in Situ , Ligando Coestimulador de Linfocitos T Inducibles , Proteína Coestimuladora de Linfocitos T Inducibles , Líquido Intracelular/metabolismo , Trasplante de Riñón/patología , Ligandos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , ARN Mensajero/genética , Linfocitos T/inmunología , Linfocitos T/patologíaRESUMEN
The recent global increase in cases of tuberculosis and the emergence of multidrug-resistant strains of tuberculosis have focused attention on the molecular mechanisms of human antimycobacterial immunity. The macrophage is not only the primary site for Mycobacterium tuberculosis growth but also ordinarily provides the primary lines of host defense against invading pathogens in its role as an effector of innate immunity. The ability of M. tuberculosis to survive and replicate in the host macrophage is critical to its pathogenesis, emphasizing a need for a clearer understanding of its interactions with the host macrophage. Macrophages use varied strategies to kill and destroy invading organisms, including production of reactive nitrogen and oxygen intermediates, phagosome maturation and acidification, fusion with lysosomes, exposure to defensins and host cell apoptosis. In human, granulysin is a recently identified antimicrobial protein expressed on cytotoxic T cells, natural killer (NK) cells and NKT cells. It has been shown that granulysin contributes to the defense mechanisms against mycobacterial infection. We hypothesized that human macrophages may possess antimicrobial substances, such as granulysin, and play a role in the defense mechanism.
Asunto(s)
Antiinfecciosos/farmacología , Antiinfecciosos/uso terapéutico , Antígenos de Diferenciación de Linfocitos T/farmacología , Antígenos de Diferenciación de Linfocitos T/uso terapéutico , Mycobacterium tuberculosis/efectos de los fármacos , Tuberculosis/tratamiento farmacológico , Tuberculosis/inmunología , Resistencia a Múltiples Medicamentos , Humanos , Inmunidad , Macrófagos/microbiología , Mycobacterium tuberculosis/crecimiento & desarrollo , Mycobacterium tuberculosis/aislamiento & purificación , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunologíaRESUMEN
OBJECTIVE: To examine the therapeutic effect of inducible costimulator fusion protein (ICOS-Ig) on airway inflammation in a murine model of allergic asthma. METHODS: Thirty-two healthy female BALB/c mice were randomly divided into four groups, namely the asthma group (group A), the ICOS-Ig treated group (group B), the control antibody group (group C), and the saline challenged group (group D), with 8 mice in each group. ICOS-Ig was produced by the eukaryotic expression technology. A murine model of allergic asthma was made by sensitizing animals with ovalbumin and exposing them to repeated ovalbumin inhalation challenges. After the mice were treated with ICOS-Ig at the time of ovalbumin challenge, the airway responsiveness, inflammatory cells and the cytokine content in bronchoalveolar lavage fluid (BALF), the level of IgE and Th1/Th2 in blood, and the lung histology were measured to observe the effect of the treatment on asthma in vivo. RESULTS: (1) FACS analysis confirmed that ICOS-Ig had the binding activity to B220 murine splenocytes. (2) Trans-pulmonary pressure change was significantly reduced in mice from group B [(33 +/- 12)%] compared with group A [(58 +/- 10)%, P < 0.01]. The total cell numbers of BALF in mice from group B [(5.9 +/- 3.1) x 10(7)/L] were decreased compared with group A [(22.6 +/- 5.3) x 10(7)/L, P < 0.01]. The percentage of eosinophils in BALF in mice from group B (0.020 +/- 0.020) was reduced significantly as compared with group A (0.070 +/- 0.030, P < 0.01). IL-4 content in BALF was reduced in mice from group B [(77 +/- 31)ng/L] compared with group A [(179 +/- 44) ng/L, P < 0.01]. IgE in blood was decreased in mice from group B [(175 +/- 33)microg/L] compared with group A [(282 +/- 22)microg/L, P < 0.01]. Th2 cell numbers in blood were reduced in mice from group B [(4.5 +/- 1.0)% ] compared with group A [(11.1 +/- 2.5)%, P < 0.01]. (3) Compared with group A, the pulmonary inflammation in group B was relieved and inflammatory changes in airway epithelium were absent. CONCLUSION: ICOS-Ig has an inhibitory effect on inflammation in a murine model of allergic asthma through the blockade of ICOS costimulatory pathway and decreases the level of IgE by altering differentiation of Th1/Th2 lymphocyte subsets in vivo.
Asunto(s)
Antígenos de Diferenciación de Linfocitos T/uso terapéutico , Asma/terapia , Animales , Asma/etiología , Modelos Animales de Enfermedad , Femenino , Inmunoglobulina E/inmunología , Proteína Coestimuladora de Linfocitos T Inducibles , Ratones , Ratones Endogámicos BALB C , Proteínas Recombinantes de Fusión/uso terapéutico , Células TH1/inmunología , Células Th2/inmunologíaAsunto(s)
Antígenos de Diferenciación de Linfocitos T/uso terapéutico , Antígenos CD40/inmunología , Ligando de CD40/inmunología , Rechazo de Injerto/prevención & control , Proteínas/uso terapéutico , Linfocitos T/inmunología , Tolerancia al Trasplante , Animales , Antígenos CD , Trasplante de Corazón/inmunología , Humanos , Ligando Coestimulador de Linfocitos T Inducibles , Proteína Coestimuladora de Linfocitos T Inducibles , Ligandos , Ratas , Linfocitos T/efectos de los fármacos , Trasplante HomólogoRESUMEN
BACKGROUND: : Blockade of the CD40-CD40L pathway results in long-term allograft survival but does not prevent chronic rejection. ICOS-ICOSL are members of the CD28-B7 family that play an important role in T-cell activation. METHODS: : The authors analyzed the effect of single or combined treatment with an anti-ICOS monoclonal antibody and CD40 immunoglobulin (Ig) on acute and chronic rejection of heart allografts in rats. RESULTS: : Treatment with anti-ICOS resulted in a modest but significant prolongation of allograft survival. Treatment with CD40Ig resulted in long-term graft survival but the cardiac grafts developed chronic rejection lesions. Combined CD40Ig+anti-ICOS treatment led to indefinite graft survival in all recipients and a significant decrease of chronic rejection lesions compared with CD40Ig alone. Importantly, four of the seven CD40Ig+anti-ICOS-treated recipients showed a complete absence of chronic rejection lesions, whereas all of the CD40Ig-treated recipients showed chronic rejection. The CD40Ig+anti-ICOS group also showed significant decreased graft infiltration, decreased antidonor cytotoxic T-lymphocyte activity, and decreased alloantibodies compared with the CD40Ig-treated group. Adoptive transfer of splenocytes indefinitely prolonged allograft survival, whereas those depleted of T cells did not, suggesting the development of T-regulatory mechanisms. CONCLUSIONS: : These data indicate that the chronic rejection mechanisms that are CD40-CD40L independent are ICOS-ICOSL dependent. These results were obtained with conservation of cognate immune responses and development of tolerogenic T cells.
Asunto(s)
Antígenos de Diferenciación de Linfocitos T/uso terapéutico , Antígenos CD40/inmunología , Ligando de CD40/inmunología , Rechazo de Injerto/prevención & control , Trasplante de Corazón/inmunología , Proteínas/uso terapéutico , Tolerancia al Trasplante , Animales , Proteína Coestimuladora de Linfocitos T Inducibles , Ligandos , Complejo Mayor de Histocompatibilidad , Masculino , Ratas , Ratas Endogámicas Lew , Trasplante HomólogoRESUMEN
Increasing evidence suggests that B7/CD28 interactions are important in clonal expansion and effector function of nai;ve CD4(+) T cells, whereas ICOS/GL50 interactions may optimize the responses of recently activated T(H) cells. In tumor models, it has been shown that engagement of ICOS, like CD28, by its ligands can be effective in enhancing tumor immunity. In this report, we have directly compared the in vivo efficacy of CD28 vs ICOS activation in the MethA fibrosarcoma and B16F1 melanoma tumor models. We studied the efficacy of systemic treatment of tumors with murine B7.2-IgG or GL50-IgG fusion proteins, and the therapeutic potential of B7.1 or GL50 vaccines given during various phases of the antitumor responses. In addition, we compare the efficacy of ICOS-ligand splice variants GL50 and GL50B in promoting tumor immunity. We find that each of these pathways is equally effective in promoting tumor immunity and that the efficacy of both GL50 and B7.1 vaccines is IFN-gamma but not IL-10 dependent. Our results suggest that CD28 or ICOS costimulation-based strategies may be equally efficacious as adjuvants to conventional cancer treatment.
Asunto(s)
Antígenos de Diferenciación de Linfocitos T/inmunología , Antígeno B7-1/inmunología , Antígenos CD28/inmunología , Neoplasias Experimentales/inmunología , Proteínas/inmunología , Linfocitos T Citotóxicos/inmunología , Animales , Antígenos de Diferenciación de Linfocitos T/uso terapéutico , Antígeno B7-1/uso terapéutico , Antígenos CD28/uso terapéutico , Línea Celular Tumoral , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Memoria Inmunológica/inmunología , Ligando Coestimulador de Linfocitos T Inducibles , Proteína Coestimuladora de Linfocitos T Inducibles , Interferón gamma/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones SCID , Neoplasias Experimentales/terapia , Proteínas/uso terapéutico , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/uso terapéutico , Linfocitos T Citotóxicos/citologíaRESUMEN
In order that cellular immune responses afford protection without risk to sensitive normal tissue, they must be adapted to individual tissues of the body. Nowhere is this more critical than for the brain, where various passive and active mechanisms maintain a state of immune privilege that can limit high magnitude immune responses. Nevertheless, it is now clear that immune responses are induced to antigens in the brain, including those expressed by cerebral malignancies. We discuss hypotheses of how this can occur, although details such as which antigen presenting cells are involved remain to be clarified. Antitumor responses induced spontaneously are insufficient to eradicate malignant astrocytomas; many studies suggest that this can be explained by a combination of low level immune response induction and tumor mediated immunosuppression. A clinical objective currently pursued is to use immunotherapy to ameliorate antitumour immunity. This will necessitate a high level immune response to ensure sufficient effector cells reach the tumor bed, focused cytotoxicity to eradicate malignant cells with little collateral damage to critical normal cells, and minimal inflammation. To achieve these aims, priority should be given to identifying more target antigens in astrocytoma and defining those cells present in the brain parenchyma that are essential to maintain antitumour effector function without exacerbating inflammation. If we are armed with better understanding of immune interactions with brain tumor cells, we can realistically envisage that immunotherapy will one day offer hope to patients with currently untreatable neoplastic diseases of the CNS.
Asunto(s)
Neoplasias Encefálicas/inmunología , Encéfalo/inmunología , Linfocitos T/inmunología , Animales , Antígenos/inmunología , Antígenos de Diferenciación de Linfocitos T/inmunología , Antígenos de Diferenciación de Linfocitos T/uso terapéutico , Neoplasias Encefálicas/terapia , Células Cultivadas , Humanos , Inmunidad Celular , Inmunoterapia , Linfocitos T/metabolismoAsunto(s)
Síndrome de Inmunodeficiencia Adquirida/terapia , Anticuerpos Antiidiotipos/uso terapéutico , Antígenos de Diferenciación de Linfocitos T/uso terapéutico , Inmunoglobulina G/uso terapéutico , Zidovudina/uso terapéutico , Inmunoadhesinas CD4 , Activación de Complemento , Humanos , Receptores Virales/uso terapéutico , Proteínas RecombinantesAsunto(s)
Síndrome de Inmunodeficiencia Adquirida/terapia , Antígenos de Diferenciación de Linfocitos T/uso terapéutico , VIH-1/efectos de los fármacos , Inmunoterapia/métodos , Receptores Virales/efectos de los fármacos , Unión Competitiva/efectos de los fármacos , Proteína gp120 de Envoltorio del VIH , Humanos , Receptores del VIH , Proteínas de los RetroviridaeRESUMEN
Non-obese diabetic (NOD) mice injected with 500 micrograms of both CD 4 and CD 8 antibodies at 5 weeks of age did not develop insulitis until 18 weeks of age, 12 weeks later than the onset of insulitis in parallel uninjected controls. Injection with both antibodies at 2 weeks or 4 weeks of age protected from insulitis for 10 and 14 weeks respectively. Insulitis was not delayed in onset in animals injected at any age with one antibody only, or who were injected at birth. Injection after the onset of insulitis achieved partial but incomplete clearing of islet infiltrates. Salivary gland infiltrates (sialitis) were also delayed in animals injected with both CD 4 and CD 8 antibodies though the degree of protection was less pronounced than that seen for insulitis.