{"id":862,"date":"2010-05-15T06:13:01","date_gmt":"2010-05-15T06:13:01","guid":{"rendered":"http:\/\/blogs.sld.cu\/reumatologia\/?p=862"},"modified":"2020-09-26T06:36:35","modified_gmt":"2020-09-26T06:36:35","slug":"terapia-biologica-en-la-ar-centro-de-reumatologia","status":"publish","type":"post","link":"https:\/\/blogs.sld.cu\/reumatologia\/2010\/05\/15\/terapia-biologica-en-la-ar-centro-de-reumatologia\/","title":{"rendered":"Terapia biol\u00f3gica en la AR: Centro de Reumatolog\u00eda"},"content":{"rendered":"

Caracterizaci\u00f3n de Mol\u00e9culas HLA tipo II y evaluaci\u00f3n de citocinas en pacientes cubanos con Artritis Reumatoide<\/a><\/p>\n

Revista Cubana de reumatolog\u00eda<\/p>\n

Vol. 8, No. 9-10 (2006)<\/p>\n

Mar\u00eda del Carmen Dom\u00ednguez Horta,<\/em> N. Lorenzo, <\/em>A. Barbera, <\/em>Mar\u00eda Victoria Hernandez, <\/em>Ana Mar\u00eda Torres Lima, <\/em>M. Nazabal, <\/em>H. Camacho, <\/em>I. Hern\u00e1ndez, <\/em>Neisy Ortiz, <\/em>V. Morera, <\/em>G. Padr\u00f3n<\/em><\/p>\n

Resumen<\/strong><\/p>\n

La artritis reumatoide es una enfermedad de etiolog\u00eda multifactorial, que involucra la presencia de factores gen\u00e9ticos, ambientales, inmunol\u00f3gicos y hormonales. En los \u00faltimos a\u00f1os se ha establecido una asociaci\u00f3n entre la predisposici\u00f3n a padecer esta enfermedad y la existencia de determinados haplotipos del HLA clase II. El objetivo fundamental de este trabajo es la caracterizaci\u00f3n del polimorfismo de las mol\u00e9culas HLA-DQB1 y HLA-DRB de un grupo de pacientes cubanos con Artritis Reumatoide, adem\u00e1s analizar una posible correlaci\u00f3n entre los niveles de varias citocinas proinflamatorias en un grupo de estos pacientes, con los alelos HLA tipo II genotipados, el sexo y el tiempo de diagnosticada la enfermedad. El estudio se llev\u00f3 a cabo en 50 pacientes cubanos con el diagn\u00f3stico de artritis reumatoide y un grupo control, compuesto de 211 donantes sanos. Los haplotipos HLA-DQ y HLA-DRB1 fueron determinados a trav\u00e9s de la reacci\u00f3n en cadena de la polimerasa. La cuantificaci\u00f3n de las citocinas se realiz\u00f3 empleando inmuno-ensayos comerciales. Los resultados obtenidos en este an\u00e1lisis indican que los alelos con un radio de la raz\u00f3n de probabilidades superior a 2 fueron para el caso de la mol\u00e9cula HLA-DQB1: HLADQB1 *03 y *06, y para la mol\u00e9cula HLA-DRB1 los alelos: *01, *04, *09 y *10. Encontramos adem\u00e1s que los niveles de la citocina interferon ganma est\u00e1n significativamente aumentados en los pacientes con menos tiempo de diagnosticada la enfermedad. Este trabajo constituye el primer reporte de caracterizaci\u00f3n de las mol\u00e9culas HLA tipo II, a trav\u00e9s de t\u00e9cnicas moleculares, en pacientes cubanos con artritis reumatoide<\/p>\n

Palabras claves:<\/strong> Artritis Reumatoide; HLA-DQ; HLA-DR; IFN.<\/p>\n

<\/p>\n

\n

Un ligando pept\u00eddico alterado como novedoso f\u00e1rmaco para el tratamiento de la artritis idiop\u00e1tica juvenil<\/a><\/p>\n

Revista Cubana de Reumatolog\u00eda<\/p>\n

Vol. 11, No. 13-14 (2009)<\/p>\n

Lorenzo P\u00e9rez Noraylis, Barber\u00e1 Betancourt Ariana, Cantera Oceguera Dolores, Alonso Amarys, Chall Elsy, Franco Lourdes, Padr\u00f3n Palomares Ram\u00f3n Gabriel, Dom\u00ednguez Horta Mar\u00eda del Carmen<\/em><\/p>\n

Resumen<\/strong><\/p>\n

La inducci\u00f3n de tolerancia perif\u00e9rica usando autoant\u00edgenos constituye una terapia muy atractiva para las enfermedades autoinmunes. El objetivo de este trabajo es demostrar el potencial terap\u00e9utico de un ligando pept\u00eddico alterado derivado de la prote\u00edna de estr\u00e9s t\u00e9rmico de 60 humana en el modelo animal de artritis inducida por adyuvante y en ensayos in vitro con c\u00e9lulas mononucleares en pacientes con artritis idiop\u00e1tica juvenil. Se comprob\u00f3 a trav\u00e9s del examen cl\u00ednico e histopatol\u00f3gico de las ratas, que el p\u00e9ptido inhibe eficientemente el desarrollo de la enfermedad; adem\u00e1s, la terapia de los animales con el p\u00e9ptido induce una reducci\u00f3n significativa de la expresi\u00f3n del TNF alfa. Por otra parte, la estimulaci\u00f3n con ligandos pept\u00eddicos alterados de las c\u00e9lulas mononucleares de pacientes con artritis idiop\u00e1tica juvenil increment\u00f3 significativamente la frecuencia de c\u00e9lulas T reguladoras CD4+CD25+Foxp3+. Estos resultados avalan el potencial terap\u00e9utico de esta mol\u00e9cula para el tratamiento de la artritis idiop\u00e1tica juvenil y otras enfermedades autoinmunes.<\/p>\n

Palabras clave:<\/strong> ligando pept\u00eddico, artritis idiop\u00e1tica juvenil, c\u00e9lulas T reguladoras<\/p>\n

\n

Observaciones cl\u00ednicas en pacientes con artritis reumatoide tratados con anticuerpo monoclonal T1h (anti CD6)<\/a><\/p>\n

Revista Cubana de reumatolog\u00eda<\/p>\n

Vol. 11, No. 13-14 (2009)<\/p>\n

Dinorah Marisabel Prada Hern\u00e1ndez, Claudino Molinero Rodr\u00edguez, Roberto Vicente Torres Moya, Ana Marta L\u00f3pez Mantec\u00f3n, Jorge Alexis G\u00f3mez Morej\u00f3n, Isabel Mar\u00eda Hern\u00e1ndez Cuellar, Jos\u00e9 Pedro Mart\u00ednez Larrarte, Yusim\u00ed Reyes Pineda, Joel Rodr\u00edguez Milera<\/em><\/p>\n

\n

Resumen<\/h4>\n
En el presente trabajo se exponen los resultados preliminares de 5 pacientes con artritis reumatoide tratados con anticuerpo monoclonal T1h (anti-CD6) utilizando un nivel de dosis de 0.4 mg\/kg\/dosis. En 4 de los 5 pacientes estudiados se logr\u00f3 respuesta cl\u00ednica ACR > 20 a las 24 semanas de evaluaci\u00f3n. Hubo una disminuci\u00f3n importante en el n\u00famero de articulaciones dolorosas e inflamadas m\u00e1s marcado en estas \u00faltimas. En la evaluaci\u00f3n del Health Assessment Questionnaire-Cuba a las 24 semanas el 60% de los pacientes presentaron discapacidad ligera y 1 paciente sin discapacidad (Health Assessment Questionnaire = 0). Los eventos adversos m\u00e1s frecuentes fueron fiebre y escalofr\u00edos de leve intensidad, No se presentaron infecciones oportunistas asociadas a la administraci\u00f3n.<\/div>\n<\/div>\n
\n

Palabras clave: <\/strong>artritis reumatoide; anticuerpo monoclonal; T1h anti-CD6; Health Assessment Questionnaire; HAQ-CU<\/p>\n

\n

Artritis Reumatoide: beneficios cl\u00ednicos observados en pacientes tratados con anticuerpo monoclonal Itolizumab. (T1h mAB), 2 a\u00f1os despu\u00e9s de recibir tratamiento<\/a><\/p>\n

Revista Cubana de reumatolog\u00eda<\/p>\n

Vol. 13, No. 17 (2011)<\/p>\n

Dinorah Marisabel Prada Hern\u00e1ndez, Norge Rosabal Callejas, Claudino Molinero Rodr\u00edguez, Jorge Alexis G\u00f3mez Morej\u00f3n, Isabel Marisabel Hern\u00e1ndez Cuellar, Ana Marta L\u00f3pez Mantec\u00f3n, Joel Rodr\u00edguez Milera, Justo M\u00e9ndez Rodr\u00edguez, Jos\u00e9 \u00c1ngel Pereira Torres, Patricia Hern\u00e1ndez Casa\u00f1a, Yisel \u00c1vila Albuerne<\/em><\/p>\n

\n

Resumen<\/strong><\/p>\n

La perdida de \u00a0la capacidad \u00a0 \u00a0funcional \u00a0 es \u00a0junto \u00a0 con \u00a0el \u00a0dolor \u00a0 la \u00a0consecuencia \u00a0m\u00e1s temida de los pacientes \u00a0con \u00a0artritis reumatoide, por \u00a0lo que \u00a0la \u00a0valoraci\u00f3n \u00a0de \u00a0la discapacidad es un desenlace \u00a0muy importante \u00a0en la \u00a0evaluaci\u00f3n de estos enfermos.Objetivos: Determinar los beneficios cl\u00ednicos en pacientes con artritis reumatoide que recibieron inicialmente tratamiento con Itolucimab y que posteriormente utilizaron \u00a0drogas modificadoras de la enfermedad.M\u00e9todo: De 22 \u00a0pacientes con artritis reumatoide activa que recibieron tratamiento en el Servicio de Referencia Nacional de Enfermedades Reum\u00e1ticas con anticuerpo monoclonal anti CD6 (Itolucimab), desarrollado \u00a0en el \u00a0Centro de Inmunolog\u00eda Molecular (CIM) en \u00a0nuestro pa\u00eds, en esquemas de dosis de (0.1- 0.2 -0.4-0.8 mg \/Kg\/dosis) durante 12 semanas, 15 pacientes cumplieron los \u00a0criterios de inclusi\u00f3n. Recopil\u00e1ndose en cada uno de ellos datos demogr\u00e1ficos y la valoraci\u00f3n \u00a0de variables cl\u00ednicas como numero de articulaciones dolorosas, inflamadas, escala visual del dolor, valoraci\u00f3n de la enfermedad por el paciente y el m\u00e9dico y la evaluaci\u00f3n de la capacidad funcional, en diferentes momentos del estudio. Seg\u00fan el comportamiento de la enfermedad al concluir el EC se establecieron nuevas estrategias de tratamiento individualizadas con \u00a0las DMARs. \u00a0 Los datos se agrupan seg\u00fan frecuencias, medidas de resumen y de dispersi\u00f3n, porcentajes, medias.\u00a0Resultados: Predomin\u00f3 el sexo femenino (93.3%), con una edad media de 56 a\u00f1os, y una media de duraci\u00f3n de la enfermedad de 6 a\u00f1os. Observ\u00e1ndose \u00a0una mejor\u00eda significativa de todas las variables cl\u00ednicas evaluadas \u00a0a los 2 a\u00f1os de seguimiento. En la evaluaci\u00f3n inicial predominaron los pacientes con discapacidad moderada y severa. A los 2 a\u00f1os, el 73% de la serie se encuentra sin discapacidad, ninguno con discapacidad moderada o severa.\u00a0Conclusiones: Las intervenciones terap\u00e9uticas utilizadas en nuestros pacientes en los diferentes momentos del estudio han contribuido de una forma u otra al control de la enfermedad, \u00a0mejorar la calidad de vida \u00a0y su incorporaci\u00f3n a la sociedad<\/p>\n<\/div>\n

\n

Palabras clave:<\/strong> artritis reumatoide; anticuerpo monoclonal; Itolizumab; t1h mAB<\/p>\n<\/div>\n<\/div>\n

\n

A clinical exploratory study with itolizumab<\/strong>, an anti-CD6 monoclonal antibody, in patients with rheumatoid arthritis<\/a><\/p>\n

Results Immunol 2012 Nov 21;2:204-11.<\/p>\n

doi: 10.1016\/j.rinim.2012.11.001<\/p>\n

Pedro C Rodriguez, Roberto Torres-Moya, Gil Reyes, Claudino Molinero, Dinorah Prada, Ana M Lopez, Isabel M Hernandez, Maria V Hernandez, Jose P Martinez, Xochel Hernandez, Angel Casaco, Mayra Ramos, Yisel Avila, Yinet Barrese, Enrique Montero, Patricia Hernandez<\/em><\/p>\n

Abstract<\/strong><\/p>\n

T cells are involved in the pathogenesis of rheumatoid arthritis (RA). CD6 is a co-stimulatory molecule, predominantly expressed on lymphocytes, that has been linked to autoreactive responses. The purpose of this study was to evaluate the safety, immunogenicity and preliminary efficacy of itolizumab, a humanized anti-CD6 monoclonal antibody, in patients with active rheumatoid arthritis. Fifteen patients were enrolled in a phase I, open-label, dose-finding study. Five cohorts of patients received a weekly antibody monotherapy with a dose-range from 0.1 to 0.8 mg\/kg. Itolizumab showed a good safety profile, with no severe or serious adverse events reported so far. No signs or symptoms associated with immunosuppression were observed in the study. Objective clinical responses were achieved in more than 80% of patients after treatment completion, and these responses tend to be sustained afterwards. This clinical study constitutes the first evidence of the safety and positive clinical effect of a monotherapy using an anti-CD6 antibody in patients with rheumatoid arthritis.<\/p>\n

Keywords:<\/strong> ACR, American College of Rheumatology; AE, adverse events; CD6; CRP, C reactive protein; DMARD, disease-modifying antirheumatic drug; ESR, eritrosedimentation rate; Exploratory study; NSAIDs, nonsteroidal antiinflammatory drugs; RA, rheumatoid arthritis; RF, rheumatoid factor; Rheumatoid arthritis; SAE, serious adverse event.; T lymphocyte; iv, intravenous; mAbs, monoclonal antibodies.<\/p>\n

\n

Therapeutic effect of two altered peptide ligands derived from the human heat shock protein 60 in experimental models of rheumatoid arthritis<\/a><\/p>\n

Biotecnolog\u00eda Aplicada<\/p>\n

2013;30:153-156<\/p>\n

Mar\u00eda del C Dom\u00ednguez, Norailys Lorenzo, Ariana Barber\u00e1, Gabriel Padr\u00f3n, Ana Mar\u00eda Torres, Mar\u00eda V Hern\u00e1ndez, Isabel Hern\u00e1ndez, Rafael Gil, Aniel S\u00e1nchez, Vladimir Besada, Luis J Gonz\u00e1lez, Hilda Garay, Osvaldo Reyes, Ever P\u00e9rez, Matilde L\u00f3pez, Yuliet Mazola, Karelia Cosme, Julio Ancizar<\/em><\/p>\n

Abstract<\/strong><\/p>\n

Induction of immune tolerance as therapeutic approach for autoimmune diseases constitutes a current research focal point. In this sense, two Altered Peptide Ligands (APLs) were evaluated for the induction of peripheral tolerance in patients with Rheumatoid Arthritis (RA). Two novel T cell epitopes from human heat-shock protein 60 (hHsp60), an autoantigen involved in the pathogenesis of RA, were identified by bioinformatics tools and two APLs were designed from these epitopes (APL-1 and APL-2). APL-1 increases the proportions of the CD4+CD25highFoxP3+ regulatory T cells in ex vivo assays using PBMCs isolated from RA patients. While, APL-2 increased the IL-10 level and suppressed IL-17 secretion, and induces the activation of T cells through his ability to modify cell cycle phase\u2019s distribution of CD4+ T cells from RA patients. Additionally, the therapeutic effect of these APLs in two animal models was evaluated: adjuvant induced arthritis (AA) in Lewis rat and collagen induced arthritis (CIA) in DBA\/1 mice. Our approach was compared to metotrexate (MTX), the treatment of reference for RA, in CIA model. Clinical score, TNF-\u03b1 levels and histopathology were monitored. Both APLs efficiently inhibited the course of AA and CIA, with significant reduction of the clinical and histopathology scores. The therapeutic effect induced by APLs is mediated by different molecular mechanisms, associ- ated with immunologic tolerance. These results indicate a therapeutic potentiality of these APLs and support further investigation for treatment of RA. This study won the Annual Award of the Academy of Sciences of Cuba in 2012.<\/p>\n

Keywords: <\/strong>rheumatoid arthritis, altered peptide ligand, hHsp60, immune tolerance, regulatory T cells<\/p>\n

\n

Tratamiento actual de la artritis reumatoide. Perspectivas para el desarrollo de las terapias ant\u00edgeno-espec\u00edficas<\/a><\/p>\n

Biotecnolog\u00eda Aplicada<\/p>\n

2012;29:137-145<\/p>\n

Ariana Barber\u00e1, Noraylis Lorenzo, Mar\u00eda del Carmen Dom\u00ednguez<\/em><\/p>\n

Resumen<\/strong><\/p>\n

La artritis reumatoide es una enfermedad degenerativa caracterizada por la inflamaci\u00f3n cr\u00f3nica de las articulaciones perif\u00e9ricas. La primera l\u00ednea de tratamiento de esta enfermedad implica el uso de potentes antinflamatorios y drogas que provocan una supresi\u00f3n global del sistema inmune. Sin embargo, estos f\u00e1rmacos no inducen una remisi\u00f3n sostenida, y su uso puede causar una inmunosupresi\u00f3n importante que puede conducir a complicaciones. Por ello es necesario el desarrollo de nuevas modalidades terap\u00e9uticas para esta enfermedad. Las terapias ant\u00edgeno-espec\u00edficas suprimen las c\u00e9lulas patog\u00e9nicas, sin afectar la propiedad del sistema inmune de responder ante las infecciones. Las prote\u00ednas de estr\u00e9s t\u00e9rmico son candidatas promisorias en esta modalidad de tratamiento. Aunque se ha avanzado en el desarrollo de terapias ant\u00edgeno-espec\u00edficas eficientes en modelos animales con excelentes resultados, ha sido dif\u00edcil trasladarlas a los seres humanos. El uso combinado de las terapias ant\u00edgeno-espec\u00edficas con los f\u00e1rmacos actuales puede ser una estrategia muy atractiva en el futuro cercano para lograr la remisi\u00f3n completa de la enfermedad. Algunas de estas combinaciones de tratamiento ya han comenzado a evaluarse en modelos animales y en pacientes con artritis reumatoide.<\/p>\n

Palabras clave:<\/strong> artritis reumatoide, c\u00e9lulas T reguladoras, terapia biol\u00f3gica, citocina proinflamatoria,<\/p>\n

terapia combinada<\/p>\n

\n

Therapeutic effect of two altered peptide ligands derived from the human heat shock protein 60 in experimental models of rheumatoid arthritis<\/a><\/p>\n

Biotecnolog\u00eda Aplicada 2013;30:153-156<\/p>\n

Mar\u00eda del C Dom\u00ednguez, Norailys Lorenzo, Ariana Barber\u00e1, Gabriel Padr\u00f3n, Ana Mar\u00eda Torres, Mar\u00eda V Hern\u00e1ndez, Isabel Hern\u00e1ndez, Rafael Gil, Aniel S\u00e1nchez, Vladimir Besada, Luis J Gonz\u00e1lez, Hilda Garay, Osvaldo Reyes,\u00a0 Ever P\u00e9rez, Matilde L\u00f3pez, Yuliet Mazola, Karelia Cosme, Julio Ancizar<\/em><\/p>\n

Induction of immune tolerance as therapeutic approach for autoimmune diseases constitutes a current research focal point. In this sense, two Altered Peptide Ligands (APLs) were evaluated for the induction of peripheral tolerance in patients with Rheumatoid Arthritis (RA). Two novel T cell epitopes from human heat-shock protein 60 (hHsp60), an autoantigen involved in the pathogenesis of RA, were identifi ed by bioinformatics tools and two APLs were designed from these epitopes (APL-1 and APL-2). APL-1 increases the proportions of the CD4+CD25highFoxP3+ regulatory T cells in ex vivo assays using PBMCs isolated from RA patients. While, APL-2 increased the IL-10 level and suppressed IL-17 secretion, and induces the activation of T cells through his ability to modify cell cycle phase\u2019s distribution of CD4+ T<\/p>\n

cells from RA patients. Additionally, the therapeutic effect of these APLs in two animal models was evaluated: adjuvant induced arthritis (AA) in Lewis rat and collagen induced arthritis (CIA) in DBA\/1 mice. Our approach was compared to metotrexate (MTX), the treatment of reference for RA, in CIA model. Clinical score, TNF-\u03b1 levels and histopathology were monitored. Both APLs effi ciently inhibited the course of AA and CIA, with signifi cant reduction of the clinical and histopathology scores. The therapeutic effect induced by APLs is mediated by different molecular mechanisms, associated with immunologic tolerance. These results indicate a therapeutic potentiality of these APLs and support further investigation for treatment of RA. This study won the Annual Award of the Academy of Sciences of Cuba in 2012.<\/p>\n

Keywords: <\/strong>rheumatoid arthritis, altered peptide ligand, hHsp60, immune tolerance, regulatory T cells,<\/p>\n

collagen induced arthritis, adjuvant induced arthritis<\/p>\n

\n

APL-2, an altered peptide ligand derived from heat-shock protein 60, induces interleukin-10 in peripheral blood mononuclear cell derived from juvenile idiopathic arthritis patients and downregulates the inflammatory response in collagen-induced arthritis model<\/a><\/p>\n

Clin Exp Med<\/p>\n

DOI 10.1007\/s10238-014-0273-x<\/p>\n

Norailys Lorenzo, Dolores Cantera, Ariana Barbera, Amaris Alonso, Elsy Chall, Lourdes Franco, Julio Ancizar, Yanetsy Nun\u02dcez, Fiorella Altruda, Lorenzo Silengo, Gabriel Padro\u00b4n, Maria del Carmen Dominguez<\/em><\/p>\n

Abstract <\/strong><\/p>\n

Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases characterized by autoimmune arthritis of unknown cause with onset before age of 16 years. Methotrexate provides clinical benefits in JIA. For children who do not respond to methotrexate, treatment with anti-tumor necrosis factor (TNF)-a is an option. However, some patients do not respond or are intolerant to anti-TNF therapy. Induction of peripheral tolerance has long been considered a promising approach to the treatment of chronic autoimmune diseases. We aimed to evaluate the potentialities of two altered peptide ligands (APLs) derived from human heat-shock protein 60, an autoantigen involved in the pathogenesis of autoimmune arthritis, in JIA patients. Interferon (IFN)-c, TNF-a and interleukin (IL)-10 levels were determined in ex vivo assays using peripheral blood mononuclear cells (PBMC) from these patients. Wild-type peptide and one of these APLs increased IFN-c and TNF-a levels. Unlike, the other APLs (called APL2) increased the IL-10 level without affecting IFN-c and TNF-a levels. On the other hand, APL2 induces a marked activation of T cells since it transforms cell cycle phase\u2019s distribution of CD4? T cells from these patients. In addition, we evaluated the therapeutic effect of APL2 in collagen-induced arthritis model. Therapy with APL2 reduced arthritis scores and histological lesions in mice. This effect was associated to a decrease in TNF-a and IL-17 levels. These results indicate a therapeutic potentiality of APL2 for JIA.<\/p>\n

Keyword: <\/strong>Altered peptide ligand Juvenile idiopathic arthritis Collagen-induced arthritis Tolerance Interleukin-10<\/p>\n

\n

An altered peptide ligand corresponding to a novel epitope from heat-shock protein 60 induces regulatory T cells and suppresses pathogenic response in an animal model of adjuvant-induced arthritis<\/a><\/p>\n

Autoimmunity, 2011; Early Online: 1\u201312<\/p>\n

DOI: 10.3109\/08916934.2010.550590<\/p>\n

Maria Del Carmen Dom\u00ednguez, Noraylis Lorenzo, Ariana Barbera, Guillaume Darrasse-Jeze, Maria Victoria Hern\u00e1dez, Ana Torres, Isabel Herna\u00b4Ndez, Rafael Gil, David Klatzmann,\u00a0 Gabriel Padr\u00f3n<\/em><\/p>\n

Abstract<\/strong><\/p>\n

Induction of immune tolerance as therapeutic approach for autoimmune diseases constitutes a current research focal point. In this sense, we aimed to evaluate an altered peptide ligand (APL) for induction of peripheral tolerance in patients with rheumatoid arthritis (RA). A novel T-cell epitope from human heat-shock protein 60 (Hsp60), an autoantigen involved in the pathogenesis of RA, was identified by bioinformatics tools and an APL was design starting from this epitope. We investigated the ability of this APL for inducing regulatory T cells (Treg cells) in mice and evaluated the therapeutic effect of this peptide in an adjuvant-induced arthritis (AA) rat model. Clinical score, TNFa levels and histopathology were monitored, as well as the capacity of this APL for inducing Treg cells. Finally, the potentialities of the APL for inducing Treg cells were evaluated in ex vivo assays using mononuclear cells isolated from peripheral blood (PBMC). The APL induced an increase of the proportions of Treg cells in the draining lymph nodes of the injected site in mice. The APL efficiently inhibited the course of AA, with significant reduction of the clinical and histopathology score. This effect was associated with an increase of the proportions of Treg cells and a decrease of TNFa levels in spleen. Finally, stimulation of PBMCs from RA patients by the APL increases the proportions of the CD4\u00feCD25highFoxP3\u00fe Treg cells. These results indicate a therapeutic potentiality of APL and support further investigation of this candidate drug for treatment of RA.<\/p>\n

Keywords:<\/strong> Rheumatoid arthritis, APL, HSP60, tolerance, regulatory T cells<\/p>\n

\n

Therapeutic effect of an altered peptide ligand derived from heat-shock protein 60 by suppressing of inflammatory cytokines secretion in two animal models of rheumatoid arthritis<\/a><\/p>\n

Autoimmunity, 2012; Early Online: 1\u201311<\/p>\n

DOI: 10.3109\/08916934.2012.697592<\/p>\n

N. Lorenzo, A. Barbera, MC. Dom\u00ednguez, AM. Torres, MV. Hern\u00e1ndez, I. Hern\u00e1ndez, R. Gil, H. Garay, O. Reyes, F. Altruda, L. Silengo, G. Padr\u00f3n<\/em><\/p>\n

Abstract<\/strong><\/p>\n

Rheumatoid arthritis is a systemic autoinmmune disease mediated by T cells. Productive engagement of T cell receptors by major histocompatibility complex-peptide leads to proliferation, differentiation and the definition of effector functions. Altered peptide ligands (APL) generated by amino acid substitutions in the antigenic peptide have diverse effects on T cell response.We predicted a novel T cell epitope from human heat-shock protein 60, an autoantigen involved in the pathogenesis of rheumatoid arthritis. Three APLs were designed from this epitope and it was demostrated that these peptides induce the activation of T cells through their ability to modify cell cycle phase\u2019s distribution of CD4 \u00fe T cells from RA patients. Also, IL-17, TNF-a and IL-10 levels were determined in PBMC from these patients. Unlike the wild-type peptide and the other two APLs, APL2 increased the IL-10 level and suppressed IL-17 secretion in these assays. Therapeutic effect of this APL inadjuvant arthritis (AA) and collagen-induced arthritis (CIA) models was also evaluated. Clinical score, histopathology, inflammatory and regulatory cytokine concentration were monitored in the animals. APL2 efficiently inhibited the progression of AA and CIA with a significant reduction of the clinical and histopathogic score. Therapeutic effect of APL2 on CIA was similar to that obtained with MTX; the standard treatment for RA. This effect was associated with a decrease of TNF-a and IL-17 levels. These results suggest that the therapeutic effect of APL2 is mediated in part by down-regulation of inflammatory cytokines and support the potential use of APL2 as a therapeutic drug in RA patients.<\/p>\n

Keywords:<\/strong> Rheumatoid Arthritis, AA, HSP60, CIA, APL, inflammatory cytokines<\/p>\n

\n

Phase I Clinical Trial with a Novel Altered Peptide Ligand Derived from Human Heat-Shock Protein 60 for Treatment of Rheumatoid Arthritis: Safety, Pharmacokinetics and Preliminary Therapeutic Effects<\/a><\/p>\n

J Clin Trials 2018, 8:1<\/p>\n

DOI: 10.4172\/2167-0870.1000339<\/p>\n

Dinorah Prada, Jorge G\u00f3mez, Norailys Lorenzo, Oreste Corrales, Ana L\u00f3pez, Evelio Gonz\u00e1lez, Ania Cabrales, Yusimy Reyes, Yuliet Bermudez, Yisel Avila, Lina P\u00e9rez, Claudio Molinero, Osmel Martinez, Leonardo Oramas, Yaysel Mi\u00f1oso, Yassel Ramos, Hilda Garay, Ever P\u00e9rez, Matilde L\u00f3pez, Osvaldo Reyes, Yolanda Cruz, Alfredo Hern\u00e1ndez, Cabal Carlos, Vladimir Besada, Luis Javier Gonz\u00e1lez, Gabriel Padr\u00f3n, and Maria del Carmen Dom\u00ednguez Horta<\/em><\/p>\n

Abstract<\/strong><\/p>\n

Background:<\/strong> CIGB 814 is an Altered Peptide Ligand (APL) from a CD4+ T-cell epitope of human heat shock protein 60 (HSP60), an auto-antigen involved in the pathogenesis of rheumatoid arthritis (RA). It induced mechanisms associated with restoration of peripheral tolerance in preclinical studies. This clinical trial was<\/p>\n

conducted to assess safety and pharmacokinetics (PK) of CIGB-814 in patients with RA.<\/p>\n

Method:<\/strong> 20 patients with moderated active RA were included in an open label trial. Sequential dose-escalation of 1, 2.5 and 5 mg of CIGB-814 was studied. Consecutive groups of six, five and nine patients received a subcutaneous dose weekly of the peptide during the first month and one dose monthly during the next five months.<\/p>\n

Clinical response in patients was evaluated according to the American College of Rheumatology (ACR) and Disease Activity Score in 28 joints (DAS 28) criteria. Function and health-related quality of life, quantification of proinflammatory cytokines and radiographic changes in patients by magnetic resonance imaging (MRI) were also<\/p>\n

assessed.<\/p>\n

Result:<\/strong> The treatment was well tolerated at all doses. Only mild events were observed. PK study showed that CIGB-814 reached the maximum concentration in plasma in 30 min and was cleared mostly after 4 h. CIGB-814 reduced disease activity and MRI score in patients. This effect was less marked with the dose of 5 mg. Five and<\/p>\n

eleven out of 18 patients achieved ACR 50 and ACR 70 respectively at the end of the treatment. In addition, patients showed decreases of DAS28 scores, during treatment and at the end of the follow-up. This therapy improved function and health-related quality of life of patients. CIGB-814 significantly decreased interleukin (IL)-17 in patients treated with 2.5 mg. Therapy with 1 mg and 2.5 mg of CIGB-814 led to significant reduction of interferon gamma (IFN-\u03b3).<\/p>\n

Conclusion: <\/strong>Phase I concluded showing safety of CIGB-814. The PK profile revealed that peptide is cleared from plasma very rapidly. Results indicated preliminary evidences of clinical efficacy and support further clinical investigation of this peptide for treatment of RA.<\/p>\n

Keywords:<\/strong> APL; HSP60; Rheumatoid arthritis; Clinical trial; Safety<\/p>\n

\n

CIGB-814, an altered peptide ligand derived from human heat-shock protein 60, decreases anti-cyclic citrullinated peptides antibodies in patients with rheumatoid arthritis<\/a><\/p>\n

Clin Rheumatol <\/span>2019 Mar;38(3):955-960.<\/span><\/p>\n

doi: 10.1007\/s10067-018-4360-3 <\/span><\/p>\n

Oreste Corrales, Laura Hern\u00e1ndez, Dinorah Prada, Jorge G\u00f3mez, Yusimy Reyes, Ana Marta L\u00f3pez, Luis Javier Gonz\u00e1lez, Maria Del Carmen Dom\u00ednguez Horta <\/em><\/p>\n

Abstract<\/strong><\/p>\n

Rheumatoid arthritis (RA) is a chronic T cell-mediated autoimmune disease. Serum autoantibodies against cyclic citrullinated peptides (anti-CCP) are significant markers for diagnosis and prognosis of this disease. Induction of immune tolerance as therapeutic approach for RA constitutes a current research focal point. In this sense, we carried out a phase I clinical trial in RA patients with a new therapeutic candidate (called CIGB-814); which induced mechanisms associated with restoration of peripheral tolerance in preclinical studies. CIGB 814 is an altered peptide ligand (APL), derived from a CD4+ T cell epitope of human heat-shock protein 60 (HSP60), an autoantigen involved in the pathogenesis of RA. Twenty patients with moderate disease activity were included in this open label trial. Sequential dose-escalation of 1, 2.5 and 5 mg of CIGB-814 was studied. Consecutive groups of six, five, and nine patients received a subcutaneous dose weekly of the peptide during the first month and one dose monthly during the next 5 months. The peptide was well tolerated and reduced disease activity. Here, we reported the quantification of anti-CCP antibodies during the treatment with this APL and in the follow-up stage. Anti-CCP antibodies were quantified in the plasma from patients by a commercial enzyme immunoassay at baseline (T0) and at weeks 28 and 48. Results showed that CIGB-814 induced a significant reduction of anti-CCP antibodies. In addition, this decrease correlated with clinical improvement in patients assessed by Disease Activity Score in 28 joints (DAS28) criteria. These findings reinforce the therapeutic potential of CIGB-814.<\/p>\n

Keywords:<\/strong> APL; Anti-CCP; CIGB-814; HSP60; Rheumatoid arthritis.<\/p>\n

\n

 <\/p>\n","protected":false},"excerpt":{"rendered":"

Caracterizaci\u00f3n de Mol\u00e9culas HLA tipo II y evaluaci\u00f3n de citocinas en pacientes cubanos con Artritis Reumatoide Revista Cubana de reumatolog\u00eda Vol. 8, No. 9-10 (2006) Mar\u00eda del Carmen Dom\u00ednguez Horta, N. Lorenzo, A. Barbera, Mar\u00eda Victoria Hernandez, Ana Mar\u00eda Torres Lima, M. Nazabal, H. Camacho, I. Hern\u00e1ndez, Neisy Ortiz, V. Morera, G. Padr\u00f3n Resumen La […]<\/p>\n","protected":false},"author":140,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[165,164,69,9,63,166,160,159,26],"tags":[168,167,169],"_links":{"self":[{"href":"https:\/\/blogs.sld.cu\/reumatologia\/wp-json\/wp\/v2\/posts\/862"}],"collection":[{"href":"https:\/\/blogs.sld.cu\/reumatologia\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/blogs.sld.cu\/reumatologia\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/blogs.sld.cu\/reumatologia\/wp-json\/wp\/v2\/users\/140"}],"replies":[{"embeddable":true,"href":"https:\/\/blogs.sld.cu\/reumatologia\/wp-json\/wp\/v2\/comments?post=862"}],"version-history":[{"count":1,"href":"https:\/\/blogs.sld.cu\/reumatologia\/wp-json\/wp\/v2\/posts\/862\/revisions"}],"predecessor-version":[{"id":863,"href":"https:\/\/blogs.sld.cu\/reumatologia\/wp-json\/wp\/v2\/posts\/862\/revisions\/863"}],"wp:attachment":[{"href":"https:\/\/blogs.sld.cu\/reumatologia\/wp-json\/wp\/v2\/media?parent=862"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/blogs.sld.cu\/reumatologia\/wp-json\/wp\/v2\/categories?post=862"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/blogs.sld.cu\/reumatologia\/wp-json\/wp\/v2\/tags?post=862"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}