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1.
J Crohns Colitis ; 10(6): 641-9, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26802087

RESUMO

BACKGROUND AND AIMS: AVX-470 is an orally administered, bovine-derived, anti-tumour necrosis factor (TNF) antibody with local activity in the gastrointestinal tract. In the first-in-human clinical trial of AVX-470 in active ulcerative colitis, we evaluated inflammatory biomarkers in colon tissue as measures of disease activity and early response to treatment. METHODS: Thirty-six patients received active drug (AVX-470 at 0.2, 1.6 or 3.5g/day) or placebo over 4 weeks. Colon biopsy samples were collected from 5 regions of colon at baseline and week 4. Tissue inflammatory biomarkers were evaluated by immunohistochemistry and quantitative reverse transcription-polymerase chain reaction (qRT-PCR), epithelial cell apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) and bovine immunoglobulin by immunohistochemistry and mass spectrometry. Endoscopic activity (Ulcerative Colitis Endoscopic Index of Severity [UCEIS]) at colonoscopy was assessed in each colonic region by a central reader. RESULTS: Bovine immunoglobulin was observed in mucosal tissue before and after dosing in lamina propria and submucosal layers of biopsy tissue. Baseline levels of TNF, myeloperoxidase (MPO), CD68 and interleukin (IL)-1ß and, to a lesser extent, IL-6 mRNA were 2- to 3-fold higher in distal vs proximal colon tissue, corresponding to the 2- to 3-fold differences in baseline severities of endoscopic scores. Reductions of >10-fold in TNF and, to lesser extents, in MPO and epithelial cell apoptosis were observed in proximal and distal colon biopsies after 4 weeks of AVX-470 3.5g/day treatment. Reductions in TNF scores were correlated with changes in MPO and CD3 immunohistochemistry scores. CONCLUSIONS: These results are consistent with anti-TNF activity of orally administered AVX-470 in colon mucosal tissue in ulcerative colitis patients and demonstrate the utility of tissue biomarkers in assessing disease and treatment response in early clinical studies. CLINICAL TRIAL REGISTRATION NUMBER: This trial was registered with Clinicaltrials.gov as study NCT01759056 and with EudraCT as study 2012-004859-27.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Anticorpos/uso terapêutico , Biomarcadores/metabolismo , Colite Ulcerativa/tratamento farmacológico , Colo/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Administração Oral , Adolescente , Adulto , Idoso , Colite Ulcerativa/diagnóstico por imagem , Colite Ulcerativa/metabolismo , Colonoscopia , Método Duplo-Cego , Esquema de Medicação , Monitoramento de Medicamentos , Feminino , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Índice de Gravidade de Doença , Resultado do Tratamento , Fator de Necrose Tumoral alfa/metabolismo , Adulto Jovem
2.
Inflamm Bowel Dis ; 19(11): 2273-81, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23949620

RESUMO

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract, which is currently treated with injected monoclonal antibodies specific for tumor necrosis factor (TNF). We developed and characterized AVX-470, a novel polyclonal antibody specific for human TNF. We evaluated the oral activity of AVX-470m, a surrogate antibody specific for murine TNF, in several well-accepted mouse models of IBD. METHODS: AVX-470 and AVX-470m were isolated from the colostrum of dairy cows that had been immunized with TNF. The potency, specificity, and affinity of both AVX-470 and AVX-470m were evaluated in vitro and compared with infliximab. AVX-470m was orally administered to mice either before or after induction of colitis, and activity was measured by endoscopy, histopathology, immunohistochemistry, and quantitative measurement of messenger RNA levels. Colitis was induced using either 2,4,6-trinitrobenzene sulfonate or dextran sodium sulfate. RESULTS: AVX-470 and AVX-470m were shown to be functionally comparable in vitro. Moreover, the specificity, neutralizing potency, and affinity of AVX-470 were comparable with infliximab. Orally administered AVX-470m effectively reduced disease severity in several mouse models of IBD. Activity was comparable with that of oral prednisolone or parenteral etanercept. The antibody penetrated the colonic mucosa and inhibited TNF-driven mucosal inflammation with minimal systemic exposure. CONCLUSIONS: AVX-470 is a novel polyclonal anti-TNF antibody with an in vitro activity profile comparable to that of infliximab. Oral administration of a surrogate antibody specific for mouse TNF is effective in treating mouse models of IBD, delivering the anti-TNF to the site of inflammation with minimal systemic exposure.


Assuntos
Anticorpos/administração & dosagem , Colite/tratamento farmacológico , Modelos Animais de Doenças , Imunoglobulina G/administração & dosagem , Inflamação/tratamento farmacológico , Mucosa Intestinal/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anticorpos/farmacologia , Anticorpos Monoclonais/farmacologia , Western Blotting , Bovinos , Colite/induzido quimicamente , Colite/imunologia , Sulfato de Dextrana/toxicidade , Ensaio de Imunoadsorção Enzimática , Humanos , Técnicas Imunoenzimáticas , Imunoglobulina G/farmacologia , Inflamação/etiologia , Inflamação/patologia , Infliximab , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ácido Trinitrobenzenossulfônico/toxicidade , Fator de Necrose Tumoral alfa/imunologia
3.
Dig Dis Sci ; 52(10): 2732-42, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17436088

RESUMO

Nanocrystalline silver (NPI 32101) has been demonstrated to have antimicrobial and anti-inflammatory properties. The purpose of this study was to assess the effect of NPI 32101 in a rat model of ulcerative colitis and the possible mechanisms of action of the effects observed. NPI 32101, 4 mg/kg intracolonically or 40 mg/kg orally, significantly reduced colonic inflammation compared to the placebo and no-treatment groups. Sulfasalazine (100 mg/kg), either intracolonically or orally, also reduced colonic inflammation. NPI 32101 significantly suppressed the expression of matrix metalloproteinase (MMP)-9, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-12, whereas sulfasalazine suppressed MMP-9, IL-1beta, and TNF-alpha, but not IL-12, compared to placebo. MMP-9 activity was reduced by NPI 32101 and sulfasalazine. NPI 32101 administered intracolonically or orally decreases ulcerative colitis in a rat model and is as effective as sulfasalazine. NPI 32101 treatment suppresses the expression and activity of MMP-9 and the expression of TNF-alpha, IL-1beta, and IL-12, mechanisms by which NPI 32101 may exert its anti-inflammatory effects. NPI 32101 may have therapeutic potential for treatment of ulcerative colitis.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Nanopartículas Metálicas/uso terapêutico , Prata/uso terapêutico , Animais , Benzenossulfonatos/toxicidade , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/patologia , Colo , Citocinas/metabolismo , Modelos Animais de Doenças , Vias de Administração de Medicamentos , Seguimentos , Haptenos , Imuno-Histoquímica , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Nanopartículas Metálicas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Índice de Gravidade de Doença , Prata/administração & dosagem , Resultado do Tratamento
4.
Clin Immunol ; 120(1): 68-75, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16635589

RESUMO

Pemphigus vulgaris (PV) is a potentially fatal autoimmune mucocutaneous disease associated with production of IgG autoantibodies to desmoglein 3 (Dsg3), a 130-kDa epidermal cadherin protein. The binding of pathogenic antibody to Dsg3 on epidermal keratinocytes leads to loss of intercellular adhesion and results in intraepithelial blister formation. Here, we describe a human monoclonal antibody, PVMAB786, a Dsg3-specific IgG4 antibody, from an untreated patient with active PV. The antibody reacts with a 130-kDa protein on keratinocyte cell surfaces and recombinant Dsg3 protein, but not desmoglein 1 protein. PVMAB786 induces acantholysis in normal human skin and mucous membranes and induces a clinical and histological profile similar to human PV when injected into neonatal mice. PVMAB786 will be a valuable tool in identifying the role of Dsg3 in epithelial cell adherence and acantholysis, mechanisms of Dsg3 processing/presentation and V gene and isotype usage in PV pathogenesis.


Assuntos
Anticorpos Monoclonais/imunologia , Desmogleína 3/imunologia , Imunoglobulina G/imunologia , Imunoterapia/métodos , Pênfigo/imunologia , Acantólise/imunologia , Animais , Animais Recém-Nascidos , Anticorpos Monoclonais/uso terapêutico , Western Blotting , Mapeamento de Epitopos , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Imunoglobulina G/uso terapêutico , Imuno-Histoquímica , Testes Intradérmicos , Queratinócitos , Camundongos , Camundongos Endogâmicos BALB C , Pênfigo/terapia
5.
Eur J Dermatol ; 13(4): 377-81, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12948919

RESUMO

Pemphigus vulgaris (PV) is an autoimmune mucocutaneous blistering disease. Recently, patients with mucosal involvement have been described to have autoantibodies to desmoglein 3 (dsg), while patients with mucocutaneous disease have autoantibodies to dsg 1 and dsg 3. The objective of this study was to prospectively analyze, over a 24-month period, the influence of intravenous immunoglobulin (i.v.Ig) therapy on autoantibody titers to dsg 3 and dsg 1, in two groups of patients with severe PV. Group A consisted of 11 patients with mucocutaneous involvement and group B consisted of 10 patients with only mucosal involvement. Levels of autoantibodies to dsg 3 and 1 were measured by ELISA, at monthly intervals. Prior to therapy initiation, group A patients' sera showed a high ELISA index value of both dsg 3 and 1 antibodies, while group B patients had a high index value to only dsg 3. During i.v.Ig therapy, a progressive decline in the ELISA index values was observed in all patients. After the initiation of i.v.Ig therapy, in group A, a statistically significant reduction (p < 0.05) in ELISA index value to dsg 3 and 1 was detected after four and five months, respectively. In Group B, a significant decline in the mean autoantibody titer values to dsg 3 (p < 0.05) was observed after six months of i.v.Ig therapy. Group A patients had a negative ELISA index value to dsg 3 and 1 after a mean period of 21 and 20 months, respectively. Group B patients had a negative dsg 3 score after a mean period of 22 months. These results indicate that autoantibody titers to dsg 3 and 1, as measured by ELISA, can be used to monitor the serological response to treatment in PV patients. A sustained serological remission is observed in patients treated with i.v.Ig therapy. .


Assuntos
Autoanticorpos/análise , Caderinas/imunologia , Imunoglobulinas Intravenosas/uso terapêutico , Pênfigo/imunologia , Pênfigo/terapia , Adulto , Idoso , Caderinas/sangue , Desmogleína 1 , Desmogleína 3 , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Estudos Prospectivos
6.
Autoimmunity ; 35(2): 87-91, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12071440

RESUMO

Pemphigus vulgaris is a potentially fatal autoimmune mucocutaneous disease associated with production of IgG autoantibodies to desmoglein 3, a 130 kDa epidermal protein. To further characterize the epitope(s) of pemphigus vulgaris antigen we established two human-human hybridoma by fusion of the peripheral blood mononuclear cells with a human and mouse heterohybridoma. These hybridomas designated as MAb Dsg-3: 06 and MAb Dsg-3: 10 and stable in culture and demonstrated yield of monoclonal antibodies specific for pemphigus vulgaris. Immunofluorescence, immunoblot, ELISA assays demonstrated that both the monoclonal antibodies bind to the intercellular cement substance and to 130 kDa protein present in the skin and specifically binds to recombinant desmoglein 3 protein, but not to desmoglein 1 protein. The IgG subclass distribution study demonstrated that both the antibodies are of IgG1 subclass in nature. Both the antibodies were non-pathogenic as demonstrated in vitro by their inability to produce acantholysis in normal human skin in organ culture or in vivo by the induction of disease in neonatal BALB/c mice. The relevance and value of these monoclonal antibodies in the pathogenesis of pemphigus vulgaris is discussed.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Caderinas/imunologia , Pênfigo/imunologia , Animais , Autoanticorpos/sangue , Autoanticorpos/imunologia , Western Blotting , Células Cultivadas , Desmocolinas , Desmogleína 3 , Ensaio de Imunoadsorção Enzimática , Epiderme/imunologia , Técnica Indireta de Fluorescência para Anticorpo , Haplorrinos , Humanos , Hibridomas/citologia , Hibridomas/imunologia , Imunoglobulina G/imunologia , Glicoproteínas de Membrana/imunologia , Camundongos , Pênfigo/sangue , Pênfigo/patologia
7.
Dermatology ; 204(2): 108-17, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-11937735

RESUMO

BACKGROUND: The simultaneous presence of features of pemphigus vulgaris (PV) in patients with bullous pemphigoid (BP) has previously been reported in the literature. OBJECTIVE: The purpose of this retrospective study is to present 13 patients with an initial diagnosis of BP, who subsequently demonstrated coexistent serological features of both BP and PV. METHODS: The following information on each patient was documented, at the time of initial diagnosis: clinical profile on presentation, histology, direct immunofluorescence, indirect immunofluorescence (IIF) using monkey esophagus as substrate, salt-split skin (SSS) and an immunoblot assay. Since all 13 patients failed to respond to conventional systemic therapy, intravenous immunoglobulin (IVIg) was used as an alternative treatment modality. Prior to initiating IVIg therapy, in all 13 patients, serological studies were performed. In addition to IIF using monkey esophagus, an immunoblot assay and SSS, an enzyme-linked immunosorbent assay (ELISA) was performed to detect antibodies to desmogleins. These different assays were done to identify pathological autoantibodies typical of BP and PV. A control group of 25 healthy normal individuals, 37 patients with BP, 17 patients with PV and 12 patients with pemphigus foliaceus were used for comparison of serological studies. RESULTS: At the time of initial presentation, histological and immunopathological studies confirmed the diagnosis of BP in all 13 patients. Prior to the initiation of IVIg therapy, results of IIF using monkey esophagus as substrate demonstrated high levels of anti-intercellular cement substance (anti-ICS) or antikeratinocyte cell surface antibody. Sera of all 13 patients on SSS bound to the epidermal side of the split. In an immunoblot, using bovine gingival lysate as substrate, sera of 6 patients bound to both a 230-kD (BP Ag1) and 180-kD protein (BP Ag2), while 7 sera bound to only a 230-kD protein. All 13 patients had high levels of antibodies to desmoglein 3 on ELISA. In a pilot experiment, the anti-ICS antibody in sera from 6 random patients was found to be predominantly of the IgG4 subclass. Use of IVIg resulted in an effective clinical response and the maintenance of a prolonged clinical remission. CONCLUSION: In patients with BP, who are nonresponsive to conventional therapy, the presence of two autoimmune diseases or a dual diagnosis should be considered.


Assuntos
Penfigoide Bolhoso/diagnóstico , Pênfigo/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/sangue , Caderinas/imunologia , Desmogleína 1 , Ensaio de Imunoadsorção Enzimática , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Immunoblotting , Imunoglobulina G/análise , Imunoglobulinas Intravenosas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Penfigoide Bolhoso/complicações , Penfigoide Bolhoso/terapia , Pênfigo/complicações , Pênfigo/terapia , Estudos Retrospectivos
8.
Clin Immunol ; 102(1): 59-67, 2002 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11781068

RESUMO

Mucous membrane pemphigoid (MMP), also known as cicatricial pemphigoid (CP), is an autoimmune mucocutaneous, blistering disease which can lead to blindness and/or death from sudden asphyxiation, secondary to a scarring process. Conventional therapy for the treatment of MMP consists of high-dose systemic corticosteroids and/or immunosuppressive agents. Some patients do not respond to these treatments and develop multiple serious side effects, which can be potentially fatal. In such patients, alternative treatment modalities are needed. This study presents the use of intravenous immunoglobulin (IVIg) therapy in 15 patients with severe MMP whose disease was nonresponsive to the prolonged use of high-dose systemic corticosteroids and immunosuppressive agents and who developed multiple side effects to them. All 15 patients received an IVIg dose of 1-2 g/kg/cycle. The following objective parameters were used to assess the clinical outcome pre- and post-IVIg therapy: number of side effects, frequencies of recurrences and relapses, duration and total dosage of prednisone therapy, and the quality of life. The differences in these variables between the pre- and post-IVIg data were statistically analyzed using the SAS UNIVARIATE software running the two-sided Wilcoxon signed-rank and sign tests. A statistically significant difference was observed between pre- and post-IVIg therapy data when comparing the aforementioned variables. All 15 patients had an effective clinical response, were able to discontinue previous systemic therapies, and eventually achieved a prolonged clinical remission. IVIg improved the quality of life in all 15 patients and demonstrated a steroid-sparing effect. No serious side effects were observed. IVIg therapy is a safe and effective alternative modality in the treatment of patients with nonresponsive and progressive MMP and can induce a sustained clinical remission.


Assuntos
Imunoglobulinas Intravenosas/uso terapêutico , Penfigoide Mucomembranoso Benigno/terapia , Idoso , Túnica Conjuntiva/patologia , Feminino , Humanos , Imunoglobulinas Intravenosas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Boca/patologia , Mucosa/patologia , Prednisona/uso terapêutico , Qualidade de Vida , Indução de Remissão
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