RESUMEN
Background & objectives: To examine ß-D-mannuronic acid (M2000) effects on L-selectin shedding and leucocyte function-associated antigen-1 (LFA-1) expression as mechanisms of action of this drug in patients with ankylosing spondylitis (AS). Methods: To investigate the molecular consequences of ß-D-mannuronic acid on L-selectin shedding, flow cytometry method was used. Furthermore, the effect of it on LFA-1 gene expression was analyzed by using quantitative real time (qRT)-PCR technique. Results: The LFA-1 expression in patients with AS was higher than controls (P=0.046). The LFA-1 expression after 12 wk therapy with ß-D-mannuronic acid was meaningfully decreased (P=0.01). After 12 wk treatment with ß-D-mannuronic acid, the frequency of CD62L-expressing CD4+ T cells in patients with AS, was not considerably altered, compared to the patients before therapy (P=0.5). Furthermore, after 12 wk therapy with ß-D-mannuronic acid, L-selectin expression levels on CD4+ T-cells in patients with AS, were not remarkably changed, compared to the expression levels of these in patients before treatment (P=0.2). Interpretation & conclusions: The results of this study for the first time showed that ß-D-mannuronic acid can affect events of adhesion cascade in patients with AS. Moreover, ß-D-mannuronic acid presented as an acceptable benefit to AS patients and could aid in the process of disease management.
Asunto(s)
Espondilitis Anquilosante , Humanos , Espondilitis Anquilosante/tratamiento farmacológico , Espondilitis Anquilosante/genética , Antígeno-1 Asociado a Función de Linfocito/genética , Antígeno-1 Asociado a Función de Linfocito/uso terapéutico , Selectina L/genética , Moléculas de Adhesión CelularRESUMEN
Over the past decade, Lymphocyte Function-Associated Antigen-1 (LFA-1, alphaLbeta2, CD11a/CD18) has emerged as an attractive therapeutic target for the treatment of multiple inflammatory diseases. Its established role in the trafficking and activation of leukocytes coupled with the recent elucidation of the global conformational changes that govern its function continue to drive pharmaceutical interest in this target. This sustained interest has led to the implementation of numerous drug discovery strategies leading to the development of antibodies, peptidomimetics, and small molecules that block LFA-1 function. The most successful demonstration of clinical efficacy to date has been with Raptiva, a humanized anti-LFA-1 antibody. In clinical trials of patients with moderate to severe psoriasis, improvements in several disease specific parameters including the Psoriasis Area and Severity Index (PASI) were observed. This review article will provide an overview of LFA-1 biology and structural regulation, as well as strategies that have been adopted in pursuit of effective therapies. Recent findings with different classes of small molecule antagonists will be highlighted with an emphasis on how their different mechanisms of action on the inserted domain (I domain) of CD11a have impacted our understanding of LFA-1 function and illuminated other potential avenues for therapeutic intervention.
Asunto(s)
Inmunoterapia/métodos , Antígeno-1 Asociado a Función de Linfocito/uso terapéutico , Tecnología Farmacéutica/métodos , Animales , Humanos , Enfermedades del Sistema Inmune/inmunología , Enfermedades del Sistema Inmune/terapia , Inmunoterapia/tendencias , Antígeno-1 Asociado a Función de Linfocito/química , Antígeno-1 Asociado a Función de Linfocito/fisiología , Tecnología Farmacéutica/tendenciasRESUMEN
1. Sepsis is associated with leukocyte activation and recruitment in the liver. We investigated the role of lymphocyte function antigen-1 (LFA-1) in endotoxin-induced leukocyte-endothelium interactions, microvascular perfusion failure, hepatocellular injury and apoptosis in the liver by use of gene-targeted mice, blocking antibodies and a synthetic inhibitor of LFA-1 (LFA703). For this purpose, mice were challenged with lipopolysaccharide (LPS)+D-galactosamine (Gal), and intravital microscopy of the liver microcirculation was conducted 6 h later. 2. The number of firmly adherent leukocytes in response to LPS/Gal was reduced by 48% in LFA-1-deficient mice. Moreover, endotoxin-induced increases of apoptosis and enzyme markers of hepatocellular injury were decreased by 64 and 69-90%, respectively, in LFA-1-deficient mice. Furthermore, sinusoidal perfusion was improved in endotoxemic mice lacking LFA-1. 3. A similar protective pattern was observed in endotoxemic mice pretreated with an antibody against LFA-1. Thus, immunoneutralization of LFA-1 reduced endotoxin-induced leukocyte adhesion by 55%, liver enzymes by 64-66% and apoptosis by 42%, in addition to the preservation of microvascular perfusion. 4. Administration of a novel statin-derived inhibitor of LFA-1, LFA703, significantly decreased leukocyte adhesion (more than 56%) and the subsequent liver injury in endotoxemic mice. 5. Thus, this study demonstrates a pivotal role of LFA-1 in supporting leukocyte adhesion in the liver. Moreover, interference with LFA-1-mediated leukocyte adhesion protects against endotoxemic liver damage, and may constitute a potential therapeutic strategy in sepsis.
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Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Endotoxemia/patología , Leucocitos/fisiología , Antígeno-1 Asociado a Función de Linfocito/fisiología , Animales , Anticuerpos Bloqueadores/farmacología , Apoptosis/efectos de los fármacos , Capilares/efectos de los fármacos , Capilares/patología , Adhesión Celular/fisiología , Relación Dosis-Respuesta a Droga , Marcación de Gen , Hemodinámica/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Hepatocitos/patología , Recuento de Leucocitos , Leucocitos/efectos de los fármacos , Hígado/enzimología , Circulación Hepática/efectos de los fármacos , Antígeno-1 Asociado a Función de Linfocito/uso terapéutico , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
PURPOSE: We established a primate model to investigate the effects of the antileukocyte function associated antigen 1 (CD 11a) mAb odulimomab (Imtix-Sangstad, Lyon, France) for preventing renal ischemia-reperfusion injury. MATERIALS AND METHODS: We randomly divided 34 Macaca cynomolgus monkeys into groups 1 and 2, which received a renal autograft after 2 hours of cold ischemia, and groups 3 and 4, which received the autograft after 24 hours of cold ischemia. Before cold ischemia all harvested kidneys were subjected to 30 to 45 minutes of warm ischemia. Groups 1 and 3 monkeys were treated with an antileukocyte function associated antigen 1 mAb before cold ischemia and then for 3 days, while groups 2 and 4 monkeys received an IgG1 isotype control. In all groups renal function was investigated before warm ischemia and 72 hours after reperfusion. Serum creatinine and the leukocyte count were determined daily. Histological studies were done and lactoferrin was measured in the autotransplanted kidney 72 hours after reperfusion. RESULTS: A decrease in renal function was shown after 2 hours of cold ischemia with tubular necrosis and mild cell infiltration, while after 24 hours of cold ischemia there was severe renal failure with tubular and glomerular necrosis, and leukocyte infiltration. A significant improvement in renal function and decrease in kidney lactoferrin content was evident in group 1 compared to group 2 at 72 hours, while no significant difference was noted in groups 3 and 4. No difference in histological patterns was evident in treated and untreated animals. CONCLUSIONS: This study provides evidence for the validity of this ischemia-reperfusion injury model in primates. The protective effects of antileukocyte function associated antigen 1 mAb on renal injury was not as dramatic as in rodent models but a significant improvement in renal function was observed in treated animals after 2 hours of cold ischemia.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Modelos Animales de Enfermedad , Trasplante de Riñón , Riñón/irrigación sanguínea , Antígeno-1 Asociado a Función de Linfocito/uso terapéutico , Daño por Reperfusión/prevención & control , Animales , Anticuerpos Monoclonales/farmacología , Haplorrinos , Riñón/efectos de los fármacos , Antígeno-1 Asociado a Función de Linfocito/farmacología , Macaca fascicularis , Distribución AleatoriaRESUMEN
BACKGROUND: Anti-CD11a (hu1124) is a humanized monoclonal antibody directed against the CD11a subunit of LFA-1. This study investigated whether treatment with anti-CD11a antibody provides clinical benefit to patients with moderate to severe plaque psoriasis. METHODS: This was a double-blind, placebo-controlled, phase II, multicenter study. In total, 145 patients with minimum Psoriasis Area and Severity Index scores of 12 and affected body surface area of 10% or more were sequentially enrolled into low-dose (0.1 mg/kg, n = 22) or high-dose (0.3 mg/kg, n = 75) groups. Within groups, patients were randomized to treatment or placebo (n = 48) in a 2:1 ratio. Drug was administered intravenously at weekly intervals for 8 weeks. RESULTS: The percentage of subjects achieving more than 50% improvement in physician's global assessment at day 56 (1 week after final dose) was 15% and 48% for placebo and 0.3 mg/kg of drug, respectively (P =.002). A physician's global assessment of excellent (>75% improvement) was greater in the 0.3 mg/kg group versus placebo (25% vs 2%, P =.0003). Average Psoriasis Area and Severity Index scores at day 56 were 13.9 +/- 7.5 (placebo) and 10.9 +/- 8.4 (0.3 mg/kg) (P <.0001). Epidermal thickness was reduced in the 0.3 mg/kg group compared with the placebo group (37% vs 19%, P =.004). Treatment was well tolerated; mild to moderate flu-like complaints were the most common adverse events. White blood cell counts and lymphocyte counts transiently increased. Depletion of circulating lymphocytes did not occur. CONCLUSIONS: Anti-CD11a antibody administered intravenously in 8 weekly doses of 0.3 mg/kg was well tolerated and induced clinical and histologic improvements in psoriasis.
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Anticuerpos Monoclonales/uso terapéutico , Antígeno-1 Asociado a Función de Linfocito/uso terapéutico , Psoriasis/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales/inmunología , Método Doble Ciego , Femenino , Humanos , Infusiones Intravenosas , Recuento de Leucocitos , Recuento de Linfocitos , Antígeno-1 Asociado a Función de Linfocito/inmunología , Masculino , Persona de Mediana Edad , Psoriasis/inmunología , Psoriasis/patología , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
The objective of the study is to establish recovery results of tibial nerve defects reconstructed using allogeneic and xenogeneic graft, in host immunosuppressed with Intercellular Adhesion Molecule-1 (ICAM-1) and Lymphocyte Function Antigen-1 (LFA-1) monoclonal antibodies (mAbs). A pilot study was conducted in fifteen Fischer rats by forming a 1 cm right tibial nerve gap, then reconstructing it with 1.2 cm long grafts, namely, Wistar allogeneic, Black mouse xenogeneic, and syngeneic (n = 5/group). The main study included forty-eight rats allocated to the following groups (n = 12/group): 1) Allograft without treatment as control group. 2) Allograft with intraperitoneal ICAM-1 and LFA-1 mAbs treatment. 3) Allograft preserved in Belzers' solution including ICAM-1 mAbs plus standard intraperitoneal treatment. 4) Syngraft as benchmark. At 3, 6 and 9 weeks postengraftment walking track analysis was performed and expressed as Tibial Functional Index (TFI). Motor and compound nerve action potential across the graft conduction velocities were measured at week 10. Xenograft did not show any functional recovery and was therefore excluded from main study. However, pilot and main study results showed recovery results in both treated allogeneic groups and were comparable to benchmark syngraft. Therefore, allogeneic nerve graft could be an alternative in peripheral nerve reconstruction and spinal cord grafting.
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Anticuerpos Monoclonales/uso terapéutico , Molécula 1 de Adhesión Intercelular/uso terapéutico , Antígeno-1 Asociado a Función de Linfocito/uso terapéutico , Regeneración Nerviosa , Nervio Tibial/trasplante , Trasplante de Tejidos/métodos , Potenciales de Acción , Animales , Modelos Animales de Enfermedad , Ratones , Conducción Nerviosa , Proyectos Piloto , Ratas , Ratas Endogámicas F344 , Ratas Wistar , Nervio Tibial/lesiones , Nervio Tibial/fisiología , Trasplante Heterólogo , Trasplante Homólogo , Trasplante Isogénico , Resultado del TratamientoRESUMEN
Resistance to autoimmune encephalomyelitis was induced by s.c. infusion of myelin basic protein (MBP) in saline in combination with i.p. injections of anti-CD11a (LFA-1) mAbs. This treatment induces resistance to EAE induction, which appears early and persists for at least one month after treatment. Some MBP-CFA-challenged resistant rats showed minimal inflammation in the central nervous system, which was, however, confined to the meninges of the lower spinal cord. Examination of the immune status of MBP-anti-LFA-1 treated rats before encephalitogenic challenge failed to reveal any priming when assessed by Ag driven proliferation and cytokine production by lymphoid cells, and by circulating Ab production. Following challenge of protected rats, lymph node cell proliferation to MBP was unaltered, indicating that reactive cells had not been deleted or energized. Resistance could not be transferred with lymphoid cells from treated rats nor abrogated by cyclophosphamide treatment. In treated rats following challenge, there was a shift in the isotype of anti-MBP Ab produced, from an IgG2a:IgG1 ratio of 2:1 to 1:1, due to an increase in IgG1 production, indicating a possible bias towards a nonpathogenic Th2 CD4+ T cell response. The IgG1 Ab was detected early after challenge suggesting that pretreatment had indeed primed the animals, and had primed them to go down the Th2 pathway following encephalitogenic challenge. The ability to divert immune reactivity from a destructive to a nondestructive response could have important therapeutic implications for autoimmune disease.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/uso terapéutico , Autoinmunidad/efectos de los fármacos , Encefalomielitis Autoinmune Experimental/prevención & control , Antígeno-1 Asociado a Función de Linfocito/inmunología , Proteína Básica de Mielina/administración & dosificación , Proteína Básica de Mielina/uso terapéutico , Traslado Adoptivo , Animales , Autoanticuerpos/biosíntesis , Ciclofosfamida/farmacología , Esquema de Medicación , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Femenino , Adyuvante de Freund/administración & dosificación , Interferón gamma/biosíntesis , Activación de Linfocitos/efectos de los fármacos , Antígeno-1 Asociado a Función de Linfocito/uso terapéutico , Ratones , Ratones Desnudos , Proteína Básica de Mielina/inmunología , Ratas , Ratas Endogámicas Lew , Solubilidad , Células Th2/inmunologíaRESUMEN
We retrospectively analyzed the outcome of bone marrow transplantation (BMT) performed in 26 patients with Wiskott-Aldrich syndrome (WAS) in one center. Twenty-eight transplantation procedures were performed. Ten unselected patients received unmanipulated marrow from a donor with genetically identical human leukocyte antigen (HLA). Eight patients were cured and survive 1.5 to 16.5 years after BMT. One patient successfully received a T-cell-depleted marrow from a matched unrelated donor. Sixteen patients were selected to receive a related HLA partially incompatible BMT because of the occurrence of life-threatening complications from the WAS (i.e., refractory thrombocytopenia, autoimmunity including vasculitis and sepsis). All but one received T-cell-depleted marrow after a conditioning regimen of busulfan and cyclophosphamide. One patient had two BMTs. Engraftment occurred in 12 of 17 attempts. The addition of monoclonal antibodies to lymphocyte function-associated antigen-1 and CD2 molecules appeared to improve engraftment. Six patients were long-term survivors, whereas others died of viral infections (n = 7), among which Epstein-Barr virus-induced B-lymphocyte proliferative disorder was predominant. Delay in development of full T- and B-cell functions accounted for severe infectious complications. These results confirm the excellent outcome of HLA genetically identical BMT in WAS, whereas BMT from HLA partially incompatible donors should be strictly restricted to patients with severe complications of WAS.