Efficacy of the fully human monoclonal antibody MOR102 (#5) against intercellular adhesion molecule 1 in the psoriasis-severe combined immunodeficient mouse model

BACKGROUND: Psoriasis is considered as a chronic immune-mediated disease characterized by inflammation and proliferation of the epidermis. OBJECTIVES: Targeting intercellular adhesion molecule 1 (ICAM-1) is an attractive therapeutic option as this molecule is critically involved in leucocyte adhesion and extravasation as well as in lymphocyte activation. METHODS: We have selected the fully human monoclonal antibody MOR102 (#5) against ICAM-1 from the Human Combinatorial Antibody Library (HuCAL). This antibody, as human IgG4 [corrected] was tested for its ability to interfere with lymphocyte activation and adhesion in vitro as well as for its antipsoriatic efficacy in vivo using the psoriasis-severe combined immunodeficient (SCID) mouse model. RESULTS: The antibody demonstrated efficient inhibition of lymphocyte adhesion to ICAM-1 in vitro, with an IC(50) of approximately 0.4 microg mL(-1) (3 nmol L(-1)). In addition, MOR102 (#5) reduced lymphocyte proliferation in mixed lymphocyte cultures by approximately 50%. The in vivo efficacy of MOR102 (#5) was tested on grafts derived from lesional skin of patients with chronic plaque-stage psoriasis transplanted on to SCID mice. Intraperitoneal injection of 10 mg kg(-1) of MOR102 (#5) antibody every alternate day over a period of 4 weeks resulted in reconstitution of orthokeratotic differentiation and a significant (P < 0.05) reduction in epidermal thickness as well as marked reduction in the inflammatory infiltrate. Therapeutic activity may be related to the targeting of ICAM-1 on keratinocytes and thus preventing efficient activation of local T cells. CONCLUSIONS: Based on the efficacy of the fully human monoclonal antibody MOR102 (#5) shown in vitro as well as in vivo in the psoriasis-SCID mouse model, initiation of clinical studies is indicated

Major histocompatibility complex class II (DR) antigen and costimulatory molecules on in vitro and in vivo activated human polymorphonuclear neutrophils

We have previously shown that normal human peripheral blood polymorphonuclear neutrophils (PMNs) contain cytoplasmic ‘stores’ of three key molecules normally associated with antigen presentation and T-cell costimulation, i.e. major histocompatibility complex class II (DR) antigen, CD80 (B7-1) and CD86 (B7-2). These cytoplasmic molecules were found to translocate to the cell surface within a few minutes following cross-linking (X-L) of Mac-1: an early neutrophil activation signal. In this study we have compared X-L of Mac −1 in parallel with four other well documented in vitro neutrophil activators: phorbol myristate acetate, N-formyl methionyl leucyl phenylalanine, lipopolysaccharide, and phagocytosis of immunoglobulin G–Latex particles. In addition, we have used paired samples of neutrophils obtained from peripheral blood (as a control) and synovial fluid from patients with rheumatoid arthritis as a source of in vivo activated cells. With the exception of phagocytosis, all activators resulted in the rapid (within 30 min) generation of two populations of activated neutrophils (designated P1 and P2) based on flow-cytometry measurements of size, granularity and phenotype. Significant up-regulation of DR and costimulatory molecules was observed, predominantly on P2 cells, with all activators except phagocytosis. CD80 and CD86 were noted to respond to the various activation signals in a different pattern suggesting that their intracellular granule location may be different. Dual-staining confocal laser microscopy studies showed that CD80 is largely confined to secretory vesicles (SVs) while CD86 appears to have a much wider distribution being found in SVs and within secondary (specific) and primary (azurophilic) granules. Increased surface expression of these antigens was also observed on P2 synovial fluid neutrophils appearing as large heterogeneous clusters on the cell surface when visualized by confocal laser microscopy

Mast cells as early responders in the regulation of acute blood–brain barrier changes after cerebral ischemia and hemorrhage

The inflammatory response triggered by stroke has been viewed as harmful, focusing on the influx and migration of blood-borne leukocytes, neutrophils, and macrophages. This review hypothesizes that the brain and meninges have their own resident cells that are capable of fast host response, which are well known to mediate immediate reactions such as anaphylaxis, known as mast cells (MCs). We discuss novel research suggesting that by acting rapidly on the cerebral vessels, this cell type has a potentially deleterious role in the very early phase of acute cerebral ischemia and hemorrhage. Mast cells should be recognized as a potent inflammatory cell that, already at the outset of ischemia, is resident within the cerebral microvasculature. By releasing their cytoplasmic granules, which contain a host of vasoactive mediators such as tumor necrosis factor-α, histamine, heparin, and proteases, MCs act on the basal membrane, thus promoting blood–brain barrier (BBB) damage, brain edema, prolonged extravasation, and hemorrhage. This makes them a candidate for a new pharmacological target in attempts to even out the inflammatory responses of the neurovascular unit, and to stabilize the BBB after acute stroke

WBC count and functional changes induced by co-administration of clofazimine and clarithromycin, in single and multiple doses, in Wistar rats

Clofazimine and clarithromycin are used to treat leprosy and infections caused by Mycobacterium avium complex. Little data on the toxicity of co-administration of these two drugs are available. Here we evaluated the potential adverse effects of polytherapy with these two drugs in male Wistar rats by determining WBCs counts and other blood cell counts, neutrophilic phagocytosis, and burst oxidative, by flow cytometry. We observed an increase in WBCs, in multiple-dose regimens, and in polymorphonuclear cells, in both single- clarithromycin only and multiple dose regimens. We also observed a reduction in mononuclear cell counts in single and multiple doses. The drugs seem to reverse the mononuclear and polymorphonuclear cell ratio. An increase in oxidative burst was observed in animals treated with the drugs administered either individually or combined. In conclusion, clofazimine and clarithromycin change WBCs counts. Our results may contribute for a better understanding of the mechanisms related to the effects of co-administrating the two drugs.<br>Clofazimina e laritromicina são utilizadas no tratamento da hanseníase e em infecções causadas pelo complexo Mycobacterium avium. Devido à escassez de dados sobre a toxicidade de esquemas terapêuticos que associam estes fármacos, este estudo teve por objetivo avaliar os efeitos adversos desta terapia, em ratos machos Wistar, por meio da determinação da contagem global e específica de leucócitos e ensaios de fagocitose e burst oxidativo de neutrófilos por citometria de fluxo. Houve aumento do número de leucócitos (dose múltipla) e de células polimorfonucleares (doses única e múltipla) nos grupos tratados com claritromicina em monoterapia ou associada à clofazimina e redução das células mononucleares, em doses única e múltipla, nos mesmos grupos. Os fármacos parecem inverter a proporção entre células mono e polimorfonucleares. Observou-se aumento do burst oxidativo nos animais tratados com os fármacos isolados ou associados. Concluindo, clofazimina e claritromicina provocam alterações leucocitárias e os resultados podem contribuir para melhor entendimento dos mecanismos relacionados aos efeitos da administração dos fármacos em associação