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Biotech / Medical : Indications -- Psoriasis/Chronic Inflammation -- Ignore unavailable to you. Want to Upgrade?

To: michael_f_murphy who wrote (202)	4/22/2002 9:17:54 PM
From: scaram(o)uche	Respond to of 631

sound familiar??....... J Immunol 1998 Apr 15;160(8):3797-804 Potent apoptotic signaling and subsequent unresponsiveness induced by a single CD2 mAb (BTI-322) in activated human peripheral T cells. Dumont C, Deas O, Mollereau B, Hebib C, Giovino-Barry V, Bernard A, Hirsch F, Charpentier B, Senik A. Centre National de Recherche Scientifique, UPR 420, Villejuif, France. Manipulation of CD2 molecules with CD2 mAb pairs has been shown to deliver apoptotic signals to activated mature T cells. We show that BTI-322, a CD2 mAb directed at a peculiar epitope of CD2, can trigger on its own the apoptotic death of IL-2-activated peripheral T cells and of OKT3-stimulated T cells, contrasting in this respect with a series of other mouse or rat CD2 mAb. F(ab')2 fragments were as potent as the whole Ab. BTI-322-induced apoptosis proceeded in a few hours and was independent of the Fas/Fas ligand system. Less than 5 ng/ml of BTI-322, added at the beginning of culture, were able to eliminate within 4 days most CD3+ cells from OKT3- and IL-2-stimulated lymphocytes, the only cells remaining being CD16+CD2- NK cells. T cell proliferative responses induced by a mitogenic CD2 mAb pair or by PHA-P (which mainly binds to CD2) were not inhibited by BTI-322. In this case, the apoptotic effect was successfully counteracted by simultaneous enhancement of T cell divisions. Thus, the killing effect of BTI-322 was most effective when T cells were exclusively stimulated through the CD3/TCR complex. Apoptosis of the responding T cells may explain why T cells recovered from a primary MLC performed in the presence of BTI-322 responded to third party cells but not to the primary stimulatory cells. These data constitute the rational basis for the use of BTI-322 for inducing tolerance in human allotransplantation. Transplantation 1999 Nov 27;68(10):1588-96 Selective deletion of antigen-specific, activated T cells by a humanized MAB to CD2 (MEDI-507) is mediated by NK cells. Branco L, Barren P, Mao SY, Pfarr D, Kaplan R, Postema C, Langermann S, Koenig S, Johnson S. Department of Immunology and Molecular Genetics, MedImmune, Inc., Gaithersburg, Maryland 20878, USA. CD2 is a 50-kDa transmembrane glycoprotein that plays an important role in T and natural killer (NT) lymphocyte functions. CD2 serves as both an adhesion molecule and as a costimulatory molecule through interactions with its ligand, CD58, on antigen presenting or target cells. Consistent with earlier studies using a rat anti-CD2 mAb, we have shown that treatment of alloantigen stimulated T lymphocytes with a humanized mAb, MEDI-507 (IgG1, kappa), induced hyporesponsiveness to subsequent stimulation with alloantigen but not to mitogen (phytohemagglutinin). Fluorescence-activated cell sorting analysis of cells from mixed lymphocyte reaction (MLR) treated with MEDI-507 revealed pronounced deletion of T and NK cells, consistent with lack of proliferation in the MLR. MEDI-507 F(ab')2 fragments did not have inhibitory activity or induce deletion of lymphocytes in the MLR. Removal of the NK cell subset by magnetic bead depletion using anti-CD16 and anti-CD56 mAbs eliminated both the T cell deletion and the inhibitory effect. Reconstitution of NK depleted responder populations using autologous NK cells restored the MEDI-507-mediated deletion activity to levels measured in the original MLR. Formaldehyde-fixed NK cells failed to mediate the MEDI-507-induced deletion effect. Altogether, our studies indicate that activated T cells with MEDI-507 bound to CD2 are preferential targets for autologous NK cells through a nonapoptotic cytotoxic mechanism.

To: michael_f_murphy who wrote (202)	4/22/2002 9:30:47 PM
From: scaram(o)uche	Respond to of 631

Expert Opin Biol Ther 2002 Apr;2(4):431-41 Selective targeting of T cell subsets: focus on alefacept - a remittive therapy for psoriasis. Krueger GG. Department of Dermatology, University of Utah Health Sciences Center, 50 N. Medical Drive, Suite 4B 454, Salt Lake City, UT 84132, USA. krueger@ultraderm.med.utah.edu Psoriasis is an immune-mediated disease in which memory-effector (CD45RO+), skin-homing T cells play a key role in driving the disease process. Available therapies are often poorly tolerated, none are curative and most only suppress disease symptoms without attacking the underlying cause of the illness. Alefacept (Amevive((R)), Biogen, Inc.) is a fully human lymphocyte function associated antigen-3/immunoglobulin G1 fusion protein that targets memory-effector T cells by binding CD2 on the T cell and Fc phi receptor III IgG receptors on accessory cells, thereby preventing T cell activation and proliferation and causing selective T cell apoptosis. To date, alefacept has been studied in moderate-to-severe chronic plaque psoriasis and in a pilot study of psoriatic arthritis. In chronic plaque psoriasis, alefacept produced significant and sustained improvements in psoriasis symptoms. There was no evidence of disease rebound or worsening of psoriasis following treatment cessation. Multiple courses provided consistent efficacy, with a trend for more rapid and greater clinical improvement in subsequent courses. Alefacept reduced circulating CD4+ and CD8+ memory-effector T cells, with relatively no change in naive (CD45RA+) T cells or B cells. Alefacept also reduced IFN-phi-secreting Tcells in lesional biopsies of psoriatic skin. These reductions all correlated with the observed clinical effect. Alefacept was well-tolerated throughout these studies, with a side effect profile similar to placebo. There was no evidence of generalised immunosuppression or increased risk of infection or malignancy. Alefacept did not alter the primary or acquired immune response in psoriatic patients. Clinical data obtained to date support the use of alefacept as a safe and remittive therapy for psoriasis.