Short-term treatment with CD3 antibody preserves residual beta-cell function for at least 18 months in patients with recent-onset type 1 diabetes.

From 1991-2002, we treated 58 patients with multiple sclerosis (MS) using the humanised monoclonal antibody, Campath-1H, which causes prolonged T lymphocyte depletion. Clinical and surrogate markers of inflammation were suppressed. In both the relapsing-remitting (RR) and secondary progressive (SP) stages of the illness, Campath-1H reduced the annual relapse rate (from 2.2 to 0.19 and from 0.7 to 0.001 respectively; both p < 0.001). Remarkably, MRI scans of patients with SP disease, treated with Campath-1H 7 years previously, showed no new lesion formation. However, despite these effects on inflammation, disability was differently affected depending on the phase of the disease. Patients with SPMS showed sustained accumulation of disability due to uncontrolled progression marked by unrelenting cerebral atrophy, attributable to ongoing axonal loss. The rate of cerebral atrophy was greatest in patients with established cerebral atrophy and highest inflammatory lesion burden before treatment (2.3 versus 0.7 ml/year; p = 0.04). In contrast, patients with RR disease showed an impressive reduction in disability at 6 months after Campath-1H (by a mean of 1.2 EDSS points) perhaps owing to a suppression of on-going inflammation in these patients with unusually active disease. In addition, there was a further significant, albeit smaller, mean improvement in disability up to 36 months after treatment. We speculate that this represents the beneficial effects of early rescue of neurons and axons from a toxic inflammatory environment, and that prevention of demyelination will prevent long-term axonal degeneration. These concepts are currently being tested in a controlled trial comparing Campath-1H and IFN-beta in the treatment of drug-naïve patients with early, active RR MS.

The lysis of cells by complement requires only the terminal components C5, C6, C7, C8 and C9 and is initiated by the cleavage of C5 to C5b. Sequential addition of C6, C7, C8, and C9 to C5b leads to the formation of the membrane attack complex (MAC)' which, when inserted into the lipid bilayer, can form transmembrane pores (1-5). It is well known that when complement of one species is activated on homologous erythrocytes, lysis is much less efficient than when it is activated on other species of cell, and even among different heterologous cell species the lytic efficiency may be very different. It has long been known that the basis of this variable lytic efficiency is found, at least in part, at the C8 and/or C9 step (6-9). More recently, specific membrane proteins have been described that appear to protect cells from homologous complement . The first of these to be described was the decayaccelerating factor (DAF), a membrane protein of -70 kD molecular mass (10). This protein interferes with the assembly of the C3 converting enzymes both of the classical and alternative pathway (10, 11) and therefore it has only indirect effects on the cell lytic mechanism. A further membrane protein that does restrict homologous lysis, and that has been described both as the C8-binding protein (C8bp) (7, 12) and as homologous restriction factor (HRF) (13), has also been isolated . It seems likely that both these descriptions apply to a single protein of 65 kD molecular mass. In addition, a 55/65-kD MAC-inhibiting protein (MIP) with the capacity to bind C8 and C9 has been identified both on human erythrocyte membranes and in normal human serum (14). The relationship ofthis to HRF/C8bp is not yet clear. Both DAF and HRF/C8bp are bound on cell membranes by a glycolipid anchor (15, 16) and can be eluted from the cell membrane, at least in part, by phosphatidylinositol-specific phospholipase C. These proteins also have the capacity when they are isolated from

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