The use of TNF family ligands and receptors and agents which modify their interaction as therapeutic agents.

The earlier known TNF family cytokines have fairly wide physiological actions, mainly in inflammation and immune responses. It is now considered feasible to develop these large proteins themselves as therapeutic agents, but in addition, modular organisation of structures of biological proteins, and the identification of localised ligand-receptor interaction sites, allow rational design of smaller, preferably nonpeptide molecules which interfere with these protein:protein interactions. Neutralising anti-TNF antibodies and soluble TNF receptor preparations were shown to have striking anti-inflammatory activities in clinical studies, particularly in rheumatoid arthritis. As the TNF beta:TNFR1 co-crystal structure was the first in the family to be solved, rational drug design based on the ligand:receptor interaction sites is more advanced. Ligand mutations and a peptide sequence from TNF-alpha have given useful information regarding ligand-receptor interactions. Small peptide sequences from TNFR I which interact with the ligand have shown some activity in blocking the biological actions of TNF. The physiological activities of several recently-discovered ligands are more limited, giving possibilities for selective treatment of several diseases. For example, TRAIL can induce apoptosis in a wide range of tumour cells with little effects on normal tissues, both in vitro and in vivo. The co-crystal structure of TRAIL with one of its signalling receptors TRAILR 2 has been solved, opening the way to rational small molecule drug design. TRANCE (RANKligand) has modulatory effects on the dendritic cell:T cell interaction in immune responses. However, it plays a more major controlling role in the development of osteoclasts and their bone resorbing activity. In this way, it is a very interesting drug development target for the treatment of bone disorders such as osteoporosis. A recombinant secreted inhibitory receptor, osteoprotegerin (OPG), is in Phase 1 clinical trial for the treatment of hyper-resorptive bone diseases. However, OPG also blocks TRAIL and may not be sufficiently specific in long term therapy, but it is hoped that inhibitors of the interaction of TRANCE and its specific signalling receptor, RANK, can be rationally designed.

The fetal/adult acetylcholine receptor antibody ratio in mothers with myasthenia gravis as a marker for transfer of the disease to the newborn.

High anti-fetal/anti-adult muscle anti-acetylcholine receptor (AChR) antibody (Ab) titer ratio is predictive of the occurrence of neonatal myasthenia gravis in a first child. The aim of the present study was to determine whether the ratio between the levels of antibodies is an intrinsic property of the mother's sera or varies with physiologic status such as pregnancy. We performed a longitudinal study of the levels of Ab directed against both fetal and adult AChRs and the ratio between them in 11 mothers with myasthenia gravis (MG). Sera were taken during, before, and after pregnancy. Absolute levels of Ab varied considerably during the time of observation as indicated by analyzing the maximum change between any two sample times during the study (adult mean percentage change 45.9 +/- 26.4; fetal 42.51 +/- 22.05). In contrast to this, the anti-fetal/anti-adult muscle AChR Ab titer ratio was much less variable (mean percentage change 16.66 +/- 10.11; p < 0.0033). The levels of the two Ab types yielded a correlation of 0.918, consistent with the stability of the ratio between them. This stability of ratio has practical value in the management of pregnancy and infant care in mothers with MG because the ratio at any time, before or during pregnancy, will predict whether the child will contract neonatal MG. We determined this for the first child, but further studies are necessary to establish if this remains true for subsequent pregnancies.