Superantigen vaccines: a comparative study of genetically attenuated receptor-binding mutants of staphylococcal enterotoxin A.

Superantigens exert their pathologic effects by direct binding to major histocompatibility complex (MHC) class II molecules and T cell antigen receptors (TCR), thus circumventing the normal, antigen-specific immune response. A direct link between disease and toxin suggests an excellent opportunity for vaccine intervention. Site-directed mutants of staphylococcal enterotoxin A (SEA) that have attenuated binding to either the TCR or the MHC class II molecule were developed. Both kinds of SEA mutants induced high levels of antibody against SEA when used as vaccines, and the immunized animals were fully protected when challenged with wild type toxin. However, a residual lethality was associated with the attenuated TCR-binding mutant. These results, combined with an understanding of the molecular nature of superantigen and receptor interactions, indicate that targeting MHC class II binding by site-directed mutagenesis will produce the most effective vaccine.

Changes in number and distribution of orthogonal arrays during postnatal muscle development.

Quantitative freeze-fracture electron microscopy was utilized to study the changes in number and distribution of orthogonal arrays (aggregates of 6-7 nm particles) of the sarcolemmas of the fast twitch extensor digitorum longus (EDL) and slow twitch soleus muscles during the first few weeks of postnatal development in the rat. In the adult rat, orthogonal arrays are present in high densities in the fast twitch type II fibers but only in low densities in slow twitch type I fibers. In this study, the changing histochemical profiles of fiber types in the EDL and soleus muscles were also determined for the first month of postnatal development and correlated with the changing number and distribution of orthogonal arrays during the same time frame. At day 3 postpartum, EDL and soleus fibers possessed few orthogonal arrays. The developing EDL fibers rapidly acquired additional orthogonal arrays until the approximate adult number and distribution were attained at postpartum day 25. In contrast, the slow twitch soleus fibers rapidly acquired orthogonal arrays and type IIA fibers until day 35 when both were in excess of adult values. Subsequently, the number of arrays and type IIA fibers declined to normal adult ranges. We suggest that the patterns of development of orthogonal arrays and fiber types are different in the EDL and soleus because the types of innervating motor units are different in the two muscles. The EDL is innervated almost entirely by fast motor units throughout early development and maturity. The soleus, however, is initially innervated by a more heterogeneous population of motor neurons. Thus, during the period of polyneuronal innervation which occurs normally during the first weeks of postnatal development, many individual soleus fibers may possess simultaneous innervation by axons from different motor neuron types. These dual influences may be responsible for the irregular pattern of development of orthogonal arrays and type IIA fibers in developing soleus fibers. Later, as the adult pattern of monosynaptic innervation is developed, expected adult values of orthogonal arrays and fiber types are attained.

Inhalation toxicity studies on cigarette smoke. V. Deposition of smoke particles in the respiratory system of rats under various exposure conditions.

This paper describes a dosimetry experiment on rats which was designed to make a contribution towards the optimisation of exposure conditions for inhalation toxicology studies with smoke aerosols. The main conclusions drawn from the work are: (i) Under continuous exposure conditions the deposition of total particulate matter (TPM) in the respiratory system and carboxyhaemoglobin (COHb) levels in blood were linearly dependent on the concentration of smoke in the exposure chamber. (ii) Intermittent exposure gave relatively lower TPM deposition compared to continuous exposure, even after allowing for differences in actual exposure times. (iii) For arithmetically equivalent exposure levels, short exposure to high concentration gave greater TPM deposition than long exposures to low smoke concentrations. (iv) There was a good correlation between lower respiratory system (LRS) and lung deposition of TPM and blood COHb level for both continuous and intermittent exposure conditions. These findings are discussed in relation to the conduct of inhalation studies with tobacco smoke.