Abstract
Chronic asthmatics norrally respond to oral
corticosteroid therapy with an increase in their ventilatory
function. However, Grant and his co- workers identified a small
proportion of severe chronic asthmatics who did not improve
their ventilatory function when given oral corticosteroid.
These patients were termed "corticosteroid resistant ". This
thesis describes the in vitro and in vivo effects of the
corticosteroid, Ilethylprednisolone (INS), on monocytes and Tcells from Corticosteroid Sensitive (CS) and Corticosteroid
Resistant (CR) asthmatics.
In vitro colony formation by mononuclear cells (MNC) from
CS asthmatics was found to be significantly more inhibited by
10⁻⁸ N MPS than was colony formation by MNC from CR
asthmatics. This in vitro assay of corticosteroid sensitivity
was subsequently used diagnostically to discriuina_te between CS
and CR asthmatics. It was demonstrated that the
unresponsiveness of MNC from CR asthmatics to MPS in vitro was attributable to the monocytes from these patients. Defects in
the corticosteroid sensitivity of T-cells, eosinophils and
polymorphs were also observed in vivo and in vitro; their
relationship to the monocyte defect was not clarified.
Monocytes are thought to affect the Type 1 hypersensitivity reaction seen in asthma by the production of
many factors. Two of these factors are of particular relevance
to this thesis: lipomodulin, which inhibits prostanoid
synthesis and is induced by corticosteroid and Interleukin 1,
which supports T- lymphocyte proliferation and is inhibited by
corticosteroid. There is therefore reason to believe that the
defect in corticosteroid responsiveness demonstrated in
monocytes from CR asthmatics in vitro could reduce the
therapeutic efficacy of these drugs in patients with this
condition.
If this is so, these findings emphasise the importance of
the actions of corticosteroid on monocyte function in the commoner CS asthma. Further investigation of this phenomenon
may have wider implications for other developmental and
pathological processes.
