Toxicology of Industrial Compounds

140 MECHANISMS OF PULMONARY SENSITIZATION
it remains likely that this class of antibody is responsible, in at least the
majority of cases, for the acute onset symptoms associated with respiratory
allergy (Karol et al., 1994).
The induction and regulation of IgE responses
IgE antibody responses are subject to a variety of immunoregulatory
control mechanisms. Chief among these are the stimulatory and inhibitory
actions of cytokines which serve to influence the induction and duration of
IgE responses. It has been found in mice that interleukin 4 (IL-4) is
necessary for the initiation and maintenance of IgE antibody production
(Finkelman et al., 1988b). The essential role for this cytokine in IgE
responses has been emphasized further by studies of mice homozygous for
a mutation that inactivates the gene for IL-4. These animals lack detectable
serum IgE and fail to mount IgE responses (Kuhn et al., 1991). Importantly,
in mice which produce constitutively high levels of IL-4, significantly
elevated concentrations of serum IgE are evident (Burstein et al., 1991). A
balance to the promotional influence of IL-4 is provided by interferon
(IFN- ), a cytokine which exerts an inhibitory affect on IgE responses
(Finkelman et al., 1988a). The reciprocal antagonistic activity of these
cytokines is not restricted to the mouse, IL-4 and IFN- have been found to
regulate human IgE production (Del Prete et al., 1988; Pene et al., 1988).
The cytokines which influence the integrity of IgE responses are the
products of discrete subpopulations of T helper (Th) cells, lymphocytes
characterized by possession of the CD4 membrane determinant. It has been
found in both mouse and man that there exists a functional heterogeneity
among Th cells. Two major populations, designated Th 1 and Th 2, have
been described (Mosmann and Coffman, 1989; Romagnani, 1991). It is
believed currently that these subsets represent the most differentiated forms
of Th cells and develop from less mature precursors as the immune
response evolves (Mosmann et al., 1991). The major functional distinction
between Th 1 and Th 2 cells resides in the spectrum of cytokines which they
elaborate (Mosmann and Coffman, 1989). The cytokine products of
murine Th 1 and Th 2 cells are displayed in Table 10.2.
It has been reported previously that chemicals known to cause
respiratory hypersensitivity in man induce in mice immune responses
characteristic of Th 2 cell activation, stimulate the production of specific IgE
antibody and cause an increase in the serum concentration of IgE.
Conversely, chemical allergens considered not to cause respiratory
sensitivity, but which are nevertheless able to induce skin sensitization,
elicit instead Th 1-type responses. In the latter case, immune responses are
characterized by comparatively high levels of IgG2a antibody (an isotype
known to be upregulated by IFN- ) and the absence of specific IgE
(Dearman and Kimber, 1991, 1992; Dearman et al., 1991, 1992a,c,d,