Zl. Lummus et al., CHARACTERIZATION OF HISTAMINE-RELEASING FACTORS IN DIISOCYANATE-INDUCED OCCUPATIONAL ASTHMA, Toxicology, 111(1-3), 1996, pp. 191-206
Immunologic mechanisms contributing to diisocyanate-induced occupation
al asthma (OA)are poorly defined. There is a relatively low incidence
of diisocyanate-specific IgE antibody responses. The frequent occurren
ce of delayed onset asthmatic responses in workers with diisocyanate a
sthma suggests a role for cellular immune mechanisms. We have shown in
vitro production of antigen-specific mononuclear cell-derived histami
ne releasing factors (HRF) by peripheral blood mononuclear cells (PBMC
s) of workers with OA. Monocyte chemoattractant protein-1 (MCP-1) and
RANTES (acronym for ''regulated on activation,normal T expressed and s
ecreted'') are chemokines found in PBMC supernatants that express HRF
activity. Diisocyanate-exposed workers were tested for diisocyanate an
tigen-stimulated enhancement of HRF, MCP-I, and RANTES production in s
upernatants of PBMCs and for serum specific IgE and IgG antibody level
s to diisocyanate antigens bound to human serum albumin (HSA). PBMCs o
f workers with diisocyanate OA showed significantly increased producti
on of antigen-specific HRF activity and MCP-1 (>300 ng/ml) compared to
diisocyanate-exposed asymptomatic workers (P < 0.05). Antigen-stimula
ted enhancement of MCP-I mRNA was demonstrated by reverse-transcriptio
n PCR. RANTES mRNA and chemokine secretion (<1 ng/ml) was also demonst
rated in PBMCs, but did not show antigen enhancement in OA workers. Ha
pten specificity for the diisocyanate chemical to which a patient had
been exposed was demonstrated for HRF enhancement and for IgG antibody
reactions, but not for IgE reactions. HRF production was demonstrated
in PBMC subpopulations, including lymphocytes and purified T cells. O
A subjects showed increased CD8(+) cells by immunofluorescence (mean C
D4(+):CD8(+) = 1.2 +/- 0.2). The results suggest that diisocyanate ant
igen enhancement of HRF and MCP-I production are stimulated by hapten-
specific T cell reactions. Since a weak association has been found bet
ween IgE antibody synthesis and induction of diisocyanate OA, the role
of T cell cytokines and chemokines in the pathogenesis of OA requires
further investigation.