SummaryInterleukin 5 (1175) has been suggested to be involved in the growth and differentiation of B cells and eosinophils. Especially, Ly-1+ B cells, which have been considered to produce autoantibodies, are selectively developed by this lymphokine in long-term bone marrow culture . To envisage the possible engagement of IL5 in the development of these cells in vivo, transgenic mice carrying the mouse IL5 gene ligated with a metallothionein promoter were generated . Transgenic mice carrying the 1175 gene exhibited elevated levels of 11,5 in the serum and an increase in the levels of serum IgM and IgA. A massive eosinophilia in peripheral blood, bone marrow, and spleen, and an infiltration ofmuscle and liver with eosinophils, were observed. When cadmiumcontaining saline was injected intraperitoneally into transgenic mice, IM production was augmented about five times within 24 h, and a distinctive Ly-1 + B cell population became apparent in the spleen after 5 d. 1175 receptors were detected on those cells by monoclonal antibodies against IL-5 receptors. Another interesting finding in these transgenic mice was an increase in polyreactive anti-DNA antibodies of IgM class. It is suggested, therefore, that aberrant expression of the IL5 gene may induce accumulation of Ly-1+ B cells and eosinophils. Furthermore, this IL5 transgenic mouse can be a model mouse for eosinophilia, and we can determine the role of IL5 in the differentiation of Ly-1 + B cells and eosinophils by using this mouse.
SUMMARY
Even though the existence of phosphodiesterase (PDE) 7 in T cells has been proved, the lack of a selective PDE7 inhibitor has confounded an accurate assessment of PDE7 function in such cells. In order to elucidate the role of PDE7 in human T cell function, the effects of two PDE inhibitors on PDE7A activity, cytokine synthesis, proliferation and CD25 expression of human peripheral blood mononuclear cells (PBMC) were determined. Recombinant human PDE7A was obtained and subjected to cyclic AMP‐hydrolysis assay. PBMC of Dermatophagoides farinae mite extract (Df)‐sensitive donors
were stimulated with the relevant antigen or an anti‐CD3 monoclonal antibody (MoAb).
PBMC produced IL‐5 and proliferated in response to stimulation with Df, while
stimulation with anti‐CD3 MoAb induced CD25 expression and messenger RNA (mRNA) synthesis
of IL‐2, IL‐4 and IL‐5 in peripheral T cells. A PDE inhibitor, T‐2585, which suppressed
PDE4 isoenzyme with high potency (IC50 = 0·00013 μM)
and PDE7A with low potency (IC50 = 1·7 μM)
inhibited cytokine synthesis, proliferation and CD25 expression in the dose range
at which the drug suppressed PDE7A activity. A potent selective inhibitor of PDE4
(IC50 = 0·00031 μM), RP 73401, which did
not effectively suppress PDE7A (IC50 > 10 μM),
inhibited the Df‐ and anti‐CD3 MoAb‐stimulated responses only weakly, even
at 10 μM. PDE7 may play a critical role in the regulation of human T cell function, and thereby selective PDE7 inhibitors have the potential to be used to treat immunological and inflammatory disorders.
T-cell-replacing factor (TRF) is a T-cellderived factor required for terminal differentiation of activated B cells to immunoglobulin-secreting cells. Previous studies have shown that a murine T-cell hybrid (B151K12) produces factor(s) that (i) induce immunoglobulin secretion by the B-cell leukemia line BCL1 and secondary anti-2,4-dinitrophenyl IgG synthesis in vitro by dinitrophenyl-primed B cells (TRF activity) and (ii) cause proliferation of the BCL1 cells [B-cell growth factor II (BCGF-H) activity]. Both activities appear to be associated with the same molecule. Here we report the production of a monoclonal antibody to murine TRF. The monoclonal antibody, designated TB13, strongly inhibited both TRF and BCGF-II activities and absorbed TRF-as well as BCGF-II-active molecules produced by B151K12 and by Xenopus oocytes that had been injected with mRNA transcribed from plasmid pSP6K-mTRF23. Inhibition was linearly dependent on the concentration of both TB13 and TRF. Monoclonal antibody TB13 did not inhibit the activities of B-cell stimulatory factor 1, interleukin 1, interleukin 2, or interleukin 3. TRF activity in dissolved samples of immunoprecipitates obtained with TB13 was recovered after NaDodSO4/PAGE, in the fractions corresponding to a protein band at Mr 46,000. Our results indicate that monoclonal antibody TB13 recognizes a molecule that has both TRF and BCGF-II activities.
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