Modulation of the Effects of Lung Immune Response on Bone Marrow by Oral Antigen Exposure

Abstract

Allergic airway inflammation is attenuated by oral tolerization (oral exposure to allergen, followed by conventional sensitization and challenge with homologous antigen), which decreases airway allergen challenge-induced eosinophilic infiltration of the lungs and bone marrow eosinophilia. We examined its effects on bone marrow eosinophil and neutrophil production. Mice of wild type (BP-2, BALB/c, and C57BL/6) and mutant strains (lacking iNOS or CD95L) were given ovalbumin (OVA) or water (vehicle) orally and subsequently sensitized and challenged with OVA (OVA/OVA/OVA and H2O/OVA/OVA groups, resp.). Anti-OVA IgG and IgE, bone marrow eosinophil and neutrophil numbers, and eosinophil and neutrophil production ex vivo were evaluated. T lymphocytes from OVA/OVA/OVA or control H2O/OVA/OVA donors were transferred into naïve syngeneic recipients, which were subsequently sensitized/challenged with OVA. Alternatively, T lymphocytes were cocultured with bone marrow eosinophil precursors from histocompatible sensitized/challenged mice. OVA/OVA/OVA mice of the BP-2 and BALB/c strains showed, relative to H2O/OVA/OVA controls, significantly decreased bone marrow eosinophil counts and ex vivo eosinopoiesis/neutropoiesis. Full effectiveness in vivo required sequential oral/subcutaneous/intranasal exposures to the same allergen. Transfer of splenic T lymphocytes from OVA/OVA/OVA donors to naive recipients prevented bone marrow eosinophilia and eosinopoiesis in response to recipient sensitization/challenge and supressed eosinopoiesis upon coculture with syngeneic bone marrow precursors from sensitized/challenged donors.

α‐Galactosylceramide suppresses murine eosinophil production through interferon‐γ‐dependent induction ofNOsynthase andCD95

“…The underlying mechanism required iNOS and CD95, was mediated by IFN‐γ, induces apoptosis and was blocked by dexamethasone and by the pro‐allergic lipid mediator, LTD 4 , as well as by NSAIDs (which induce cysteinyl‐leukotrienes). Together, these observations: (i) show, for the first time, a regulatory role for iNKT cells in eosinophil production, which may be relevant to their reportedly beneficial effects in asthma models; (ii) establish the iNOS‐CD95L pathway as inducible by innate cellular immunity; and (iii) substantially increase understanding of this pathway by highlighting its relationship to the pro‐allergic effects of dexamethasone and cysteinyl‐leukotrienes, and to recent observations on the control of eosinopoiesis by regulatory lymphocytes (Xavier‐Elsas et al ., ) and glucocorticoids (Masid‐de‐Brito et al ., ).…”

“…This approach allowed us to define unambiguously iNKT cell function on the basis of α‐GalCer reactivity and restriction by CD1d, just as they can be defined by flow cytometry on the basis of binding of α‐GalCer/CD1d fluorescent complexes (Matsuda et al ., ). We conclude that α‐GalCer‐activated iNKT cells are one of the regulatory lymphocyte subsets that can suppress eosinopoiesis in bone marrow, which differs from those previously described in an oral tolerization model (Xavier‐Elsas et al ., ) because it is CD1d‐restricted.…”

The In Vivo Granulopoietic Response to Dexamethasone Injection Is Abolished in Perforin‐Deficient Mutant Mice and Corrected by Lymphocyte Transfer from Nonsensitized Wild‐Type Donors

“…As such, it extends the range of manifestations associated with perforin deficiency and raises the issue of how perforin contributes to regulation of granulocyte lineages in vivo. Because the wild-type lymphocyte populations interact with a drug (dexamethasone) which initiates signaling through the RU486-inhibitable glucocorticoid receptor, to stimulate in vivo eosinophil and neutrophil production, these observations may be relevant to processes in which bone-marrow is stimulated by immune responses [ 9 ] or trauma [ 10 ] with involvement of the same receptor and of endogenous glucocorticoids released by the adrenal glands.…”

“…In both cases, allergen challenge of sensitized subjects increases eosinopoiesis in the bone-marrow [ 7 , 8 ]. This effect is antigen-specific and can be abolished by inducing oral tolerance to the allergen, which affects both eosinophils and neutrophils in bone-marrow [ 9 ]. The effects of oral tolerization in bone-marrow neutrophil and eosinophil granulocytes can be duplicated by transfer of splenic T lymphocyte subpopulations from tolerized/sensitized/challenged donors to histocompatible naive recipients [ 9 ].…”

“…This effect is antigen-specific and can be abolished by inducing oral tolerance to the allergen, which affects both eosinophils and neutrophils in bone-marrow [ 9 ]. The effects of oral tolerization in bone-marrow neutrophil and eosinophil granulocytes can be duplicated by transfer of splenic T lymphocyte subpopulations from tolerized/sensitized/challenged donors to histocompatible naive recipients [ 9 ]. These observations highlight the importance of acquired cellular immunity in regulating the hematological response to allergen sensitization and challenge.…”