Bone marrow stromal cells use TGF-beta to suppress allergic responses in a mouse model of ragweed-induced asthma.

Bone marrow stromal cells [BMSCs; also known as mesenchymal stem cells (MSCs)] effectively suppress inflammatory responses in acute graft-versus-host disease in humans and in a number of disease models in mice. Many of the studies concluded that BMSC-driven immunomodulation is mediated by the suppression of proinflammatory Th1 responses while rebalancing the Th1/Th2 ratio toward Th2. In this study, using a ragweed induced mouse asthma model, we studied if BMSCs could be beneficial in an allergic, Th2-dominant environment. When BMSCs were injected i.v. at the time of the antigen challenge, they protected the animals from the majority of asthma-specific pathological changes, including inhibition of eosinophil infiltration and excess mucus production in the lung, decreased levels of Th2 cytokines (IL-4, IL-5, and IL-13) in bronchial lavage, and lowered serum levels of Th2 immunoglobulins (IgG1 and IgE). To explore the mechanism of the effect we used BMSCs isolated from a variety of knockout mice, performed in vivo blocking of cytokines and studied the effect of asthmatic serum and bronchoalveolar lavage from ragweed challenged animals on the BMSCs in vitro. Our results suggest that IL-4 and/or IL-13 activate the STAT6 pathway in the BMSCs resulting in an increase of their TGF-beta production, which seems to mediate the beneficial effect, either alone, or together with regulatory T cells, some of which might be recruited by the BMSCs. These data suggest that, in addition to focusing on graft-versus-host disease and autoimmune diseases, allergic conditions--specifically therapy resistant asthma--might also be a likely target of the recently discovered cellular therapy approach using BMSCs.

Inhibitory receptor gp49B regulates eosinophil infiltration during allergic inflammation.

gp49B, an Ig-like receptor, negatively regulates the activity of mast cells and neutrophils through cytoplasmic immunoreceptor tyrosine-based inhibition motifs. To characterize the role of gp49B further in vivo, gp49B-deficient mice were tested in two allergic models. Responses to ragweed (RW) challenge in the lung and conjunctiva were assessed in models of allergic inflammation and during an infection with parasitic larvae of the nematode Ascaris suum. Infiltration by inflammatory cells into the lung during allergic responses was under negative control of the inhibitory receptor gp49B. Furthermore, an increase in conjunctival inflammation with a predominance of eosinophils, neutrophils, and degranulated mast cells was observed in RW-sensitized, gp49B-deficient mice, which had been challenged in the eye, as compared with C57BL/6 wild-type (WT) controls. Finally, an increase in allergic inflammation in the lungs of A. suum-infected, RW-sensitized mice was observed upon RW challenge, as compared with C57BL/6 WT controls. The observed influx of eosinophils into mucus membranes is characteristic of allergic asthma and allergic conjunctivitis and may contribute to airway hyper-responsiveness, airway remodeling, and mucus production. Expression of gp49B was detected on peripheral eosinophils of control mice and on eosinophils from lungs of mice treated with RW, suggesting a role for gp49B on eosinophils in dampening allergic inflammatory responses.

IL-10 confers protection from mast cell degranulation in a mouse model of allergic conjunctivitis.

IL-10 is a regulatory cytokine known to inhibit allergic and inflammatory events. Mast cells (MC) are effector cells which when stimulated release histamine, chemokines and cytokines that initiate the allergic inflammatory response. Recent studies have shown that IL-10 regulates MC function by affecting cytokine production and expression of FcvarepsilonR1 in in vitro assays. Using IL-10 knockout (IL10KO) mice, we examined the effect of its absence on MC susceptibility to degranulation by the basic secretagogue, Compound 48/80 (C48/80). C48/80 is a receptor mimetic that directly activates G proteins and stimulates vigorous MC degranulation. For these studies we stimulated conjunctival MC with C48/80 and found that conjunctival MC of IL10KO mice exhibit increased degranulation compared with wild type mice. Reconstitution of IL10KO mice by adding rIL-10 24h prior to challenge with C48/80 conferred increased resistance of MC to the degranulatory effects of C48/80. The protective effect therefore appears to be due to the presence of IL-10. This is the first in vivo rodent study which reports a novel role of IL-10 in stabilizing mast cells from degranulation by a secretagogue, by as of yet an unknown mechanism.

Ascaris suum-derived products suppress mucosal allergic inflammation in an interleukin-10-independent manner via interference with dendritic cell function.

We have previously demonstrated that protection from allergic inflammation by Ascaris suum infection was characterized by a global increase in interleukin-10 (IL-10) and the development of protective CD4(+)/CD25(+) T cells (L. Schopf, S. Luccioli, V. Bundoc, P. Justice, C. C. Chan, B. J. Wetzel, H. H. Norris, J. F. Urban, Jr., and A. Keane-Myers, Investig. Ophthalmol. Vis. Sci. 46:2772-2780, 2005). Here, we used A. suum pseudocoelomic fluid (PCF) in lieu of infection to define molecular mechanisms of allergic protection in a mouse model of allergic inflammation. Mice were sensitized with ragweed (RW) and PCF (RW/PCF), PCF alone, or RW alone and then challenged intratracheally, intranasally, and supraocularly with RW. Histological examination of the eyes and lungs, analysis of the bronchoalveolar lavage fluid (BALF), and characterization of ex vivo cytokine responses were performed to determine allergic inflammatory responses. RW/PCF-treated mice had suppressed allergic immune responses compared to mice given RW alone. To investigate whether IL-10 was involved in PCF-mediated allergic protection, similar experiments were performed using mice genetically deficient for IL-10. Persistent protection from allergic disease was observed in the absence of IL-10, indicating the primary mechanism of PCF protection is IL-10 independent. Ex vivo and in vitro analysis of PCF-treated dendritic cells (DC) demonstrated reduced activation receptor expression and cytokine production in response to either RW or lipopolysaccharide stimulation. These findings extend previous studies that showed infection with A. suum alters expression of allergic disease and suggest that PCF can contribute to this effect by interference with DC function.

Animal models of ocular allergy.

PURPOSE OF REVIEW: This review focuses on reports on animal models of ocular allergy published within the past year. A number of animal models are currently being used to clarify the pathophysiology of ocular allergy and to improve the therapeutic interventions for this disease. RECENT FINDINGS: Published literature examined the role of cytokines and other effector molecules which drive the immunopathology of ocular allergies in several animal models. Animal models were also used to compare the safety and efficacy of currently available drugs, and were utilized in initial trials of novel therapeutic agents. Novel therapeutic options being studied include DNA immunizations and recombinant peptides that block enzymes involved in the inflammatory processes. SUMMARY: Several animal models are currently being used in the study of ocular allergy. These include different strains within the mouse, rat, guinea pig, rabbit and dog species. Continuing investigations are needed to elucidate the complex molecular and cellular processes involved in the pathogenesis of ocular allergies. A better understanding of the interplay of effector cells, cytokines, adhesion molecules and a number of other inflammatory mediators will broaden our knowledge of the pathophysiology of ocular allergy and allow improved therapeutic options for this disease.