The role of eosinophils in ocular allergy.
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Conjunctivitis, Allergic↗
Biomedical subjects
Sanjiv Sur
Publications and source records attributed to Sanjiv Sur.
Interleukin-12: potential role in asthma therapy.
Asthma is an inflammatory disease of the airways leading to significant morbidity and mortality. With advances in the understanding of the molecular and cellular mechanisms involved in the asthmatic response, researchers have identified specific mediators that may be targeted to control the inflammatory state of asthma. The Th2 hypothesis proposes that the inflammation in asthma arises from an imbalance between the two CD4+ T lymphocyte subsets, T helper (Th) type 1 and Th2. Th2 cells release many cytokines that have been shown to regulate the inflammatory response, while the Th1 cytokines counteract this response. The Th1 cytokine, interleukin (IL)-12, has been a target of intense study because it mediates the Th1 response and offers a means of modifying the asthmatic inflammatory response. Numerous murine studies have shown that this cytokine can potently inhibit allergic airway inflammation in asthma. Inhalation of IL-12 has been shown to increase its efficacy in inhibiting allergic inflammation in murine models while decreasing adverse effects seen with systemic administration of this cytokine. However, an initial study of inhaled IL-12 in humans with asthma was terminated because of adverse effects. The use of systemically administered IL-12 in patients with asthma has been limited due to cytokine toxicity. Another treatment option that has the potential of inducing a Th1 cytokine response is the use of IL-12 linked to polyethylene glycol (PEG) moieties. This mode of administration is likely to enhance cytokine delivery to the target organ, while decreasing its toxicity. IL-12 gene therapy has also been examined as a means of suppressing airway hyperreactivity in murine asthma, but its potential in human asthma has not been explored. Several recent studies have investigated the role of CpG DNA motifs as endogenous inducers of IL-12 with encouraging results in both mice and humans. These studies may result in novel Th1- inducing CpG-based immunotherapies for asthma.
Adjuvants, Immunologic↗
Safe administration of a humanized murine antibody after anaphylaxis to a chimeric murine antibody.
BACKGROUND: Basiliximab and daclizumab are potent and relatively safe immunosuppressive induction agents used in transplantation. These chimeric or humanized monoclonal antibodies, respectively, act by binding to the alpha chain of interleukin-2 receptors on activated T lymphocytes. Herein, the authors describe successful transplant induction therapy with a humanized murine antibody in a patient with a history of anaphylaxis to a chimeric murine antibody. METHODS: The authors report a 42-year-old woman who received a dose of basiliximab without adverse reaction before an anticipated renal transplant that was canceled. Two weeks later, she received a second dose of basiliximab. Within 10 min of receiving the second dose, she developed chest tightness, shortness of breath, tongue swelling, diffuse pruritic rash, and skin flushing. RESULTS: The authors hypothesized that her anaphylaxis was mediated by immunoglobulin (Ig) E antibodies to basiliximab. Consistent with this hypothesis, intradermal administration of a 1:100 dilution of basiliximab induced a 10 x 10-mm flare. The authors sought to find an alternative immunosuppressive agent for this patient. The patient elicited prick and intradermal skin testing responses to horse and rabbit polyclonal antithymocyte antibody preparations. However, she mounted neither a prick nor an intradermal response to daclizumab. The patient was administered daclizumab without any adverse effects. CONCLUSIONS: The negative skin test and safe administration of daclizumab is surprising because the similarity of these hybrid antibodies would have predicted similar IgE responsiveness and clinical outcome. The authors propose that patients who develop anaphylaxis to basiliximab or other chimeric antibodies may be candidates for treatment with a humanized antibody preparation such as daclizumab in the presence of a negative skin test to the humanized agent.
Adult↗
Identification of UNC119 as a novel activator of SRC-type tyrosine kinases.
Lyn, an Src-type tyrosine kinase, is associated with the interleukin (IL)-5 receptor in eosinophils. The mechanism of its activation is unknown. Through yeast two-hybrid screening we have cloned and characterized a new signaling molecule, Unc119, that associates with IL-5Ralpha and Src family tyrosine kinases. Unc119 induces the catalytic activity of these kinases through interaction with Src homology 2 and 3 domains. IL-5 stimulation of eosinophils increases Unc119 association with Lyn and induces its catalytic activity. Lyn is important for eosinophil survival. Eosinophils that are transduced with Unc119 have increased Lyn activity and demonstrate prolonged survival in the absence of IL-5. Inhibition of Unc119 down-regulates eosinophil survival. To our knowledge Unc119 is the first receptor-associated activator of Src family tyrosine kinases.
Amino Acid Sequence↗
In vivo role of p38 mitogen-activated protein kinase in mediating the anti-inflammatory effects of CpG oligodeoxynucleotide in murine asthma.
DNA containing unmethylated CpG motifs is intrinsically immunostimulatory, inducing the production of a variety of cytokines and chemokines by immune cells. The strong Th1 response triggered by CpG oligodeoxynucleotide (ODN) inhibits the development of Th2-mediated allergic asthma in mice. This work documents that CpG ODN-induced IL-12 production plays a critical role in this process, because intrapulmonary CpG ODN inhibits allergic inflammation in wild-type but not IL-12(-/-) mice. CpG ODN rapidly localized to alveolar macrophages (AM), thereby triggering the phosphorylation of p38 mitogen-activated protein kinase (MAP kinase). AM cultured with CpG but not control ODN up-regulated IL-12 p40 expression and release, and these effects were blocked by the highly specific p38 MAP kinase inhibitor SB202190. Intrapulmonary administration of this inhibitor blocked the ability of CpG ODN to produce IL-12 in the lungs and reversed the anti-inflammatory effects of CpG ODN on allergic lung inflammation. These findings indicate that IL-12 production by AM is stimulated by intrapulmonary CpG ODN administration through a p38 MAP kinase-dependent process, and IL-12 is a key cytokine that mediates CpG ODN-induced protection against allergic lung inflammation.
Adjuvants, Immunologic↗
Lyn tyrosine kinase is important for IL-5-stimulated eosinophil differentiation.
IL-5 plays a pivotal role in growth and differentiation of eosinophils. The signal transduction mechanism of IL-5Ralpha is largely unknown. We have demonstrated that IL-5 induces tyrosine phosphorylation of IL-5Ralpha in eosinophils. To identify IL-5Ralpha-associated tyrosine kinases, we have examined the expression of Src family tyrosine kinases in eosinophils. Among the Src family members, Lyn, Hck, Fgr, and Lck are present in eosinophils, and, among these four kinases, only Lyn is associated with the IL-5Ralpha under basal conditions. We also confirm the association of Janus kinase (Jak)2 with IL-5Ralpha. Lyn kinase phosphorylates both IL-5Ralpha and betacR in vitro. The importance of Lyn kinase for eosinophil differentiation was studied using antisense oligodeoxynucleotides. Lyn antisense oligodeoxynucleotide blocks eosinophil differentiation from stem cells in a dose-dependent manner. The Jak2 inhibitor tyrphostin AG490 also inhibits eosinophil differentiation. The importance of Lyn for eosinophil differentiation was further studied using Lyn knockout mice. The IL-5-stimulated eosinophil differentiation from bone marrow cells is significantly inhibited in Lyn(-/-) mice as compared with that in control mice. We conclude that both Lyn and Jak2 play an essential role in IL-5Ralpha signaling, leading to eosinophil differentiation. The effect of Lyn appears to be relatively specific for the eosinophilic lineage.
Animals↗
CCL7 and CXCL10 orchestrate oxidative stress-induced neutrophilic lung inflammation.
Oxidative stress from ozone (O(3)) exposure augments airway neutrophil recruitment and chemokine production. We and others have shown that severe and sudden asthma is associated with airway neutrophilia, and that O(3) oxidative stress is likely to augment neutrophilic airway inflammation in severe asthma. However, very little is known about chemokines that orchestrate oxidative stress-induced neutrophilic airway inflammation in vivo. To identify these chemokines, three groups of BALB/c mice were exposed to sham air, 0.2 ppm O(3), or 0.8 ppm O(3) for 6 h. Compared with sham air, 0.8 ppm O(3), but not 0.2 ppm O(3), induced pronounced neutrophilic airway inflammation that peaked at 18 h postexposure. The 0.8 ppm O(3) up-regulated lung mRNA of CXCL1,2,3 (mouse growth-related oncogene-alpha and macrophage-inflammatory protein-2), CXCL10 (IFN-gamma-inducible protein-10), CCL3 (macrophage-inflammatory protein-1alpha), CCL7 (monocyte chemoattractant protein-3), and CCL11 (eotaxin) at 0 h postexposure, and expression of CXCL10, CCL3, and CCL7 mRNA was sustained 18 h postexposure. O(3) increased lung protein levels of CXCL10, CCL7, and CCR3 (CCL7R). The airway epithelium was identified as a source of CCL7. The role of up-regulated chemokines was determined by administering control IgG or IgG Abs against six murine chemokines before O(3) exposure. As expected, anti-mouse growth-related oncogene-alpha inhibited neutrophil recruitment. Surprisingly, Abs to CCL7 and CXCL10 also decreased neutrophil recruitment by 63 and 72%, respectively. These findings indicate that CCL7 and CXCL10, two chemokines not previously reported to orchestrate neutrophilic inflammation, play a critical role in mediating oxidative stress-induced neutrophilic airway inflammation. These observations may have relevance in induction of neutrophilia in severe asthma.
Adjuvants, Immunologic↗
Asthma: future directions.
Asthma continues to be a significant health care problem, as reflected by the increasing rise in disease morbidity and mortality. Because steroids are relatively safe, clinically effective, and easy to administer, they remain the gold standard of treatment. After many decades of use, however, it is apparent that inhaled corticosteroids have failed to halt the progression of the asthma epidemic. Newer, more effective drugs are being developed to combat this disease, and the interest in developing new medications to treat allergic disease and asthma has increased exponentially. The financial burden of asthma has also been a significant motivating factor in the development of new medications. It is estimated that in 1998 the total cost of asthma on society was $11 billion [175]. This consideration has further intensified the quest to develop more effective asthma medications. Table 1 reviews the wide array of drugs currently being investigated. With the development and approval of novel asthma treatments, millions of asthma sufferers will undoubtedly have increased therapeutic options for control of their disease in the near future.
Anti-Asthmatic Agents↗