2008 — 2009 |
Bryce, Paul J |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
A Novel Murine Model of Food Allergy to Peanut or Egg @ Northwestern University
[unreadable] DESCRIPTION (provided by applicant): Food allergy affects approximately 11 million Americans and is escalating in prevalence. There are currently no available treatments and affected individuals are dependent on strict elimination diets and epinephrine to prevent the life-threatening reactions if accidental exposure occurs. Very little is known about the mechanisms that underlie the incidence, severity and spectrum of responses seen in food allergic patients. A significant reason for this has been the lack of an animal model that recapitulates the physiological and immunological features of food allergy. Previously utilized models are severely limited to specific strains of mice, large antigen doses or nonphysiological routes of immunization and have failed to elicit the hallmark immunological responses. We have developed a novel model using commonly used inbred mouse strains, antigen doses that are [unreadable] comparable to dietary levels and exposure via ingestion. Our model uses administration of food antigens (egg and peanut) concurrently with low amounts of Staphylococcus aureus enterotoxin B (SEB), a common food contaminant. This elicits immunological and physiological responses that mirror food allergic patients and represents a significant advance from other models. This proposal centers upon improving food allergy research in three directions: optimization of our model (Aim 1), development of state-of-the-art physiological monitoring (Aim 2) and potential application to screening therapeutics (Aim 3). There aims are: Aim 1: Establish the threshold levels of sensitizing antigen, SEB and challenging antigen doses. Aim 2: Develop methodology that will allow standardized, investigator independent, methods for monitoring physiological responses in our food allergy model. [unreadable] Aim 3: Test the effectiveness of a highly novel, bispecific antibody that inhibits IgE-mediated allergic [unreadable] responses in preventing anaphylaxis to peanut. We believe that these aims will facilitate our abilities to investigate the pathogenesis and immunological mechanisms underlying this disease and prove a novel, important tool for developing future therapies and clinical treatments. [unreadable] [unreadable] [unreadable]
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2008 — 2012 |
Bryce, Paul J |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Regulation of T Cell Migration by Histamine @ Northwestern University At Chicago
DESCRIPTION (provided by applicant): The recruitment of T lymphocytes into tissues is essential for local immune and inflammatory responses in both health and disease. The mechanisms that regulate T lymphocyte trafficking into tissues are not well characterized. Mast cells are constitutively resident in all tissues and are a rich source of preformed mediators. One of the most abundant mediators is histamine which is release upon mast cell activation by antigen- mediated activation or to insult. Despite being one of the most extensively studied molecules in biology, histamine has only recently been found to have several novel immunoregulatory properties and a fourth receptor was discovered in 2000. In addition, there is now growing evidence that other cell types are capable of synthesizing histamine, including dendritic cells and neutrophils.We have made the exciting finding that T cells that lack a specific receptor for histamine, H1R, fail to migrate into the lung upon allergen challenge. Mice lacking H1R also fail to develop allergic airway disease but respond normally to T cell derived mediators or when normal (H1R+) T cells are adoptively transferred. Treatment of wildtype mice with selective pharmacological inhibitors of H1R also reduced allergic airway responses. Based on our preliminary observations, we hypothesize that mast cell release of histamine promotes the recruitment of T cells into tissues and that the expression levels of H1R on T cells serves to regulate this. We predict these processes will be conserved across different tissues and that histamine serves as a ubiquitous regulator of T cell mediated inflammation and immunity. These concepts will be addressed by three specific aims using both in vivo and in vitro approaches: Specific Aim 1 will test the role of tissue-resident mast cells as a source of histamine and test their ability to recruit T lymphocytes in allergic airway disease. Specific Aim 2 will focus on the influence of H1R on T lymphocytes and will investigate the expression of H1R on subsets of T lymphocytes and the functional involvement of H1R in migration and transendothelial trafficking (in collaboration with Dr Joan Cook-Mills). Specific Aim 3 will investigate the involvement of histamine-driven T lymphocyte recruitment to the skin, using models of delayed-type hypersensitivity, and will test the hypothesis that histamine is a ubiqitous mechanism by which T lymphocytes are recruited into tissues.
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2011 |
Bryce, Paul J |
R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
Regulation and Functions of Mast Cell-Derived Il-33 @ Northwestern University At Chicago
IL-33 is a newly identified member of the IL-1 family of cytokines. Administration of recombinant IL-33 has been shown to alter a diverse range of diseases, including atherosclerosis, infection and allergy via its receptor ST2. Endothelial and epithelial cells have been shown to express IL- 33 but in the nucleus where it acts as a transcriptional regulator while we have shown mast cells produce IL-33 during inflammation. As such, IL-33 has been proposed to have duel functions: a immunomodulatory cytokine and a transcriptional regulator. Mast cells are tissue-resident cells and have been shown to be important in controling the generation of immunity in a diverse range of diseases, including autoimmunity, cancer, and allergy. We have discovered that mast cells express IL-33 basally and upregulate expression after activation by crosslinking of IgE by specific antigens. This is highly dependent on calcium, since upregulation was blocked by EDTA and ionomycin was sufficient to induce expression. Unlike endothelial and epithelial cells, we observe IL-33 in both the cytoplasmic and nuclear compartments. We have demonstrated that ST2 and IL-33 are critical for the recruitment of inflammatory cells into the skin during the latephase inflammatory response of anaphylaxis. Based on our preliminary data, we hypothesize that mast cells release IL-33 during activation (extrinisic activity) to promote recruitment and escalation of inflammation, as well as IL-33 altering the transcriptional profile of the mast cell (intrinsic activity) by regulating gene expression. We predict that the expression of IL-33 is highly dependent on calcium and NFAT binding to the proximal promoter region of the il33 gene. These concepts will be addressed by 3 specific aims that utilize both in vitro and in vivo approaches. Specific Aim 1 will test the role of mast cell-derived IL-33 in the generation of tissue inflammation and immunity in models of anaphylaxis. Specific Aim 2 will focus on the effects of IL-33 on regulating mast cell gene expression and chromatin remodeling. Specific Aim 3 will determine the requirements for calcium and NFAT-mediated transcription on the expression of IL-33 in mast cells. Our study will define the mechanisms through which mast cell-derived IL-33 modulates inflammation.
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2013 — 2017 |
Bryce, Paul J |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Regulation of Allergic Inflammation by Histamine @ Northwestern University At Chicago
DESCRIPTION (provided by applicant): Cytokines and their receptors have an incredible ability to regulate a diverse range of cellular responses, important for homeostasis and control of protective immune responses. Increasingly, context or cell-specific influences of cytokines are being observed but the mechanisms that regulate this remain unclear given the limited repertoire of intracellular signaling molecules within the Jak and Stat family. Recently, the concept of modifiers of cytokine receptor functions has emerged, whereby signals from other receptors can alter those through the cytokine receptor. Our exciting findings have established that histamine, acting via its receptor H2R, is necessary for cellular responses to IL-4. This cytokine is critically important in allergic responses and we have demonstrated that H2R KO mice have ablated IgE generation and eosinophil recruitment to the lungs. In studying this interaction further, we have identified that both hematopoietic and non-hematopoietic cells possess histamine-dependent and independent responsiveness to IL-4. We hypothesize that H2R functions as a modifier of signaling from the IL-4 receptor and is necessary for switching from the homeostatic functions of IL-4 to a pro- allergic response. We propose to examine this with three specific aims that investigate this concept in murine models and in allergic patients. Specific Aim 1 will examine the functional requirements for H2R on responses through the IL-4Ralpha chain (in collaboration with Dr Talal Chatila). Specific Aim 2 will map the unique profile of histamine-dependent and independent genes in human and murine cells using state-of-the-art mRNA deep sequencing (in collaboration with Dr Nadereh Jafari). Specific Aim 3 will examine histamine-associated gene patterns in the pathogenesis of eosinophilic esophagitis and build on our existing work demonstrating the mast cells and histamine are important in this disease.
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2013 |
Bryce, Paul J |
R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
Regulation of Food Allergy and Anaphylaxis by Il-33 @ Northwestern University At Chicago
DESCRIPTION (provided by applicant): IL-33 is a recently discovered member of the IL-1 family of cytokines. Administration of recombinant IL-33 has been shown to have profound effects on a diverse range of diseases, including arthritis, infection and allergy that are mediate though its receptor ST2. Several different cell types have been shown to express IL-33 and we, and others, have shown that epithelial cells have a high constitutive expression and release it during damage. Consequently, IL-33 has been coined an alarmin, important for the communication between tissue cells and the immune response. However, we have demonstrated that inflammatory cells, such as mast cells, have low levels at rest but are induced to express IL-33 upon their activation. The functional consequences of these different sources of IL-33 have not been studied and determining these is the basis for our study. Our preliminary data establishes that ST2 is necessary for both the sensitization to allergens, as well as efficiently mounting an inflammatory response when sensitization in bypassed. Interestingly, our findings show that ST2 is only required for sensitization through the intestine and that, by injecting the same antigen, ST2 KO mice are capable of becoming allergic. We hypothesize that epithelial cells are the necessary source of IL-33 that drives allergic sensitization while mast cell-derived IL-33 is the critical signal for inflammation after sensitization has occurred. We wil examine this hypothesis using murine models of food allergy and anaphylaxis that we have developed. Since food allergy is increasing in prevalence and there are very few therapeutic options available at this time, our work has the potential to facilitate new therapies for these patients. We propose to test our hypothesis with two distinct specific aims that address the overall theme of 1) sensitization and 2) elicitation of allergic responses. These aims are: Specific Aim 1: Determine the role of cell-specific IL-33 expression in the generation of peanut-specific antibody and T cell responses. Specific Aim 2: Determine the mechanisms through which IL-33 regulates the generation of tissue inflammation to allergens.
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2014 — 2017 |
Bryce, Paul J |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Regulation of Food Allergy and Anaphylaxis by Il 33 @ Northwestern University At Chicago
DESCRIPTION (provided by applicant): IL-33 is a recently discovered member of the IL-1 family of cytokines. Administration of recombinant IL-33 has been shown to have profound effects on a diverse range of diseases, including arthritis, infection and allergy that are mediate though its receptor ST2. Several different cell types have been shown to express IL-33 and we, and others, have shown that epithelial cells have a high constitutive expression and release it during damage. Consequently, IL-33 has been coined an alarmin, important for the communication between tissue cells and the immune response. However, we have demonstrated that inflammatory cells, such as mast cells [and dendritic cells], have low levels at rest but are induced to express IL-33 upon their activation. The functional consequences of these different sources of IL-33 have not been studied and determining these is the basis for our study. Our preliminary data establishes that ST2 is necessary for both the sensitization to allergens, as well as efficiently mounting an inflammatory response when sensitization in bypassed. Interestingly, our findings show that ST2 is only required for sensitization through the intestine and that, by injecting the same antigen, ST2 KO mice are capable of becoming allergic. We hypothesize that epithelial cells are the necessary source of IL-33 that drives allergic sensitization while mast cell-derived IL-33 is the critical signal for inflammation after sensitization has occurred. We will examine this hypothesis using murine models of food allergy and anaphylaxis that we have developed. Since food allergy is increasing in prevalence and there are very few therapeutic options available at this time, our work has the potential to facilitate new therapies for these patients. We propose to test our hypothesis with two distinct specific aims that address the overall theme of 1) sensitization and 2) elicitation of allergic responses. These aims are: Specific Aim 1: Determine the role of cell-specific IL-33 expression in the generation of peanut-specific antibody and T cell responses. Specific Aim 2: Determine the mechanisms through which IL-33 regulates the generation of tissue inflammation to allergens.
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