Serious food allergies are a significant health problem for both the affected individuals and in the context of public health, where general measures to prevent life-threatening exposure to allergic individuals are a major logistical challenge. Approximately 2.1% of US children are affected with peanut (PN) allergies, and PN anaphylaxis is both the primary cause of food-related deaths and accounts for 60% of all fatal/near-fatal anaphylactic reactions. Peanut allergy commonly develops early in childhood, and unlike many food allergies does not wane over time in ~80% of affected individuals. Current management is limited to strict avoidance and rescue epinephrine upon exposure. Thus the young and healthy patient population at risk, the severity of PN hypersensitivity, its rising prevalence and the publc health costs to limit accidental exposure underscores the great need for new treatment strategies. We have reasoned that targeting the immune components necessary for the anaphylactic response to PN, and then preventing their regeneration, will greatly reduce the risk of life-threatening exposures. It is clear that anaphylaxis is exquisitely dependent on PN-specific IgG and IgE antibody (Ab) titers. How these titers are sustained is poorly characterized, and we have demonstrated for the first time there are both antigen (Ag)-dependent (e.g. wane over time) and Ag-independent (persistent >12 mos) antibody titers in PN-sensitized mice that are not re-exposed to PN. This was reflected in diminished but persistent anaphylactic responses upon challenge 6-12 mos after initial sensitization. How PN-specific Ab titers persist long-term without re-exposure is unknown, but durable humoral immunity following vaccination requires continuous Ag-independent immunoglobulin production by long lived plasma cells (LLPC) that can survive for decades/lifetime in specific bone marrow (BM) niches. We have recently reported that an essential requirement for LLPC survival and long-term humoral immunity is plasma cell (PC)-intrinsic function of CD28. CD28 is predominantly characterized as the prototypic costimulatory receptor on T cells that, in conjunction with TCR signaling, results in T cell activation, enhanced function (including help necessary for B cell responses) and survival. PC also express CD28, and delivers an essential pro-survival signal to LLPC that is necessary for long-term maintenance of antigen-specific Ab titers in vivo. This raises the novel hypothesis that CD28 activation plays a central role in PN anaphylaxis by both costimulating Ag-dependent helper T cell activation during sensitization/recall responses and maintaining Ag-independent LLPC production of anti-PN IgG/IgE titers. We propose that the novel approach of targeting CD28 will eliminate established PN-specific antibody titers and prevent resensitization by tolerizing PN-specific helper T cells, leading to a significant reduction of PN hypersensitivity tht can be maintained without chronic continuing therapy.
The Specific Aims are: 1). Define the role of CD28 in generating and maintaining PN-specific immune responses involved in PN anaphylaxis, 2). Determine if blocking CD28 activation overcomes established PN hypersensitivity.

Public Health Relevance

Serious food allergies are a significant health problem for both the affected individuals and in the context of public health, where general measures to prevent life-threatening exposure to allergic individuals are a major logistical challenge. Approximately 2.1% of US children are affected with peanut (PN) allergies, and PN anaphylaxis is both the primary cause of food-related deaths and accounts for 60% of all fatal/near-fatal anaphylactic reactions. Current management is limited to strict avoidance and rescue epinephrine upon exposure. We hypothesize that activation of the CD28 receptor on T cells and antibody-producing plasma cells (PC) plays a central role in PN anaphylaxis by activating PN-specific T cells and maintaining production of anti- PN IgG/IgE antibodies. This points to a novel therapeutic approach of targeting CD28 to eliminate established PN-specific antibody titers and prevent resensitization by tolerizing PN-specific T cells, leading to a significant reduction of PN hypersensitivity that can be maintained without chronic continuing therapy.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI105502-02
Application #
8713918
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Davidson, Wendy F
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
City
Buffalo
State
NY
Country
United States
Zip Code
14263
Murray, Megan E; Gavile, Catherine M; Nair, Jayakumar R et al. (2014) CD28-mediated pro-survival signaling induces chemotherapeutic resistance in multiple myeloma. Blood 123:3770-9