Tolerance Following Peanut Oral Immunotherapy
| Status: | Active, not recruiting |
|---|---|
| Conditions: | Allergy, Allergy, Neurology |
| Therapuetic Areas: | Neurology, Otolaryngology |
| Healthy: | No |
| Age Range: | 7 - 55 |
| Updated: | 4/21/2016 |
| Start Date: | May 2013 |
| End Date: | July 2016 |
Clinical Desensitization and Tolerance Following Peanut Oral Immunotherapy and Subsequent Allergen Avoidance
The unifying objective of this project is to determine whether peanut oral immunotherapy (PN
OIT) induced clinical tolerance in the context of food allergy is significantly associated
with the expansion of a specific regulatory T cell subset (CD45RA- CD25++ FoxP3++) that is
thought to be inducible in the gut-associated lymphoid compartment and associated with
immunological tolerance.
The hypothesis of the study is that the induction of Treg cells will be associated with
clinical tolerance.
The investigators will measure the change from baseline of induced Treg cells as a frequency
of total CD4 T cells during active treatment and compare that between participants who
achieve significant clinical tolerance (Tolerance and Partial Tolerance Groups as defined
below) and those who do not (Treatment Failure Group).
OIT) induced clinical tolerance in the context of food allergy is significantly associated
with the expansion of a specific regulatory T cell subset (CD45RA- CD25++ FoxP3++) that is
thought to be inducible in the gut-associated lymphoid compartment and associated with
immunological tolerance.
The hypothesis of the study is that the induction of Treg cells will be associated with
clinical tolerance.
The investigators will measure the change from baseline of induced Treg cells as a frequency
of total CD4 T cells during active treatment and compare that between participants who
achieve significant clinical tolerance (Tolerance and Partial Tolerance Groups as defined
below) and those who do not (Treatment Failure Group).
Clinical Objectives:
1. To evaluate whether PN OIT induces increased tolerance, defined as a statistically
significant increase in the median eliciting dose (ED) from a double-blind
placebo-controlled food challenge (DBPCFC) before and after treatment with PN OIT and
after subsequent allergen avoidance.
2. To evaluate whether PN OIT induces clinical desensitization, defined as 1) a median
10-fold or greater increase in ED at DBPCFC before and after PN OIT treatment period 2)
a statistically significant higher median ED at DBPCFC following treatment period
between active and control treatment; and 3) a significantly lower frequency of
accidental ingestion reactions in active versus control treatment.
3. To evaluate the safety of PN OIT.
Mechanistic Objectives:
1. To determine whether PN OIT induces a statistically significant increase in the TCR
clonal diversity of Treg populations during active treatment among participants who
achieve increased clinical tolerance (Tolerance and Partial Tolerance Groups as defined
in clinical endpoints) versus the Treatment Failure Group.
2. To determine whether PN OIT suppresses mast cells by inducing a significant suppression
of the median ED on end-point dilution skin testing in actively treated participants by
the end of maintenance therapy.
3. To determine whether PN OIT suppresses basophils as defined by a 10-fold suppression of
peanut-specific basophil ED in actively treated participants by end of a maintenance
period.
4. To determine whether either mast cell or basophil suppression at the end of maintenance
therapy is significantly associated with clinical outcomes following avoidance.
Exploratory Objectives:
1. To describe the gene expression profiles and clonal diversity of regulatory and
effector T cell subsets before and after OIT to better understand the phenotype and
ontogeny of these subsets and potentially discover new therapeutic pathways.
2. To engineer human MHC class II tetramers on common HLA backgrounds and map T cell
epitopes of the dominant peanut allergens for use in validating earlier findings and
for future studies of peanut-specific immune responses in humans.
1. To evaluate whether PN OIT induces increased tolerance, defined as a statistically
significant increase in the median eliciting dose (ED) from a double-blind
placebo-controlled food challenge (DBPCFC) before and after treatment with PN OIT and
after subsequent allergen avoidance.
2. To evaluate whether PN OIT induces clinical desensitization, defined as 1) a median
10-fold or greater increase in ED at DBPCFC before and after PN OIT treatment period 2)
a statistically significant higher median ED at DBPCFC following treatment period
between active and control treatment; and 3) a significantly lower frequency of
accidental ingestion reactions in active versus control treatment.
3. To evaluate the safety of PN OIT.
Mechanistic Objectives:
1. To determine whether PN OIT induces a statistically significant increase in the TCR
clonal diversity of Treg populations during active treatment among participants who
achieve increased clinical tolerance (Tolerance and Partial Tolerance Groups as defined
in clinical endpoints) versus the Treatment Failure Group.
2. To determine whether PN OIT suppresses mast cells by inducing a significant suppression
of the median ED on end-point dilution skin testing in actively treated participants by
the end of maintenance therapy.
3. To determine whether PN OIT suppresses basophils as defined by a 10-fold suppression of
peanut-specific basophil ED in actively treated participants by end of a maintenance
period.
4. To determine whether either mast cell or basophil suppression at the end of maintenance
therapy is significantly associated with clinical outcomes following avoidance.
Exploratory Objectives:
1. To describe the gene expression profiles and clonal diversity of regulatory and
effector T cell subsets before and after OIT to better understand the phenotype and
ontogeny of these subsets and potentially discover new therapeutic pathways.
2. To engineer human MHC class II tetramers on common HLA backgrounds and map T cell
epitopes of the dominant peanut allergens for use in validating earlier findings and
for future studies of peanut-specific immune responses in humans.
Inclusion Criteria:
- Diagnosis of peanut allergy by a positive skin prick test to peanut (reaction wheal
at least 5 mm larger than saline control) and by medical history or Serum
peanut-specific IgE >5 kU/L at screening visit.
- Ara h 2 specific IgE >0.35 kU/L at screening visit
- Ability to provide informed consent.
- Males and females of all ethnic/racial groups aged 7-55 years old who are otherwise
healthy.
- React to less than 443 mg of peanut protein during DBPCFC1
Exclusion Criteria:
- History of severe anaphylaxis as defined by hypoxia (cyanosis or SpO2 <92% during
reaction), documented hypotension (documented systolic BP >30% below predicted normal
for sex, height, weight or from known baseline), neurological compromise (confusion,
loss of consciousness), or incontinence.
- Severe or Moderate asthma as defined using the severity criteria of the current NHBLI
Guidelines for the Diagnosis and Management of Asthma
(http://www.nhlbi.nih.gov/guidelines/asthma/).
- Poorly-controlled asthma as defined by FEV1 <80% or any of the following symptoms:
nighttime awakening >2 days/week or rescue medication use >2 days / week.
- Diagnosis of other severe or complicating medical problems, including autoimmune or
chronic immune inflammatory conditions or gastrointestinal inflammatory conditions,
including Celiac Disease, Inflammatory Bowel Disease and Eosinophilic
Gastrointestinal Disorders
- Inability to cooperate with and/or perform oral food challenge procedures.
- Primary Immune Deficiency
- Allergy to oat confirmed by skin prick testing and history
- Current use of beta blockers, angiotensin converting enzyme inhibitors, or monoamine
oxidase inhibitors
- Women of childbearing potential who are pregnant, planning to become pregnant, or
breastfeeding
- Hemoglobin level less than 12.5 gm/dL at screening. Weight <23 kg
- Use within the past 6 months of other systemic immunomodulatory treatments including
allergen immunotherapy, or use of biologics with an immune target, including
omalizumab.
- Past or current medical problems or findings from physical examination or laboratory
testing that are not listed above, which, in the opinion of the investigator, may
pose additional risks from participation in the study, may interfere with the
participant's ability to comply with study requirements or that may impact the
quality or interpretation of the data obtained from the study may also exclude a
participant from the study.
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