Immunologic Basis of Anti-IgE Therapy (Study II: On Patients With Asthma)
| Status: | Completed |
|---|---|
| Conditions: | Allergy, Asthma, Psoriasis, Dermatology, Dermatology, Dermatology |
| Therapuetic Areas: | Dermatology / Plastic Surgery, Otolaryngology, Pulmonary / Respiratory Diseases |
| Healthy: | No |
| Age Range: | 18 - 55 |
| Updated: | 12/9/2017 |
| Start Date: | February 2004 |
| End Date: | December 2008 |
The purpose of this study is to look at measures that will help scientists understand the way
Omalizumab, an FDA-approved anti-allergy medication, works.
Omalizumab, an FDA-approved anti-allergy medication, works.
IgE is a key molecule involved in immediate hypersensitivity and plays a major role in the
pathogenesis of allergic diseases. Recently, a therapy based on the use of anti-IgE antibody
has been developed by a pharmaceutical company, Genentech. A number of clinical trials have
demonstrated that these antibodies are efficacious in treatment of allergies, including
allergic rhinitis and asthma. The medication Omalizumab (Xolair) has recently been approved
by the FDA for treatment of asthma.
The mechanism underlying the beneficial effect of this therapy is not completely understood,
but is likely to be related to the marked reduction in the IgE level. Of note is the
concomitant accumulation of IgE-anti-IgE complexes in the sera. Another remarkable effect of
the treatment is the substantial reduction in the FcεRI level on basophils, which is likely a
key factor contributing to the therapeutic benefit of the drug. The existing literature
suggests that the reduction in the IgE level is likely to result in a down-regulation of
another IgE receptor, FcεRII/CD23. Because of the known immunomodulatory function of FcεRII,
anti-IgE therapy may result in alterations of the immune system, in addition to simple
absorption of IgE.
We propose to conduct mechanistic studies of anti-IgE therapy. The objectives are to address
how anti-IgE therapy works and how it might affect the immune system in general. The proposed
studies also take advantage of this well-defined therapy to address some basic questions
regarding the immune system. Our hypothesis is that anti-IgE therapy may have general effects
on the immune system, such as reduced IgE-mediated antigen presentation by antigen-presenting
cells and suppressed allergen-specific IgE and IgG production. The specific aims of the
proposed research are:
1. Determination of the effect of anti-IgE therapy on FcεRI expression and basophil
responses. We will first confirm that anti-IgE therapy causes a reduction in the FcεRI
level on basophils and then analyze whether this occurs at a transcriptional level. We
will confirm that the therapy causes a reduction in basophil response to cross-linkage
of FcεRI and then determine whether it also affects basophil response induced by non-IgE
stimuli. The effect of the therapy on the FcεRI level on skin mast cells will also be
investigated.
2. Determination of the effect of anti-IgE therapy on FcεRII expression and antigen
presentation. We will determine whether the therapy results in a down-regulation of
FcεRII/CD23 on B cells. Because of the demonstrated function of FcεRII/CD23 in antigen
presentation, we will determine the antigen presentation to T cells by B cells from
anti-IgE-treated and control subjects.
3. Determination of the effect of anti-IgE therapy on antibody production. We will
determine whether anti-IgE therapy results in a suppression of IgE production, in
addition to sequestration of IgE. Whether IgE-anti-IgE complexes directly suppress IgE
production by B cells in vitro will be investigated.
pathogenesis of allergic diseases. Recently, a therapy based on the use of anti-IgE antibody
has been developed by a pharmaceutical company, Genentech. A number of clinical trials have
demonstrated that these antibodies are efficacious in treatment of allergies, including
allergic rhinitis and asthma. The medication Omalizumab (Xolair) has recently been approved
by the FDA for treatment of asthma.
The mechanism underlying the beneficial effect of this therapy is not completely understood,
but is likely to be related to the marked reduction in the IgE level. Of note is the
concomitant accumulation of IgE-anti-IgE complexes in the sera. Another remarkable effect of
the treatment is the substantial reduction in the FcεRI level on basophils, which is likely a
key factor contributing to the therapeutic benefit of the drug. The existing literature
suggests that the reduction in the IgE level is likely to result in a down-regulation of
another IgE receptor, FcεRII/CD23. Because of the known immunomodulatory function of FcεRII,
anti-IgE therapy may result in alterations of the immune system, in addition to simple
absorption of IgE.
We propose to conduct mechanistic studies of anti-IgE therapy. The objectives are to address
how anti-IgE therapy works and how it might affect the immune system in general. The proposed
studies also take advantage of this well-defined therapy to address some basic questions
regarding the immune system. Our hypothesis is that anti-IgE therapy may have general effects
on the immune system, such as reduced IgE-mediated antigen presentation by antigen-presenting
cells and suppressed allergen-specific IgE and IgG production. The specific aims of the
proposed research are:
1. Determination of the effect of anti-IgE therapy on FcεRI expression and basophil
responses. We will first confirm that anti-IgE therapy causes a reduction in the FcεRI
level on basophils and then analyze whether this occurs at a transcriptional level. We
will confirm that the therapy causes a reduction in basophil response to cross-linkage
of FcεRI and then determine whether it also affects basophil response induced by non-IgE
stimuli. The effect of the therapy on the FcεRI level on skin mast cells will also be
investigated.
2. Determination of the effect of anti-IgE therapy on FcεRII expression and antigen
presentation. We will determine whether the therapy results in a down-regulation of
FcεRII/CD23 on B cells. Because of the demonstrated function of FcεRII/CD23 in antigen
presentation, we will determine the antigen presentation to T cells by B cells from
anti-IgE-treated and control subjects.
3. Determination of the effect of anti-IgE therapy on antibody production. We will
determine whether anti-IgE therapy results in a suppression of IgE production, in
addition to sequestration of IgE. Whether IgE-anti-IgE complexes directly suppress IgE
production by B cells in vitro will be investigated.
Inclusion Criteria:
- Mild or moderate persistent asthma
- Allergic rhinitis
- Atopic dermatitis
Exclusion Criteria:
- Other lung diseases
- Blood clotting disorder
- Pregnant or lactating women
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