Allergen Specific Immunotherapy for Atopy

J.M. MacDonald
College of Veterinary Medicine, Auburn University, Auburn, AL, USA.

ATOPY
Atopy is a common disease affecting a number of animal species with approximately 10-15% of the
canine population having the condition with evidence of increasing incidence. Atopic dermatitis is a
hereditable predisposition to develop IgE antibodies to environmental allergens commonly resulting in
allergic dermatitis. The elicitation of plasma cells to produce IgE requires preceding events with the
genetic tendency to over react through the expression of T-helper cells (Th2 cells). The first phase of
disease development is sensitization. In this stage, specific proteins (allergens) such as a grass, tree or
weed pollen, is absorbed into the skin where a specific cell type (Langerhan's cell) located in the lower
part of the epidermis acts as an antigen processing cell and binds the allergen. The allergen then is
processed by the Langerhan's cell which migrates from the skin to the regional lymph node where it
interacts with T-cells. More specifically, these T-cells are T-helper cells. In addition to the presentation
of the allergen protein to the T-helper cells, there is stimulation and proliferation of other memory T-
cells and effector T-cells. These T-cells, in turn, interact with B-cells which are used for the production
of antibody. During the sensitization stage no disease is observed. The second stage involves the
elicitation of disease. Subsequent exposure to the specific allergen and percutaneous absorption in the
sensitized individual, leads to the processing of the allergen by the Langerhan's cell, which again
presents the allergen to the immune system already producing specific IgE against the offending
allergen. The presentation of the allergen to memory T-helper cells then leads toward the elicitation of
cytokines that induce cellular proliferation and IgE production from B-cells (e.g. interleukin 4). The
IgE is bound to mast cells and basophils. The mast cells are important in the subsequent development
of the clinical signs of the disease through the release of pro-inflammatory mediators. The allergen
binds to the specific IgE on the mast cell and the cross-binding of IgE molecules results in
degranulation. Subsequent inflammation is observed as allergic dermatitis and pruritus. Latent
reactions (late phase response) occur as a consequence of the initial immediate reaction of mast cell
degranulation and subsequent recruitment of inflammatory cells through cytokine release. This reaction
is assumed to be responsible for a protracted course of inflammation lasting hours to days.

USE AND EFFECT OF ALLERGEN IMMUNOTHERAPY

Allergen specific immunotherapy (ASIT) is utilized in the treatment of atopic dermatitis as a means of
down-regulation of the immune response. It has been used in human medicine for the treatment of
asthma, allergic rhinitis, allergic sinusitis and allergic bronchitis since the early 1900's. Immunotherapy
has also been successful in the treatment of venomous bee allergy in humans and dogs. Early use of
allergen immunotherapy in veterinary medicine in the US occurred in the 1960's with greater
sophistication as time went on. The appeal of allergen immunotherapy includes the moderate cost,
effectiveness and the low incidence of adverse reactions. Another desirable characteristic is the fact
that the treatment is actually modifying the disease mechanism in contrast to the effect of symptomatic
therapy which is merely suppressing the clinical signs. The greatest disadvantage includes the necessity
for injection administration, the lack of response by a percentage of individuals and the need for
protracted therapy in most cases. Cost factors may be an issue for the respective pet owner as well as
the personality of animal with regard to acceptance of the injection therapy.
Most of the effects of allergen immunotherapy are thought to be allergen-specific rather than
nonspecific, meaning representation of offending allergens in the extract solution is necessary to elicit a
desirable response. Original theories of mechanism included the "blocking antibody" theory, whereby
IgG produced through the injection of allergens was thought to remove allergen by binding them to the
respective IgG molecule before there was contact with IgE on the mast cell, hence alleviating
degranulation and inflammation. More recent theories includes the down regulation of IgE production
through Th2-Th1 switching leading to decreased IL4 which is the cytokine derived from Th2 cells
signaling B cells to produce IgE. An increase in interferon gamma also occurring through allergen
immunotherapy inhibits IgE synthesis. The late phase reaction in desensitized individuals is
characterized by the presence of T-lymphocytes with a Th1 profile. In essence, by administering large
amounts of allergen, the balance between Th1 cells and Th2 cells is shifted toward the Th1 response
favoring IgG production in contrast to IgE.

ALLERGEN EXTRACT PREPARATION AND ADMINISTRATION

The development of the therapeutic allergen solution is based upon the results of either serum allergy
testing, intradermal testing or the combination of both. Since the response to the therapy is allergen
specific, identification of relevant allergens for inclusion in the solution is critical for optimal response.
The considerations for allergy testing include the tentative diagnosis of atopy through the historical and
clinical signs and the prospect of allergen immunotherapy. The prospect of allergen immunotherapy is
for animals whose season of itchiness exceeds three months out of the year, has sufficient severity of
disease with limited response to conservative (non-steroidal) therapy and are one year of age or older,
although younger dogs have been treated with allergen immunotherapy due to the severity of the atopic
component. The intention of immunotherapy is the only reason for considering allergy testing.
Allergen immunotherapy is administered by subcutaneous injection. Due to the excellent safety of this
treatment, it may be administered at home by the pet owner. The schedule of injections is somewhat
variable depending upon the laboratory or dermatologist involved with the case, but classically starts
with a dilute solution or two dilute solutions before reaching the more concentrated maintenance vial.
The diluent solutions are typically 1:100 and 1:10 concentrations of the maintenance solution. Allergen
concentration is standardized by allergen laboratories with most utilizing either protein nitrogen units
(PNU) where 1 mg of protein equals 100,000 PNU's. Weight: volume concentration is also used for
representing some allergen concentrations. A 1:10 concentration equals 1 gram of basic allergen
extracted in 10 cc of buffer. Most maintenance allergen solutions are prepared at 15,000 to 20,000
PNU/ml although evidence suggests that lower concentrations may be effective. The ideal number of
allergens per solution vial (10 ml) has been established by veterinary allergists although there is not an
absolute consensus of opinion. It is recognized that limiting the number of allergens is ideal to achieve
the specific response desired for each allergen represented. Usually between 10-15 allergens are
included and chosen on the basis of clinical relevance, size of reaction, exposure factors and interaction
of allergen groups. Some allergists do not mix mold allergens with pollen allergens since enzymes from
the mold(s) may result in degradation of the pollen protein. The molds may be administered
independently and concurrent to the pollen allergens.
The initial injections are given in increasing increments in volume and progressively changes from the
least concentrated to the most concentrated vials with an interval of injection that becomes less
frequent. The initial injection schedule utilizes an every other day or every third day injection for the
first 28-38 days. Rapid administration of the induction phase of therapy has been developed and
successfully used to avoid the traditional schedule requiring weeks of alternate day or every third day
treatment. This is known as RUSH allergen immunotherapy where the animal receives full induction in
6-8 hours by administering injections every 20-30 minutes. RUSH therapy should be performed under
the care and observation of the veterinarian with precautions taken for the possibility of allergic
reaction, although rarely observed (indwelling IV catheter, antihistamine and glucocorticoid
availability, epinephrine, IV fluids, endotracheal tube, oxygen or pneumobag). Overall this treatment is
very safe and over many years of using this induction process the author has never observed an adverse
reaction. The response for animals undergoing the RUSH induction versus conventional induction
therapy is the same or better. The technique is traditionally used primarily for convenience in lieu of
more expedient therapeutic response although this is likely. Animals that are service dogs resulting in
limited pet owner participation in immunotherapy are prime candidates. Other situations where RUSH
therapy may be preferred include animals with personalities limiting the feasibility of alternate day
injection, pets owned by elderly individuals not able to administer allergen injections or in cases where
pet owners are reluctant to pursue administration of the allergen themselves. RUSH therapy has also
been successfully used in cats with feline atopy. Following the induction phase of allergen
immunotherapy the pet is placed on a maintenance regimen which may be modified to accommodate
specific circumstances in cases receiving RUSH allergen therapy. Whether using a conventional
schedule or the RUSH schedule, animals less than 10 kg should receive no more than 0.5 ml of
maintenance solution. Smaller animals should be limited further and increased pending response and
tolerance.
Maintenance therapy is administered at a dosage and frequency dependent upon the individual response
or tolerance of the treatment. Animals administered small amounts, more frequently may respond better
than larger amounts with less frequent administration. Injections once weekly or every two weeks seem
preferable to a three week interval. Decreasing the quantity of allergen is necessary when administering
more frequently. Animals under 10 kg should be restricted to 0.5 ml. or less at the maximum
maintenance dose. Selected animals may require more dilute solution to avoid increased pruritus from
the allergen therapy. Extra small animals may tolerate only one tenth of the standard maximal dose
(e.g. 0.1-0.15 ml per injection). Larger dogs may require greater amount of allergen to attain maximal
response. Determining the optimal schedule for an animal by trying different regimens (dose and
frequency variations) will often enhance the response in many cases. Weekly injections of 0.35-0.5 ml
of maintenance solution may be preferable to 1.0 ml every 21 days. Injections administered every two
weeks may require 0.4 - 0.6 ml while some animals may respond best to a small amount twice weekly
(0.15-0.3 ml). Maximal treatment effect often requires observation and modification. Planned revisits
are ideal to achieve the best results.

RESPONSE TO ASIT
ASIT requires a significant period of time to observe response. This may take as long as 5-7 months
but is typically seen between 3-5 months. Early responders have been reported in as few as several
weeks although the placebo effect may be an influencing factor or merely the concurrent resolution of
secondary complications such as parasitism or infection. A full year of therapy should be provided for
full assessment. The attributes of allergen immunotherapy include the development of long term
control while decreasing the need for adjunctive therapy, in particular glucocorticoids. Complete
desensitization has been observed in rare situations where therapy may be discontinued. In general, it is
perceived that allergen specific immunotherapy has a better chance of being effective if started early in
the disease progression. It has become the mainstay of treatment alternatives with its appealing
response rate but does not usually eliminate the need for adjunctive therapy although it may decrease
the intensity of concurrent medication required to attain optimal control. The concurrent use of
antihistamine drugs, essential fatty acids or low dose, short acting, alternate day oral glucocorticoid
therapy has not been shown to impair the overall response. Controversy still exists with the concurrent
use of cyclosporine A (CsA) which theoretically would be contraindicated in conjunction with ASIT
because of its immunosuppressive properties. Individual case assessment is necessary rather than
restricting combined therapy at this time. Allergen specific immunotherapy is not utilized for the
treatment of flea allergy where aggressive and persistent flea control is advised. Likewise, dietary
allergy is controlled exclusively through the process of avoidance with limited ingredient or
hypoallergenic diets.
Failure to respond to specific allergen immunotherapy may be relevant to coexisting problems that
have not been identified and treated. These may include dietary allergy, canine scabies or complicating
infections such as bacterial pyoderma, cutaneous malassezia, dermatophytosis, or demodicosis.
Incomplete recognition of offensive allergens may require repeat allergy testing to acquire recognition
of further allergens that may be problematic in a given animal. Inconsistent treatment or treatment
regimens that are not optimal may also lead toward failure. Non-responders may represent as many as
25-35% of the animals placed on therapy. Dogs with a large number of allergen reactions may be good
responders and should not be perceived as ineligible for allergen treatment. Some of the better
responders are dogs that have > 20-30 allergens identified in their profile. Multiple solution sets are
utilized to include the relevant reactions while still limiting the number of allergens per maintenance
vial. Modification of immunotherapy should be integrated with intermittent evaluations and
modification of the treatment interval and the volume of allergen administered. Integrated adjunctive
therapy should be utilized as part of the maintenance regimen. Repetitive bathing with ongoing
parasiticidal treatment is also necessary.

ADVERSE REACTIONS TO ASIT

Adverse reactions to allergen therapy are uncommon in the dog and cat. Cutaneous reactions are most
likely and include increased pruritus in as many as 20 % of the dogs treated. Modification of the
injection schedule usually resolves the problem. These animals may ultimately become the better
responders when reaching the optimal dose. Urticaria and angioedema are rarely observed and may
represent the summation effect of natural allergen exposure or other concurrent allergic condition such
as dietary allergy. Systemic reactions are likewise rare and include the following: anxiousness, panting,
hyperactivity, frequent swallowing, drowsiness/lethargy, vomiting or diarrhea, and collapse/shock. It is
always prudent to dispense oral glucocorticoids for animals on ASIT for use in the event of perceived
reactions. Dosages should be provided and a plan for handling the situation discussed. Continuation of
the treatment should be encouraged in the event of an adverse reaction although many pet owners are
apprehensive to persist with the therapy. Known reactors may be treated with an antihistamine or low
potency, low dose, oral glucocorticoid therapy 1-2 hours prior to the injection and additional treatment
following the injection. Concurrent immunization vaccines should be avoided in conjunction with
allergen treatment to avoid summation of exogenous antigenic stimulation. The benefits of allergen
specific immunotherapy out weigh the liabilities and should be considered an integral part of the
treatment alternatives for the atopic dog and cat.

References

• 1. Hillier A, Foster, AP, Kwochka, KW: Advances In Veterinary Dermatology, Volume 5,

Proceedings of the Fifth World Congress of Veterinary Dermatology, Vienna Austria.
Blackwell Publishing, Ltd, Oxford, United Kingdom, 2005.
• 2. Scott DW, Miller WH, Griffin CE: Muller & Kirk's Small Animal Dermatology. 6th edition,
WB Saunders Co., Philadelphia, 2001.