Veterinary Dermatology 2004, 15, 115 126

Blackwell Publishing, Ltd.

Immunomodulation and immunodeficiency

AIDEN P. FOSTER
Department of Clinical Veterinary Science, University of Bristol, Langford House, Langford, UK
(Received 27 March 2003; accepted 30 July 2003)

Abstract This article briefly reviews the concepts of immunodeficiency and immunomodulation as they relate
to selected skin diseases in the dog and cat. Immunodeficiency states are uncommon and may be associated
with a subnormal or down-regulated immune system, including humoral deficiencies, such as IgA, and abnormal
lymphocyte or neutrophil function. Establishing a causal relationship between a skin disease and presumed
immunodeficient state has been difficult due to the rarity of such conditions, and the limited nature of the
techniques used to characterise the immune system response. Severe combined immunodeficiency in dogs is a well
characterised primary immunodeficiency state involving lymphocytes; retrovirus infection in cats may lead to an
acquired immunodeficient state with some association with certain dermatological conditions although it
remains unclear that infection is causally linked with disease.
Immunomodulation usually implies stimulating the immune system along a beneficial pathway. Such a
therapeutic approach may involve a wide variety of agents, for example intravenous immunoglobulin. There are
few randomised controlled trials with veterinary patients that unequivocally demonstrate beneficial responses to
immunomodulatory agents. Interferons are cytokines of major interest in human and veterinary medicine for
their antiviral, anti-tumour and immunomodulatory effects. The advent of veterinary-licensed products containing recombinant interferon may enable demonstration of the efficacy of interferons for conditions such as canine
papillomatosis and feline eosinophilic granuloma complex. Canine pyoderma has been treated with a number
of presumed immunomodulatory agents with limited success. With more detailed knowledge of the pathogenesis
of pyoderma it may be possible to develop efficacious immunomodulators.
Keywords: immunomodulation, immunodeficiency, interferon, intravenous immunoglobulin, cat, dog.

INTRODUCTION
The host immune system is intimately involved in the
pathogenesis of many skin diseases. Understanding the
complex and varied interactions between the skin and
the immune system enables veterinary dermatologists
to therapeutically influence the course of the immune
response and thereby the skin disease. Immune
responses in dogs and cats may be seen in allergic conditions such as atopic dermatitis (AD),1 autoimmune
disease as in pemphigus foliaceus,2 cell-mediated
responses to dermatophyte infection3 and neoplastic
conditions such histiocytoma4 and papillomatosis.5 In
some of these conditions anti-inflammatory or immunosuppressive therapy is used to control the immune
response, or such therapy is avoided when the host
immune system would be compromised as an infectious process is resolved. In these examples the immune
response is usually considered to be aberrant and
upregulated. In contrast, immunodeficiency states are

Correspondence: Aiden P. Foster, Department of Clinical Veterinary

Science, University of Bristol, Langford House, Langford,
BS40 5DU, UK. E-mail: a.p.foster@bris.ac.uk
2004 European Society of Veterinary Dermatology

uncommon and may be associated with skin disease as

a consequence of the subnormal or downregulated
immune system. Similarly by contrast, immunomodulation usually, but not exclusively, implies stimulation
or promotion of the immune system.
The aim of this article is to briefly review the concepts
of immunodeficiency and immunomodulation as they
relate to selected skin diseases in canine and feline
patients. The reader is encouraged to refer to textbooks
on immunology that provide a background for understanding the complex immune responses that may take
place in allergic, infectious, parasitic and neoplastic
diseases.612 The subject of immunotherapy, particularly
as it relates to atopic disease, will be covered elsewhere.

IMMUNODEFICIENCY
An immunodeficient condition may be primary and
congenital (or appear with time), or secondary and
acquired. In a primary condition a genetic defect in the
immune system leads to clinical disease, whereas a
secondary condition is usually associated with factors
such as viral and other infections, endogenous hormones, drugs, age and malnutrition that lead to
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A. P. Foster

impairment of the immune system and subsequently

the development of various disease conditions.9,10,12
The cutaneous manifestations of an immunodeficient condition may be recognized in neonatal and
adult human patients. Primary problems with the
immune system are often severe and likely to lead to
clinical signs early in life. Many immunodeficiency disorders do not have specific dermatological findings.
The suspicion that an immunodeficiency disorder is
present may arise from the development of an unusual
type of cutaneous infection or an infection that follows
an unusual course. In general, in human patients, these
unusual infections may be challenging to diagnose;
however, familiar cutaneous infections rarely reflect
the presence of an underlying immunodeficiency.13
In veterinary patients there is limited evidence of a
causal relationship between an apparent immunodeficiency disorder and the development of cutaneous disease. In part this reflects:
the rarity of such disorders;
the lack of techniques that enable a full understanding of the presumed deficiency in the immune
response which usually leads to microbial and
parasitic infections;
the failure to fully characterize the cutaneous disease;
failure to analyse the risk factors for such disease
within and without a cohort of animals with the
immunodeficiency disorder.
Humoral deficiencies
The techniques available to investigate humoral deficiencies may include quantification of total serum IgA,
IgG and IgM compared with age-matched normal
controls. This is a very crude method for evaluating the
humoral response and by no means implies a causal
relationship between the serum antibody concentrations
and the skin disease. It could be argued that it is often
difficult to identify specific immunologic lesions and
even if we can document a deficiency there is often little
that can be done to specifically correct the lesion.12,14,15
For example, low serum IgA concentrations have
been reported in canine scabies compared with normal
healthy dogs and dogs with inflammatory skin disease.
After treatment the dogs with scabies had marked
increases in serum IgA. The possible causes of the initial low IgA concentrations were considered but no
specific mechanism could be identified.16
Low serum IgA measurements have been one of a
number of immunological defects associated with
recurrent infections in Weimeraners. Dermatological
disease is not a major feature of this breed-related primary immune disorder, which may include severe pedal
pyoderma and subcutaneous nodules, although there
have been no detailed descriptions of the nature of the
pyoderma or of the nodules.17,18
Serum IgA deficiency has been reported in the Chinese Shar pei dog. In one of the initial reports there
were two pups, one of which was described as having
a pyoderma.19 A report by Miller et al.20 described a

further six cases with low IgA and either allergic dermatitis and recurrent folliculitis, or recurrent nonpruritic folliculitis, but up to 77% of normal Shar pei dogs
have low IgA concentrations.19 In another report of 10
Chinese Shar pei dogs with various recurrent problems
including demodicosis, recurrent bacterial otitis and
pyoderma, they also had low serum IgA measurements.21
Again the relevance of such antibody measurements
was considered unknown given the high frequency of
healthy dogs with low IgA.19,21
There are also reports of IgA deficiency in research
beagle colonies with some dogs having a chronic
antibiotic-responsive dermatitis that was not considered
to be atopic disease. However, the dermatological disease
was not clarified beyond intradermal testing.22 Finally,
in another study of IgA concentrations, dogs with a
variety of chronic skin disease, including pyoderma
and demodicosis, had comparatively elevated antibody
concentrations, compared with normal healthy dogs.23
The significance of low serum IgA measurements and
the relationship to skin and other diseases remain unclear
while normal dogs of the same breeding may have low
persistent serum IgA titres.18,22 Low titres may be a consequence rather than a causal factor in the disease state.
Cellular deficiencies
The lymphocyte blastogenesis test is a widely used
method for evaluation of the competence of the T-cell
system. 10 The test includes the isolation of lymphocytes from peripheral blood cells and culturing
them with antigens (nonspecific mitogens) including
concanavalin A, pokeweed mitogen and phytohaemagglutin. The results of this test can be extremely
variable, require substantial volumes of blood and
generally are available only from institutions studying
particular conditions. The use of nonspecific mitogens
is also a crude approach that will only detect global Tcell dysfunction. To detect a specific immunodeficiency
it would be preferable to use antigens specific to the disease being considered, e.g. canine atopic skin disease24
Malassezia dermatitis25 and leishmaniosis.26
Examples of primary disorders that may include
dermatological disease are severe combined immunodeficiency disease, lethal acrodermatitis in English bull
terriers (Fig. 1a,b),27 defective neutrophil function in
Weimeraners (abstract referenced in Ref. 28), leucocyte
adhesion deficiency of Irish setters,29,30 canine granulocytopathy syndrome of Irish setters with juvenile bacterial pyoderma,31 canine cyclic haematopoiesis of grey
collies,32 hypotrichosis and thymic aplasia in Birman
kittens33 and Chdiak Higashi syndrome of Persian cats.34
Neutrophil function has been tested in a variety of
ways including phagocytosis, super-oxide production,
chemotaxis, bactericidal activity, neutrophil iodination, and glucose oxidation including chemoluminescence in response to phorbitol esters.17,28
Severe combined immunodeficiency
In humans severe combined immunodeficiency (SCID)
may be associated with marked deficiencies of T- and

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Immunomodulation and immunodeficiency

117

Figure 2. (a, b) Cat with generalised neutrophilic alopecia,

inflammatory bowel disease, FIV positive and demodicosis
(histological section b).

Secondary immunological deficiencies

Figure 1. (a, b) Lethal acrodermatitis in an English bull terrior

dog.

B lymphocytes. Cutaneous manifestations may include

chronic oral candidiasis, Staphylococcus aureus and
streptococcal infection, and in some cases dermatophytosis, herpes simplex virus and Pseudomonas
aeruginosa infection.13 A morbilliform eruption can
also be recognized in affected infants and may represent a form of graft vs. host reaction.13,35 An X-linked
SCID syndrome has been extensively investigated in
young Basset hounds and Cardigan Welsh corgis. The
immunological defects have been well characterized
and research colonies of such dogs established as a
model for human X-SCID syndrome. The dogs usually
die from generalized S. aureus infection that may
include the skin.3638

FIV/FeLV. Retrovirus infection has been considered

an example of an acquired immunodeficiency that is
similar to human immunodeficiency virus infection.
In cats, infection has been associated with a number of
dermatological conditions especially infectious diseases
(Fig. 2a,b).39,40 FIV infection has been associated with
Bowens disease (squamous cell carcinoma in situ) and
concurrent demodicosis, plasma cell pododermatitis,
stomatitis and chondritis. FeLV infection has been associated with cutaneous horns, giant cell dermatosis and
vasculitis.40
The initial reports of FeLV and FIV infection that
included descriptions of dermatological conditions
lacked clear statistical evidence of a causal link
between infection and the dermatological condition.41
An odds risk analysis of cats in Australia with FIV or
FeLV demonstrated no association with viral infection
and cat fight abscesses, allergic dermatitis, squamous
cell carcinoma and cryptococcosis.42
It may seem likely for there to be a direct link
between retrovirus infection and chronic dermatophytosis, cowpox infection, mycobacterial infection and
demodicosis where immune suppression could promote the skin disease. Statistical analysis of the frequency of fungal isolation in FIV- and FeLV-positive
cats reported no difference compared with healthy
cats.43 Mancianti et al.44 reported the prevalence of

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A. P. Foster

M. canis infection to be three times higher in FIVpositive cats than healthy controls although positive
cultures in both groups were not associated with
dermatological signs of infection; while Mignon and
Losson45 reported no association between FIV infection and M. canis infection or carriage in a casecontrolled study. Although FIV has been associated with
exacerbation of feline orthopoxvirus infection, up to
30% of cowpox cases can be antibody positive with no
apparent adverse effect on the clinical outcome.46,47
Feline demodicosis is generally considered to be a rare
condition and it is unclear, without a cohort-case analysis, whether or not retrovirus infection is a risk factor
for demodicosis.

IMMUNOMODULATION
The term immunomodulation implies regulation,
adaptation or adjustment of the immune system within
a disease state where the immune system is construed
to be suppressed in some way, including deficient as
discussed above, or the immune response is inappropriate. In general immunomodulation implies at least supporting or preferably stimulating the immune system
along an alternative pathway that is beneficial for the
patient. It is considered distinct from prophylaxis for
infectious disease, immunotherapy for atopic disease,
anti-inflammatory therapy for allergic disease, and
immunosuppressive therapy for immune-mediated and
neoplastic conditions.
In view of the complexity of the immune system it
is not surprising that many methods are considered
potentially useful for modulating the immune system.
Ideally, immunomodulators are restricted in their
action to specific pathways that redirect or block the
aberrant immune response associated with the disease
state being treated, with minimal adverse effects. As
before, in veterinary dermatology there are few randomised controlled trials that unequivocally demonstrate beneficial responses to immunomodulation.
Examples of immunomodulation that have been
described with relation to the skin in humans and veterinary patients include the following.
Immunomodulation of equine sarcoid lesions with
intralesional Bacille Calmette-Gurin (BCG) products derived from Mycobacterium bovis, recommended particularly for periocular lesions.4850
The European Academy of Allergology and Clinical
Immunology (EAACI) has established a taskforce
to critically evaluate the potential use of microbial
products in allergy prevention and therapy.51 The
nonpathogenic mycobacterium Mycobacteria vaccae
has been proposed as an agent for preventing allergic
disease by promoting a Th-1 cytokine response.
Clinical trials with M. vaccae-derived products are
reported in small numbers for human atopic asthma
and eczema patients and further studies are awaited
with interest.51,52 Previously, the use of BCG was not

considered efficacious in terms of preventing the development of allergic disorders in human patients.53,54
A fusion protein of a tumour necrosis factor (TNF) receptor and a neutralizing antibody directed
against TNF- have both been used to block the
TNF- cytokine particularly for psoriasis.55
Cell-surface epitopes (CD molecules 2, 4, 25, 80, 86)
can be blocked by humanized and chimeric monoclonal antibodies in some skin conditions notably
psoriasis and possibly atopic dermatitis.56,57
The interleukins are attracting interest for the
treatment of dermatological conditions including
interleukin (IL)-2, -4, -6, -7, -12 and granulocyte
macrophage-colony stimulating factor (GM-CSF)
in melanoma and IL-12 in cutaneous T-cell lymphoma (CTCL), and IL-4, -10 and -11 in psoriasis.58
See below for information about the use of interferon
gamma (IFN-) for atopic dermatitis.
Tick and insect vaccination of host species with recombinant proteins leading to antibody production
and effects on arthropod survival. For example, the
Bm86 antigen for Boophilus microplus in cattle.5961
Melanoma in humans immunotherapy with
tumour associated antigen peptides and adjuvants
including dendritic cells.62,63
Animal papillomavirus infection may be influenced
by the administration of autogenous/heterogenous
wart extracts, bacterial-expressed proteins notably
L1 and L2 which are major capsid proteins for papillomaviruses, virus-like proteins (VLPs) and DNA
vaccination may influence papillomatosis in various
animal models.5
Chemokines and their receptors have attracted considerable interest in their role in allergic conditions;
the recent description of CCR4 in canine atopic lesional
skin will focus interest in using receptor antagonists
that abrogate such inflammatory mediators.64,65

It is not possible to review all of these examples of

immunomodulation in detail. The remainder of this
article is devoted to the use of interferons which are
becoming available as veterinary licensed products.
Products based on pooled human immunoglobulin
have been used for some veterinary patients. The use of
interferons and pooled immunoglobulin may become
more common as veterinary licensed products become
available and dosage schedules are established; they will
be discussed with particular relation to AD a common
condition in dogs and humans. Immunomodulating
agents have been recommended for a number of years
for canine pyoderma and such agents will be reviewed
briefly.

INTERFERONS
Interferons (IFNs) are cytokines of major interest in
human and veterinary medicine for their antiviral,
antitumour and immunomodulatory effects.6 9,58,66,67
These endogenous glycoproteins are produced in

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Immunomodulation and immunodeficiency

response to mitogens, double-stranded (ds) RNA and
of course viruses. IFNs interact with specific receptors
that initiate complex cell-signalling pathways leading
to IFN-stimulated gene transcripts. Such pathways
include signal transducers and activators of transcription (STATs) and Janus kinases (JAKs).68 Type I IFNs
include IFN-, IFN- and IFN-; with IFN- and
IFN- restricted to ruminants. Type I IFNs are important in antiviral immunity. Type II IFNs primarily
include IFN- produced by NK cells, CD4+ T helper
and CD8+ cytotoxic cells. Two recent studies report the
identification of another family of molecules that have
similar properties to the type I IFNs but are otherwise
structurally and genetically distinct. IFN- 13 (also
designated IL-29, IL-28a, IL-28b) use IL-10R and
IL-28R receptors and have antiviral activity.69,70
IFN therapy in human dermatology
There have been trials of IFN- for neoplasia for
melanoma, cutaneous T-cell lymphoma, Kaposi sarcoma, basal cell carcinoma, papilloma-virus associated lesions.58 A randomised placebo-controlled study
of AD reported 45% of rIFN--treated patients had
greater than 50% improvement in physicians overall
response evaluation compared with 21% of the placebo
group. There were significant reductions in erythema
and excoriations or erosions in the treated group.71
Interferon-gamma has been used for atopic dermatitis
in several studies by daily or alternate day subcutaneous
injection of 50 g M2, for 612 weeks, with proven
efficacy in up to 80% of patients. Expense and repeated
injection are drawbacks and side effects include
influenza-like symptoms early in the course of treatment such as fever, chills, headache, fatigue, myalgia
and nausea.58,72,73
IFN therapy in veterinary medicine
There are no controlled studies of the use of interferons
in veterinary dermatology although there are anecdotal reports of their use in a variety of skin diseases
including feline eosinophilic granuloma complex.7476
This may change with the introduction of veterinarylicensed products such as Virbagen Omega (Virbac;
www.virbagenomega.com). This contains recombinant
feline-origin IFN- and is licensed for the treatment of
canine parvovirus infection at a dose of 2.5 106 units
kg1, administered intravenously daily for 3 days. The data
sheet states that side effects may include hyperthermia
several hours after injection, vomiting and transient
decrease in peripheral blood cells including white cells
platelets and red blood cells.77 There is clearly a need
for randomised controlled trials to evaluate the efficacy
and dose regimen for interferons in the treatment of
canine and feline dermatological diseases, including
perhaps canine atopic skin disease. For example, there
is a need to extend the anecdotal reports of the use of
IFN- for the treatment of severe canine papillomatosis
using, for example, a dose of 1.52.0 106 units m2
body surface area three times a week by subcutaneous
injection.78

119

INTRAVENOUS IMMUNOGLOB ULIN

Intravenous immunoglobulin (IVIG) is prepared from
pooled plasma from thousands of donors and contains
intact IgG molecules that are able to interact, via their
Fc region, with Fc receptors on phagocytes, B cells
and other cells, and Fc-binding plasma proteins
including complement. There are also trace components of IgA, IFN-, soluble CD4, CD5, CD8, CD40,
IL-4 receptor, IL-1, IFN-, TNF-, IL-6, GM-CSF,
and HLA molecules major histocompatibility (MHC)
class I and II.79,80
Effects of IVIG on the immune system7981
Fc receptors
Blockade of Fc-receptors on macrophages and
effector cells.
Induction of antibody-dependant cellular cytotoxicity.
Induction of inhibitor Fc receptor IIB.
Inflammation
Attenuation of complement-mediated damage.
Decrease in immune complex-mediated
inflammation.
Induction of anti-inflammatory cytokines.
Inhibition of activation of endothelial cells.
Neutralization of microbial toxins.
Reduction in corticosteroid requirements.
B cells and antibodies
Control of emergent bone marrow B-cell repertoire.
Negative signalling through Fc receptors.
Selective downregulation and upregulation of
antibody production.
Neutralization of circulating autoantibodies by
anti-idiotypes.
T cells
Regulation of the production of helper T-cell
cytokines.
Neutralization of T-cell superantigens.
Cell growth
Inhibition of lymphocyte proliferation.
Regulation of apoptosis including agonistic/blocking
antibodies to Fas receptor CD95.
Diseases in which controlled clinical trials have shown a
benefit for IVIG7981

Pediatric HIV disease.

Idiopathic thrombocytopenic purpura.
GuillainBarr syndrome.
Chronic inflammatory demyelinating polyradiculoneuropathy.

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A. P. Foster

Multifocal motor neuropathy.

Corticosteroid-resistant dermatomyositis.
Kawasakis disease.
Further verification has been suggested by some authors
for the following disorders:7981

Antibody deficiency diseases

Myasthenia gravis
Prevention of graft vs. host disease
Antineutrophil cytoplasmic autoantibody-positive
vasculitis
Autoimmune uveitis
Multiple sclerosis
Asthma
Chronic lymphocytic leukaemia
Parvovirus B-19 induced anaemia
Sepsis
Antiphospholipid syndrome

Atopic dermatitis
In human AD the mode of action is unknown, but
may involve diverting a Th2-mediated disease to a
Th1 cytokine profile, interference with staphylococcal
superantigens, alterations in the recirculation of skin
homing T cells, changes in costimulatory molecules
required for activation and proliferation, and alterations in chemokines.82 The IVIG may also contain
IgG that combines with allergens to form allergenIgG
complexes that then interact with FcRIIB and coaggregate with FcRI, thereby inhibiting IgE-mediated
mast cell activation.83
In a small open study three human AD patients
received IVIG at 2 g kg1 monthly for over 11 months.
All three patients had severe chronic AD and had
received multiple therapies; they had improved
clinical scores with IVIG which allowed a reduction
in their steroid dose.82 One patient was in remission
off IVIG but the follow-up period was not stated;
the other two patients had IVIG dosing reduced to
every 2 months. Sources of IVIG in the UK include
Flebogamma (Grifols, UK), Gammagard S/D
(Baxter BioScience) Octagam (Octapharma, Solihull, UK), Sandoglobulin (Sandoz) and Vigam
(BPL).
The efficacy of IVIG remains poorly established for
AD, and there are some concerns about side effects.
Adverse effects may include hypersensitivity reactions
involving chest tightness and wheezing, anaphylaxis
rarely, hyperviscosity, aseptic meningitis and transmission (potentially) of infectious agents.72 Undesirable
effects in human patients include headache, chills,
fatigue, arthralgia, back pain and nausea. Care should
be used with patients with renal disease or risk of
hypertension.79
The cost of IVIG for the treatment of AD or other
diseases is substantial and double-blind placebocontrolled trials are required to decide on the
suitability of such therapy for patients with severe,
therapyresistant AD.

The use of IVIG in veterinary medicine

IVIG has been used in various studies including a prospective open trial with immune-mediated haemolytic
anaemia in the dog.84 Although IVIG might be useful
in stabilization of dogs with this condition there was no
improvement in survival rates compared with conventionally treated dogs and there remains a need for large
randomized controlled studies of IVIG in this and
other immune-mediated conditions. The half-life of
human IVIG in humans may be up to 21 days or more,
whereas in dogs there may be antibodies produced
which may trigger anaphylaxis and reduce the half-life
of human IVIG to 79 days.84
One cat and a dog with severe generalized erythema
multiforme and toxic epidermal necrolysis, respectively,
were reported to have improved within several days of
treatment with IVIG (Sandoglobin; Sandoz), with no
adverse effects.85 Because EM and TEN may be associated with drug reactions, IVIG has been suggested as
a possible therapeutic option especially as it may abrogate
apoptosis and block Fas via autoantibody effects.

CANINE PYODER MA
The recurrent deep bacterial pyoderma syndrome of
German shepherd dogs is a well-recognized condition
associated with a variety of possible underlying conditions including allergic, infectious, parasitic and endocrine diseases (Fig. 3a,b).86
A form of immunodeficiency disorder has been suspected but its nature has proven difficult to determine.
For example, recurrent deep pyoderma has not been
associated with functional disturbances in peripheral
and lesional neutrophils,87,88 although lymphocyte blastogenesis may be depressed.86,89 Serum antibody concentrations may show high levels of IgG and low levels of
IgA; together with elevations in the number of circulating
CD8 cells and a decrease in CD4 (T lymphocytes) and
CD21 (B lymphocytes) cells.90,91 The number of IgGbearing cells in skin lesions in German shepherd dogs
is not significant from that observed in other breeds with
deep pyoderma, and there is a predominance of IgG2
and IgG4 subclasses in dogs with deep pyoderma of
any breed.92 These abnormalities in immunological
parameters may reflect in part the underlying conditions associated with German shepherd dogs or the
pyoderma itself they do not necessarily imply causality. Staphylococcal bacterins have been administered to
some cases of German shepherd dogs with apparent
benefit claimed in a small number of cases.86,89
The immune response in canine pyoderma remains
poorly understood. In recurrent superficial pyoderma
there may be a dramatic response to antibacterial
therapy both in terms of the pyoderma and pruritus,
in some cases, which warrants consideration of an
allergic response to bacterial antigens.9396 Pyoderma
may be associated with increased anti-Staphylococcal
antibody production, which merely reflects the
extent and duration of exposure to staphylococci,

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Immunomodulation and immunodeficiency

Figure 3. German shepherd dog pyoderma (GSP) (a) pre and (b) post
antibacterial therapy.

and opsonization and phagocytosis of bacteria by

neutrophils.97,98
There is limited information about the nature of the
Staphylococcal enterotoxins (SEA-E and toxic shock
syndrome toxin-1, TSST-1) produced by canine S. intermedius isolates and their possible role in the immunopathogenesis of canine atopic dermatitis.99 Several
studies have attempted to isolate and characterize canine
staphylococcal toxins, and have reported variable rates
of isolation of such toxins from various sites including
from the skin.100106 Antigen-specific lymphocyte blastogenesis studies have reported significant stimulation
of canine T cells and support further studies of such
toxins, especially because they are considered to be potent
superantigens in human atopic dermatitis.106108
There have been several reviews of the use of bacterial
vaccines for Staphylococcal pyoderma and particularly
the immunomodulation of recurrent superficial bacterial pyoderma.109111 There is very little known about
the mode of action of such vaccines although it may be
anticipated that they may induce antibodies that influence bacterial adherence, promote phagocytosis and
neutralize toxic proteins.110,112 In the future, antibacterial mechanisms may involve modification of the role
of Toll receptors and the genetic regulation of exoprotein transcription.110,113 There are only two randomized controlled studies of the use of bacterin
vaccines. In one such study intravenous injections of a
commercial product based on Propionibacterium acnes
were administered. There was a significant difference
in the favourable clinical response in the treated group

121

compared with the placebo-controlled group.114 All of

the dogs in the study had antibiotics chosen on the
basis of culture results and there were substantial differences in the antibiotic used and the length of therapy. Consequently, the benefit of the bacterin vaccine is
less clear. In a second study oxacillin antibiotic therapy
was given to 21 dogs that were assigned to either treatment with a placebo or a commercial staphylococcal
bacterin (Staphage lysate, Delmont Laboratories, PA,
USA). The dogs receiving the bacterin had a significantly better treatment response than the placebo control group.115 This bacterin is used in North America
but is unavailable as a licensed product in Europe.
Autogenous vaccines have had limited investigation
until recently. Curtis et al.116 reported an open pilot
study in which 9/13 dogs with recurrent pyoderma
made favourable responses to an autogenous vaccine
prepared from culturing a Staphylococcus intermedius
isolate from each dog. In a small controlled study there
were significant differences in the clinical scores of
dogs treated with an autogenous vaccine (administered
twice weekly for 3 weeks then once weekly thereafter)
compared with a placebo-controlled group.116 There
are numerous other drugs such as levamisole, cimetidine and acemannan that have been claimed to have
immunomodulating activity in various conditions
although efficacy has not been reported in veterinary
species in controlled trials and there are concerns
about adverse effects especially with levamisole.

CONCLUSION
From this brief review of some aspects of immunodeficiency it is apparent that further detailed studies are
required to characterize primary and secondary disorders in veterinary patients and how they may be causally related to skin disease.
While immunodeficiency states are comparatively
rare clinicians are constantly presented with skin conditions that involve the immune system responding to
microbial infection, ectoparasites and allergens with
cutaneous manifestations. Such common conditions
require further detailed study. Even though much is
known about some conditions, such as canine atopic
dermatitis, it remains to be determined which particular inflammatory mediators, such as cytokines and
chemokines, are important in this condition. Further
studies are also required of conditions such as canine
demodicosis and pyoderma, which reflect, in part, an
imbalance in the host immune response to commensal
parasites and bacteria. Obviously the immune response
ongoing in the skin will be influenced by other factors
such as genetic background, intercurrent disease and
drug therapy.
With more knowledge of the pathogenesis of skin
conditions such as AD, pyoderma and demodicosis
it may be possible to consider the potential value of
immunomodulators modifying the immune response.
It is important that any clinical trials of (presumed)

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A. P. Foster

immunomodulating agents are large, extensive, randomised controlled studies that provide a clear evidence base for the use of such agents. The cost of some
agents may be prohibitive for routine veterinary use
but efficacy and lack of side effects are factors that may
encourage their use in certain situations.

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Rsum Cet article dcrit brivement les concepts de limmunodficience et de limmunomodulation dans les
aspects lis certaines dermatoses du chien et du chat. Les immunodficits sont rares et peuvent tre associs
un systme immunitaire subnormal ou dficient, ce qui inclut des dficits humoraux (par exemple IgA), ou des
fonctions des lymphocytes ou des neutrophiles. Il est difficile dtablir un lien de cause effet entre une dermatose
et une anomalie du systme immunitaire cause de la raret des maladies en cause et de labsence de techniques
dtude du systme immunitaire. Limmunodficit svre combin du chien est un immunodficit primaire bien
rapport qui touche les lymphocytes. Linfection rtrovirale du chat peut provoquer un immunodficit acquis,
en association avec certaines dermatoses, bien que le rapport entre linfection et la maladie soit encore peu clair.
Limmunomodulation ncessite gnralement de stimuler le systme immunitaire. Cette approche thrapeutique peut faire appel de multiples molcules, par exemple les immunoglobulines intraveineuses. Il existe peu
dtudes randomises en mdecine vtrinaire qui dmontrent sans quivoque une rponse positive lutilisation
de molcules immunomodulatrices. Les interfrons sont des cytokines dun intrt majeur en mdecine humaine
et vtrinaire du fait de leurs proprits antivirales, antinoplasiques et immunomodulatrices. Larrive de produits vtrinaires contenant un interfron recombinant pourrait permettre la dmonstration de lefficacit des
interfrons dans des entits comme la papillomatose canine ou les lsions du complexe granulome osinophilique
flin. Les pyodermites canines ont t traites avec des agents potentiellement immunomodulateurs avec des
succs limits. Lamlioration des connaissances sur la pathognie des pyodermites permettra peut tre le
dveloppement dimmunomodulateurs efficaces dans le futur.
Resumen Este artculo revisa los conceptos de inmunodeficiencia e inmunomodulacin, ya que se encuentran
relacionados con algunas enfermedades cutneas seleccionadas del perro y el gato. Los estados de inmunodeficiencia son infrecuentes y pueden estar asociados a un sistema inmunitario por debajo de lo normal o disminuido,
incluyendo las deficiencias humorales, como las IgA, y la funcin anormal de linfocitos o neutrfilos. Ha sido
difcil establecer una relacin causal entre una enfermedad cutnea y una presunta inmunodeficiencia debido a
la infrecuencia de estas anomalas, y a las limitaciones de las tcnicas utilizadas para caracterizar las respuestas
del sistema inmunitario. La inmunodeficiencia combinada grave en perros es un estado de inmunodeficiencia primaria bien caracterizado que afecta linfocitos; la infeccin por retrovirus en gatos puede llevar a un estado de
inmunodeficiencia adquirida con cierta asociacin con algunas alteraciones dermatolgicas, aunque no est claro
si la infeccin est causalmente relacionada con la enfermedad.
La inmunomodulacin implica normalmente estimular el sistema inmunitario de forma beneficiosa. Este
planteamiento teraputico puede implicar una gran variedad de agentes, por ejemplo inmunoglobulina intravenosa. Existen pocas pruebas clnicas controladas y al azar con pacientes veterinarios que demuestren inequvocamente respuestas beneficiosas a agentes inmunomoduladores. Las interferonas son citoquinas de gran inters
en medicina humana y veterinaria por sus efectos antivirales, anti-tumourales e inmunomoduladores. La llegada
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A. P. Foster
de productos con licencia veterinaria que contienen interferon recombinante pueden permitir demostrar los
efectos del interfern en cuadros como la papilomatosis canina y el complejo del granuloma eosinoflico felino.
Se ha tratado con poco xito la pioderma canina con diferentes agentes supuestamente inmunomoduladores. Con
un mayor conocimiento de la patogenia de la pioderma podra ser posible desarrollar inmunomoduladores
eficaces.
Zusammenfassung Dieser Artikel bespricht kurz Konzepte bezglich Immunschwche und Immunmodulation,
soweit wie sie sich auf ausgewhlte Hauterkrankungen bei Hund und Katze beziehen. Immunschwche ist eine
ungewhnliche Erkrankung und kann mit einem subnormalen oder herunterregulierten Immunsystem,
einschlielich humoralen Defiziten wie zum Beispiel an IgA und mit anormaler Lymphozyten- oder Neutrophilenfunktion verbunden sein. Aufgrund der Seltenheit dieser Erkrankungen und der begrenzten technischen
Mglichkeiten, die Immunantwort zu charakterisieren, war es schwierig, einen kausalen Zusammenhang
zwischen der Hauterkrankung und der angenommenen Immunschwche herzustellen. Die schwere kombinierte
Immunschwche bei Hunden ist eine gut beschriebene primre Immunschwche, in die Lymphozyten verwickelt
sind; Retrovirusinfektionen bei Katzen knnen zu einer erworbenen Immunschwche mit gewisser Verbindung
mit bestimmten Hautvernderungen fhren, obwohl es unklar bleibt, ob die Infektion kausal mit der Erkrankung
verbunden ist.
Immunmodulation impliziert normalerweise den Ansto des Immunsystems in eine ntzliche Richtung. Solch
eine therapeutische Annherung kann eine groe Vielzahl von Wirkstoffen miteinbeziehen, wie z.B. die intravense Gabe von Immunglobulinen. Es gibt wenig randomisierte und kontrollierte Untersuchungen mit veterinrmedizinischen Patienten, die unwidersprochen eine ntzliche Reaktion auf immunmodulatorische Agentien
nachweisen. Interferone sind Cytokine, die wegen ihrer antiviralen, antitumorsen und immunmodulatorischen
Wirkungen von besonderer Bedeutung in der Human- und Veterinrmedizin sind. Die Einfhrung von zugelassenen veterinrmedizinischen Produkten mit rekombinantem Interferon, mag den Nachweis der Wirksamkeit
von Interferonen bei Erkrankungen wie die canine Papillomatose oder der felinen Eosinophile-GranulomKomplex ermglichen. Die canine Pyodermie ist mit einer Reihe von vermutlich immunmodulatorischen
Wirkstoffen mit begrenztem Erfolg behandelt worden. Mit mehr detailliertem Wissen um die Pathogenese der
Pyodermie mag es mglich sein, wirksame Immunmodulatoren zu entwickeln.

2004 European Society of Veterinary Dermatology, Veterinary Dermatology, 15, 115 126