20TH ANNIVERSARY
5 May 1999
CE Refereed Peer Review
FOCAL POINT
★A rigorous approach to the
recognition and assessment
of canine systemic lupus
erythematosus (SLE) is necessary
for a better understanding of this
complex disease, which could be
relevant to the investigation of
human SLE.
KEY FACTS
■ The 1982 revised American
Rheumatism Association
diagnostic criteria for humans
can be adapted and used as a
basis for a definitive diagnosis
and prediction of the clinical
course of canine SLE.
■ Evaluating the severity of canine
SLE is important in establishing a
diagnosis or prognosis.
■ Immunosuppression is vital to
controlling the abnormal immune
response associated with canine
SLE; an original treatment
that combines levamisole and
prednisone has been developed.
■ The paucity of detectable
antinative DNA antibodies and
deficient suppressor activity
associated with canine SLE give
new insight into its pathogenesis.
Vol. 21, No.
Canine Systemic Lupus
Erythematosus. Part II.
Diagnosis and Treatment *
Veterinary School of Lyon, Claude Bernard University and the Blood
Marcy l’Etoile, France Center of Lyon, Lyon, France
Luc Chabanne, DVM, PhD Dominique Rigal, MD, PhD
Corinne Fournel, DVM, PhD Jean-Claude Monier, MD, PhD
ABSTRACT: The diversity of clinical and biologic features in canine systemic lupus erythem-
atosus necessitates diagnostic rules, such as the 1982 revised American Rheumatism Associ-
ation criteria, and indices of disease activity to enable practitioners to choose an appropriate
therapy. Treatment commonly involves corticosteroids in association with other drugs, such
as levamisole. The canine model also provides new insights into the pathogenesis of the dis-
ease; antinative DNA antibodies are rare, T-cell abnormalities are prominent, and genetic fac-
tors are important.
T
he clinical and biologic signs of canine systemic lupus erythematosus
(SLE) are highly diverse and constitute a major diagnostic challenge. A
rigorous approach to particular cases should allow better understanding
of the cause, pathogenesis, and treatment of the disease. This is the second part
of a two-part presentation on canine SLE. Part I reviewed clinical and biologic
aspects of the disease; this article discusses physiopathology, cause, diagnosis,
prognosis, and treatment.
DIAGNOSIS
This multisystem disease, with its numerous clinical manifestations, variable
course, dormant periods, and absence of pathognomonic abnormalities, presents
major diagnostic challenges, and a set of rules based on diagnostic criteria is nec-
essary for establishing a definitive diagnosis. Different schemes have been sug-
gested.1 In our work,2 we use the 1982 revised American Rheumatism Associa-
tion (ARA) diagnostic criteria for humans3 adapted for dogs (Table I; Figure 1).
The advantage of this scheme is that it includes both clinical and immunologic
criteria. The main alterations from the human ARA criteria are in the tenth cri-
terion of Table I—antihistone antibodies replace antinative DNA antibodies and
anti–type 1 antibodies are included.
Antinuclear antibody (ANA) test results are almost always positive in dogs
with SLE, with titers frequently higher than 256. As discussed in Part I, howev-
er, ANAs are also found in other canine diseases as well as in normal dogs (al-
*Part I of this two-part presentation appeared in the February 1999 (Vol. 21, No. 2) issue
of Compendium.
Compendium May 1999 20TH ANNIVERSARY Small Animal/Exotics

though frequency and titers are low). Titers higher than
4000 are occasionally found in control animals, notably
German shepherds.4 Thus this criterion cannot be tak-
en as a specific sign.
According to the modified ARA criteria, a definitive
diagnosis of canine SLE is established if a patient pre-
sents with four or more of the 11 criteria in question,
either consecutively or simultaneously, during any giv-
en observation period. A diagnosis of “probable” SLE
results from the identification of three criteria (consec-
utive or simultaneous) or polyarthritis with ANAs.
It is vital that the evaluation procedure should in-
clude a differential diagnosis. Particularly in southern
Europe, this involves the exclusion (at least in serologic
terms) of leishmaniasis. Leishmaniasis is very wide-
spread in this area and presents numerous similarities
to SLE in its pathogenic mode (it is an immune-com-
plex disease), clinical manifestations, and frequency and
titers of ANAs.5
PROGNOSIS
Evaluating the severity of SLE is an important second
step in establishing diagnosis and prognosis. In veteri-
nary medicine, there is currently no universally accept-
ed definition of SLE activity; there are, however, certain
prognostic factors that are beyond controversy. For ex-
ample, renal disease suggests a poor prognosis.2,6,7 In ad-
dition, we can assume that the earlier diagnosis is
achieved, the better the chance will be that in-depth
treatment will lead to a cure. Disease severity can be
used to evaluate the effects of different possible treat-
ments (see Parameters of Disease Severity).
THERAPY
Immunotherapy
Immunosuppression is the key to controlling an ab-
normal immune response. The treatment of canine
SLE (Table II) is based mainly on high doses of corti-
costeroids1 (e.g., oral prednisone or prednisolone), ini-

TABLE I
Criteria for the Diagnosis of Canine Systemic Lupus Erythematosusa
Criterion Definition

1. Erythema Redness in areas of skin that are thin or poorly protected by the haircoat
(particularly the face)
2. Discoid rash Depigmentation, erythema, erosions, ulcerations, crusts, and keratotic scaling that
selectively affect the face (e.g., nose pad, forehead, lips, and periocular region)
3. Photosensitivity Skin rash resulting from an unusual reaction to sunlight
4. Oral ulcers Oral or nasopharyngeal ulceration, usually painless
5. Arthritis Nonerosive arthritis involving two or more peripheral joints, characterized mainly
by pain during movement (progressive forced flexion–extension); swelling or
effusion are often not very marked
6. Serositis Presence of a nonseptic inflammatory cavity effusion (pleuritis or pericarditis)
7. Renal disorders Persistent proteinuria (>0.5 g/L or >3+ if quantification is not performed) OR
cellular casts (red cell, hemoglobin, granular, tubular, or mixed)
8. Neurologic disorders Seizures or psychosis in the absence of offending drugs or known metabolic
disorders (e.g., uremia, ketoacidosis, or electrolyte imbalances)
9. Hematologic disorders Hemolytic anemia (with reticulocytosis) OR leukopenia (<3000/mm3 total on two
or more occasions) OR lymphopenia (<1000/mm3 total on two or more occasions)
OR thrombocytopenia (<100,000/mm3 in the absence of offending drugs)
10. Immunologic disorders Antihistone (antibody to histone at an abnormal titer) OR anti-Sm (antibody to the
Sm nuclear antigen) OR anti-type 1 (antibody to a 43-kD nuclear antigen) OR T-
cell subsets (a striking decrease in the CD8+ population [<200/mm3] or a
CD4+:CD8+ ratio higher than 4.0)
11. Antinuclear antibodies (ANAs) An abnormal titer of ANAs as shown by immunofluorescence or an equivalent assay
in the absence of drugs known to be associated with their formation

a
Adapted from the 1982 revised American Rheumatism Association criteria.3

AMERICAN RHEUMATISM ASSOCIATION CRITERIA ■ DEFINITIVE DIAGNOSIS ■ LEISHMANIASIS

Small Animal/Exotics 20TH ANNIVERSARY Compendium May 1999

Diagnosis of Canine Systemic Lupus Erythematosus (SLE)

Indicative clinical sign (see Table I)

Risk factors Physical examination History

• Age
• Breed
• Genetic background
• Environmental factors

Radiographs Biologic analysis Histopathologic findings

• Joints • Renal biopsy
• Chest (cavity effusion, • Skin biopsy
pleuritis, or
pericarditis?)

Renal evaluation Immunologic parameters Hematologic parameters

• Urinalysis and • Complete blood count
biochemical
parameters (BUN)

Other autoantibodies Measure ANA Cellular immunity

(e.g., antierythrocyte abnormality?
antibodies [Coombs’
test], anti-IgG antibodies
[rheumatoid factors])?

ANA titer > 256 ANA titer < 256

Three ARA criteria or Four ARA criteria =

polyarthritis with ANAs = Definitive diagnosis of SLE SLE improbable
“Probable” SLE

Follow evolution Reconsider the

of disease? diagnosis

ANA = antinuclear antibody; ARA = American Rheumatism Association; BUN = blood urea nitrogen.

Figure 1—Algorithm for the diagnosis of canine systemic lupus erythematosus.

tially at doses of 1 to 3 mg/kg every 12 hours to induce
remission, and then decreasing to administration on al-
ternate days. Remission is, however, usually brief, and
permanent corticosteroid therapy at the lowest effective
dose is generally required.
The most common alternative to this form of treat-
ment is to combine corticosteroid therapy with an im-
munosuppressant (e.g., azathioprine [0.5 to 2 mg/kg
orally every 24 hours]). 6,11,12 For acute episodes of
hemolytic anemia, cyclophosphamide should be given
Compendium May 1999 20TH ANNIVERSARY Small Animal/Exotics

at 2 mg/kg (50 mg/m2) once daily on alternate days or much of this overzealous activity can be curtailed by re-
every 24 hours four days per week.1,13 When thrombo- moving the spleen.1 Splenectomy allows erythrocytes
cytopenia is evident, intravenous vincristine (0.01 to and platelets to remain functional, even when covered
0.025 mg/kg once a week)1,6,11,13 should be considered. with antibodies, notably in terms of the erythrocytes’
When clinical remission oxygen-carrying capacity.
Parameters of has been achieved, drug do- Plasmapheresis using protein A of purified staphylo-
sages should be decreased coccus makes it possible to eliminate IgG and immune
Disease Severity to the lowest possible sched- complexes containing IgG and, to a lesser degree, IgM
■ Clinical criteria (e.g., ule that clinically controls and IgA in plasma. The adsorbed plasma is returned to
the disease. the blood cells before being reinjected into the dog.
the indices of activity
An original treatment 2 Plasmapheresis, which is associated with low-dose im-
given for humans by the combines prednisone (0.5 munosuppressive therapy, has been tested on dogs that
American Rheumatism to 1 mg/kg) twice daily and were refractory to traditional treatment.14,15 In one re-
Association 8), provided levamisole (2 to 5 mg/kg fractory patient, plasmapheresis led to clinical remis-
that they are adapted [maximum of 150 mg per sion accompanied by a lowered ANA titer and return to
for dogs: For example, patient]) on alternate days. a normal level of serum complement. This technique is
The prednisone is progres- difficult, however, and should be reserved for persistent
central nervous
sively reduced and eliminat- or initially severe cases.
system signs are very
ed over 1 to 2 months. Lev-
important in humans amisole is administered New Approaches
but may go unnoticed orally at the same dose for 4 Immunotherapy as applied to autoimmune diseases
in dogs. months. In cases of relapse, in general and SLE in particular is directly correlated
■ Antinuclear antibody levamisole is administered with increases in knowledge about the mechanisms re-
alone for 4 months. When sponsible for autoantibody production. New therapeu-
titer: This is roughly
diagnosis has been estab- tic strategies are being developed that conform to a
proportional to the common general principle—replacing immunosuppres-
lished, an in-depth treat-
severity of the ment of this kind is recom- sion of immune-system cells as a whole with selective
condition, decreasing mended. Such treatment immunosuppression targeting specific molecules and/or
slowly with clinical has had very good results; of cells involved in deregulation or the occurrence of le-
improvement. 4 33 animals treated, 25 (ap- sions. The wide variety of potential targets corresponds
proximately 75%) had a pe- to the diversity of new immunopharmacologic ap-
■ Serum levels of the
riod of remission ranging proaches. The main lines of inquiry currently being
components of the pursued include tolerance to autoantigens, the use of
from several months to a
complement9 number of years (maxi- specific monoclonal antibodies (to selectively deplete
■ Cellular immunity mum, 9 years2). The least certain populations or subpopulations of immune-sys-
parameters (e.g., favorable results occurred in tem cells),16,17 and immunomodulation via the action of
number of circulating dogs with advanced disease cytokines. These different strategies have sometimes
and glomerular lesions. Side been developed directly in humans, but animal models
CD8+ lymphocytes,
effects of long-term lev- can also provide a useful framework for evaluation.
CD4+:CD8+ ratio, or Murine models are particularly useful for this purpose,
amisole treatment are rare
degree of lymphocyte in dogs. Prolonged neu- but dogs can also be used, especially for SLE.
activation)10 tropenia that interrupted
treatment after only 10 days Complementary Treatments
was seen in one patient; It is also important to deal with associated organ fail-
there was also one case of a neurosensorial disorder with ure, avoid bacterial infections, and treat any identified
excited behavior and aggressiveness.2 infections specifically and aggressively. Infections may
develop secondary to treatment, but dogs with SLE are
Nonmedical Options for Refractory Patients also prone to infection because of their immunologic
Splenectomy is the best course of action in cases of deficiencies.
hemolytic anemia and/or thrombocytopenia that resist
traditional treatment.1 The reticuloendothelial system, Evaluating Effectiveness
particularly the spleen, is programmed to remove cells The disappearance or diminution of clinical signs
with antibodies or complement on their surface, but unquestionably constitutes one of the main ways in

PREDNISONE AND LEVAMISOLE TREATMENT ■ SPLENECTOMY ■ PLASMAPHERESIS

Small Animal/Exotics 20TH ANNIVERSARY Compendium May 1999

TABLE II lesions. Anti–double-stranded DNA (anti-dsDNA) anti-

Principal Drugs Used to Treat Canine bodies seem to be less prevalent in canine than in human
Systemic Lupus Erythematosus or murine SLE, although the amount of anti-dsDNA
antibodies found in canine SLE is still a matter of con-
Drug Recommended Dosage troversy.18 Some authors4,19–21 report an almost complete
Corticosteroids lack of anti-dsDNA antibodies in dogs with SLE,
Prednisone or 1–3 mg/kg IV, IM, or PO every whereas others22 claim to have found these antibodies in
prednisolone 12–24 hr until signs disappear significant quantities. Even when DNA-reactive anti-
and then on alternate days or bodies are observed in canine SLE sera, however, their
with progressive reduction levels are often found to be lower than those in human
Antimetabolite SLE.
Azathioprine 0.5–2 mg/kg (50 mg/m2) PO Various factors could be responsible for the discrep-
every 24 hr ancies observed in canine research, such as differences
among the populations studied, diagnostic criteria, or
Alkylating agent methods used to detect the antibodies. For example, us-
Cyclophosphamide 1.5–2.5 mg/kg (50 mg/m2) PO
ing mammalian DNA that has not been highly purified
once daily every 48 hr or every
24 hr 4 days per week for 1 to 4 and that contains histone contaminants or anti–single-
wk (4 or 5 mo maximum) stranded DNA (anti-ssDNA) antibodies could result in
false-positive results because canine SLE sera often con-
Vinca alkaloid tains antihistone or anti-ssDNA antibodies. In addi-
Vincristine 0.01–0.025 mg/kg (1 mg/m2) IV tion, antibodies to native DNA can be produced by
once weekly
dogs after hydralazine treatment, although without any
Immunomodulator clinical consequences indicative of SLE. However, the
Levamisole 2–5 mg/kg (maximum of 150 view that anti-dsDNA antibodies are mainly responsi-
mg) PO every 48 hr for 4 mo ble for lupus nephritis in humans has been chal-
lenged.23,24 In dogs, the high incidence of glomeru-
IM = intramuscularly; IV = intravenously; PO = orally.
lonephritis and paucity of detectable antinative DNA
antibodies suggest that anti-dsDNA antibodies are not
which treatment success is determined. However, im- a precondition to the development of lupus nephritis,
munosuppressive action and antiinflammatory effects although IgG antihistone antibodies may be involved
are sometimes difficult to differentiate. Apparent bene- in its pathogenesis.20
ficial effects may at least initially result more from the
drugs’ (particularly corticosteroids) antiinflammatory Abnormalities in Cellular Immunity
effects than from genuine immunosuppressive effects. The immunologic imbalance found in canine and
Considering the complexity of canine SLE, methods human SLE may be caused by defective suppressor
of evaluating the disease’s severity and the real efficacy of cells. In canine studies, there are four results that seem
particular treatments are needed. The number of circu- to support this hypothesis: (1) a rapid decline in the
lating CD8+ lymphocytes varies with the degree of level of a soluble thymic factor in canine SLE sera21;
severity of the disease.10 During the second month of (2) resistance to induced tolerance in some cases of ca-
treatment, a noticeable increase in the number of CD8+ nine SLE25; (3) deficient concanavalin A–induced sup-
cells is observed in dogs with SLE that is associated with pressor-cell function25; and (4) a striking decrease in
a good response to therapy. By contrast, no significant the number of circulating CD8+ lymphocytes, as
CD8+ cell increase is seen in dogs that respond poorly. shown by studies on T-cell subsets.10 The extent of this
An important threshold seems to exist at approximately last abnormality is directly related to the severity of the
200 CD8+ cells/µl. If the number of CD8+ lympho- disease.
cytes does not rapidly rise above this threshold, another
therapeutic strategy should be considered. CAUSE
Genetic Factors
PHYSIOPATHOLOGY The causes of autoimmune diseases are multifactori-
Antinative DNA Antibodies al. However, one of the strongest influences on the clin-
Autoantibodies to native DNA are regarded as the ical expression of autoimmunity is the genetic back-
hallmark of SLE in humans and may be partly responsi- ground of the patient.
ble for its clinical manifestations, particularly glomerular Genetic aspects feature strongly in studies of canine

CD8+ LYMPHOCYTES ■ ANTI–DOUBLE-STRANDED DNA ANTIBODIES ■ SUPRESSOR CELLS

Small Animal/Exotics 20TH ANNIVERSARY
SLE. In one of the earliest of these studies, conducted
in 1971 by Lewis and Schwartz,26 founder dogs with
SLE produced progeny with serum autoantibodies and
a range of autoimmune pathologies. At the Veterinary
School of Lyon (France), a canine line named Man-
athos25 was established from two parents with severe
SLE; a breeding colony of German shepherds in
Béziers, France, has also been analyzed.27 Studies of
these two pedigrees clearly show a high proportion of
ANA carriers (more than 50% of dogs) and high inci-
dence of the disease (25% to 30% of dogs). There is a
strong association between the dog leukocyte antigen
(DLA) phenotypes and the occurrence of SLE.28 DLA-
A7, a class 1 major histocompatibility complex (MHC)
molecule, is positively associated with SLE (relative
risk, 11.93), whereas DLA-A1 and DLA-B5 (a class 2
MHC molecule) are negatively associated with SLE
(relative risk, 0.06 and 0.05, respectively).
More refined molecular methods of identifying
MHC polymorphisms are now needed.29 A canine line
such as Manathos could be very useful in studies that
link clinical and biologic manifestations of SLE to gene
polymorphism.
Environmental Factors and Infectious Agents
The clinical expression of SLE generally results from
a combination of genetic background and other causes,
such as environmental factors and infectious agents.
Sunlight is capable of triggering or aggravating SLE in
humans and dogs. This fact may partly explain why a
large number of SLE cases have been received at the
Veterinary School of Lyon (many cases come from the
south and southeast of France).
There is, however, a shortage of quantitative data for
France, Europe in general, and North America. It
would be interesting to compare such data with figures
for the incidence of certain diseases that are similar to
SLE, at least in clinical terms, that could cause mistak-
en diagnoses. In southern Europe, for example, leish-
maniasis is very widespread and needs to be part of a
differential diagnosis.5
CONCLUSION
The amount of controversy that exists regarding the
definition of canine SLE makes it important to achieve
a certain degree of consensus on this question. It is far
from clear which assay will finally prove to be best for
diagnostic purposes. It is certain, however, that we are
not yet at the point at which we can hope for any
definitive biologic conclusions about the nature of ca-
nine SLE. What is currently needed is a rigorous ap-
proach to recognizing signs and assessing particular cas-
es of SLE.
GENE POLYMORPHISM ■ SUNLIGHT ■ MISTAKEN DIAGNOSIS
Compendium May 1999
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About the Authors
Dr. Chabanne and Professor Fournel are affiliated with
the Department of Small Animal Clinical Sciences, Veteri-
nary School of Lyon, Marcy l’Etoile, France. Dr. Rigal and
Professor Monier are affiliated with the Laboratory of Im-
munology, Claude Bernard University and the Blood Cen-
ter of Lyon, Lyon, France.