T H E M E C H A N I S M OF D E S E N S I T I Z A T I O N INT ALLERGY
B Y HERMAN
In this communication I am making no attempt
to present new and startling disclosures of the
mechanism of immunity. I am simply endeavoring to summarize briefly the already adequate
knowledge on the subject; to attempt to disentangle some simple facts from a maze of a needlessly complex nomenclature; and to correlate
these facts with clinical experience.
One of the problems of the allergist is that of
convincing the well informed person that one and
the same substance can cause illness when it is
taken into the body inadvertently, and then
cure him when willfully injected by the allergist.
In other words how can one blow hot and cold
with the same breath? To answer this question
I wish to point out, first, that some of the present
explanations of desensitization in allergy are
unsatisfactory; second, that much of the research
in allergy brings forth a common factor, namely,
that immunization of tissue at the site of contact
with an antigen often increases immunologic
vulnerability; third, that a new shock organ can be
produced at the site of injection, which protects
the original shock organ; and finally, that the
ultimate goal in the treatment of allergic diseases
is the production of humoral immunity. Clinical
experience will be cited which gives further evidence
concerning the mechanism of desensitization.
The understanding of the problem is obscured
by nomenclature.
The mechanism of desensitization in the treatment of allergies has not been satisfactorily
explained.f For example, Alexander1 clearly
states the problem thus: "The mechanism involved is not clearly understood. Presumably, by
giving a very small quantity of atopen in the
early doses,., corresponding quantities of antibody
are neutralized until, as the final dose reached
1000 times or more the initial one, there is little
antibody left to react.when contact with atopen
* Read before the Twenty-first Annual Meeting of
the American Society of Clinical Pathologists, Philadelphia, June 1942.
t Since this paper was written Urbach and Gottlieb
have published an adequate explanation of some
important phases of immunity. Urbach, E. and
Gottlieb, P.: De-allergization Versus Hypo-sensitization, Annals of Allergy 1: 27, 1943 and 1: 139, 1943.
A. H E I S E ,
M.D.
occurs from without. Against this hypothesis
is the fact that positive skin reactions, as well as
reagin content of the blood are not reduced after
completion of treatment."
The true explanation of desensitization in man
must, therefore, clarify certain apparent paradoxes. First, how can an antigen that ordinarily
causes immunity suddenly turn about and decrease
immunity; and second, how can immunity be
decreased when experience shows that it is usually
actually increased by injections? The problem is
definitely complicated by the many terms that
have been invented to supplant the use of the
well understood words antigen and antibody.
The new words attempted to differentiate between
immunologic reactions of man and lower animals,
or even to indicate differences on the basis of
heredity. Furthermore, when one considers that
the same substance may be injected to
"immunize," "sensitize," and "desensitize" it is
apparent that our nomenclature has become
decidedly cumbersome.
The desensitization following anaphylactic shock
is entirely different from desensitization in the
treatment of human allergies.
Unfortunately the phenomenon of anaphylaxis
has been used to explain the entirely different
reactions occurring in desensitization in man.
To produce anaphylaxis, an experimental animal
is injected with a suitable antigen. The animal
usually remains well until a second injection is
given after a certain interval of time. The animal
then goes into shock and may die. However, if
it recovers, it is found that further injections of
the same antigen are incapable of provoking;
reactions, but for a limited time only. The term
desensitization may properly be applied to a condition that results from the reinjection of a sublethal dose of an antigen, which causes a temporary
refractory state to subsequent injection of that
antigen. This process is apparently due to the
"specific neutralization, exhaustion, or saturation
of the anaphylactic antibodies present in the cells
of the sensitized tissues." 2 In serum therapy the
same principles apply when preliminary small
doses of foreign serum are given in order to avoid
the danger from a subsequent large intravenous
dose of the same serum. However, desensitiza-
78
HERMAN A. HEISE
tion following anaphylactic shock is of no permanent value, since the injected excess of antigen
gradually disappears leaving the antibodies rampant, and the animal again sensitive. In the
treatment of allergic diseases, on the other hand,
there is no attempt to obtain an excess of antigen
over antibodies, since we are dealing with a simple
process of immunization.
Some important scientific contributions furnish
a common factor, namely, that shock organs may
be produced at sites of contact with antigens.
In order to simplify our understanding of
immunologic and allergic phenomena, let us consider some important contributions to a better
understanding of the mechanism of immunity.
Besredka 3 has shown that the tissue at the site of
primary contact with foreign proteins may develop
a defensive mechanism, specific immune bodies
being formed. This tissue may then become a
"shock organ," because a destructive, immunologic
battle is waged whenever the antigen again comes
in contact with the tissue cells containing the
specific antibodies. Arthus 4 has shown that
repeated subcutaneous injection of substances such
as serum and milk produced increasingly violent
local reactions. Opie5 has clearly explained this
phenomenon by his demonstration that inflammation caused by nontoxic proteins is really a manifestation of tissue immunity. He has also shown
that the fundamental principle of immunity is the
localization and destruction of antigen, and that
this phenomenon is frequently associated with
inflammation. Shwartzman has demonstrated
the development of a hemorrhagic lesion at the
site of an intracutaneous injection of a bacterial
filtrate, when an intravenous injection of the same
filtrate was given 24 hours later. The common
factor in all of these observations is the production
of new shock organ at the site of inoculation.
The allergic state presents extremes on a
quantitative basis.
Topley and Wilson7 have most clearly explained
the difference between the undesirable anaphylactic state and the desirable immune state as
quantitative rather than qualitative. "The anaphylactic state is associated with fixed antibody
and absence of circulating antibody. The immune state involves circulating antibody in a
concentration sufficient to protect fixed antibody."
With these facts as a foundation, it becomes
possible to offer an explanation for the beneficial
results in the treatment of allergic individuals by
antigen injections. The tendency to produce
antibodies against nontoxic antigens is particularly marked in certain individuals. These people
are said to be allergic and differ from other individuals only by their greater readiness to produce
a defense mechanism against inoffensive substances. They may well be called the Don
Quixotes, who are abnormal only in the choice of
their enemies, and owe their downfall, not to the
valor of their opponents, but to their own overenthusiastic defense. Improvement to the sufferer
of some allergic disturbance is not due to a reduction of immunity of the primary shock organ, as
the lung in asthma, but depends first of all upon
establishment of a new shock organ, such as the
skin. This is brought about by increasing the
immunity of the skin until it overshadows the
immunity in the tissue we wish to protect. Thus,
an antigen, which would ordinarily provoke an
undesirable antigen-antibody reaction in the lung,
will be localized and destroyed in the skin, consequently protecting the lung.
Shock organs may shift spontaneously.
Shock organs often shift spontaneously in the
allergic individual. For example, the allergic
child usually exhibits gastrointestinal disturbances
in early infancy. Later eczema appears with
disappearance of the gastrointestinal symptoms.
Very often the eczema disappears and nasal
allergy develops. The nasal trouble may alternate
with asthma and asthma with arthritis or migraine.
I t must have been an allergic patient who first
voiced the complaint, "Well, if it isn't one thing
it's another." Reactions in certain shock organs
are easier to bear than those in others, and patients
often welcome a shift of shock organs. Why
then, should one not purposely shift the burden
to the organ which is best suited for producing
immunity?
The skin as a shock organ.
An observation which is important in the understanding of the mechanism of desensitization is the
fact that the skin has been shown to be capable of
greater immunity than any other organ of the
body. This has been demonstrated quantitatively by Kahn 8 and has additional confirmation
in clinical experience. I t is well known, for
example, that diseases which are characterized
by extensive skin involvement, usually confer
long lasting immunity. The absence of skin
involvement in these diseases, on the other hand,
is often a sign which justifies an unfavorable
prognosis. Many examples present themselves
to the mind of the clinician, such as the unfavor-
DESENSITIZATIOX IX ALLERGY
able course of measles without the typical skin
lesions; or the well known fact t h a t marked
cutaneous manifestations in syphilis and tuberculosis are rarely associated with serious visceral
lesions.
Shock organs can be purposefully produced
a t t h e sites of inoculations.
T h a t antigens are readily ' : d r a w n " to a tissue
whose immunity is greater than t h a t a t the site of
injection, is evident from repeated observations
t h a t the sites of previous injections frequently
"flare" on subsequent injections with the same
antigen. One of the most dramatic incidents
t h a t I have repeatedly observed occurred when an
individual who had received all his pollen extract
injections in the right a r m without unusual reactions had a severe general reaction as well as a
local one in the right a r m when an ordinary dose
of the antigen was injected in the left arm for the
first time. There was no visible reaction in the
left arm. Such reactions are interpreted as the
localization and destruction of circulating antigen
in the regions in which the tissues have the greatest
immunity. T h e most convincing evidence of
antigen migration is t h a t the injection into the
skin of more antigen than can be localized and
destroyed may cause an unfavorable reaction in
the very shock organ which we wish to protect,
such as an attack of hay fever following an injection of pollen. This phenomenon is the typical
focal reaction. T h a t an antigen m a y travel in
the opposite direction, t h a t is, from the original
shock organ to the skin, is shown by the following
observation.
E. F., age 45, architect, suffered from severe fall
hay fever and pollen asthma for many years. Perennial immunization by intracutaneous injections of
ragweed extract proceeded at a slow rate because of a
tendency toward severe local and occasional focal
reactions. All injections had been given in the left
arm. At the opening of the hay fever season he continued to be symptom free. In order to test his
immunity he walked through a field of ragweed and
to his surprise noticed within a few minutes urticarial
wheals on his left arm at the sites of previous injections.
He did not develop hay fever, but described this
experience as similar to that following mild overdosage
of injected pollen, when the neighboring sites had
flared. This phenomenon was not repeated, but it is
important to realize that this man was later able to
tolerate a single subcutaneous dose of 1 cc. of a 10
per cent solution of pollen extract without even a local
reaction, and has continued to be free from hay fever
and asthma.
79
Two other patients reported similar experiences.
T h e explanation of the phenomenon seems obvious.
T h e patients have not been desensitized b u t
have developed a new, more powerful shock organ
(the skin a t the sites of the injections) which
protects the less immune nasal mucous membrane
from shock. T h e original shock organ is n o t
affected since the humoral antibodies are sufficient
to protect the cells; b u t the artificially immunized
skin, with its greater tissue immunity is still
affected by the antigen, since the circulating antibody is insufficient for complete protection. T h e
evanescence of t h e phenomenon is probably due
to the rapidly rising humoral immunity which
tends to protect equally the original shock organ
and t h e skin a t t h e site of previous injection.
T h a t ordinary methods or immunization m a y
also have disastrous results is shown in the following experience:
A. S., male, age 38 in 1940, who had never before
suffered from asthma was given a series of "cold
shots." After each injection he complained of a
swollen arm and with later doses, asthma within 24
hours after the treatment. After his last injection,
the asthma continued and became chronic.
I n this case the excess antigen probably stimulated
t h e latent i m m u n i t y in t h e lung tissue faster t h a n
immunity could be produced in the skin, so t h a t
t h e lung became the primary shock organ. T h i s
unfortunate occurrence could have been prevented
b y the use of smaller doses of antigen if the doctor
in charge had understood the warning sign of t h e
large local reactions.
After 2 years of asthma this patient (A. S.) presented
himself for treatment. The cause of his trouble
seemed obvious, so treatment was limited to the intracutaneous injections of a tremendously diluted antigen
prepared from the staphylococci of his nose and a filtrate made from his streptococci (viridans) from his
throat. Marked improvement followed a total of
sixteen treatments during the year 1942 and he has
continued to be well in 1943.
An a p p a r e n t paradox demands explanation;
namely, t h a t as skin i m m u n i t y progresses, skin
reactions decrease. I t seems t h a t t h e skin
becomes increasingly unable to localize t h e huge
amounts of antibodies produced, the excess going
into the body fluids. T h u s , the injected antigen
eventually finds its antagonistic antibody in b o t h
the skin and t h e body fluids, the latter bearing
the brunt of t h e immunologic conflict, t h u s
80
HERMAN A. HEISE
sparing the skin as well as the original shock
organ by a process of insulation. This phenomenon is of the greatest importance since it
explains the evolution of undesirable local tissue
immunity, or allergy, to true humoral immunity.
Symptoms of certain infections may be explained
on the same basis as allergic reactions.
Since allergy is evidently but a phase of immunity and desensitization is actually the process
of the purposeful shifting of the shock organ with
the ultimate goal of humoral immunity, it now
becomes easier to explain some phenomena of
infection. Most bacteria and their products are
nontoxic and cause tissue reactions only in the
early phases of immunity, when these tissues, by
virtue of developing early immunity, become
shock organs. The skin at the site of the original
inoculation is particularly vulnerable as in infections like syphilis, tuberculosis, and tularemia and
those caused by pyogenic organisms. However,
an incubation period is necessary, which is short
when immunity is quickly produced and long
when immunity is • slowly produced. Actual
determinations of antibody content also indicate
that the incubation period is actually the time
interval from the original infection to the time of
the production of sufficient immunity to produce
an antigen-antibody conflict, which is marked by
the first symptoms in the tissues of greatest
immunity. After that, the period of recovery, or
natural desensitization, takes place, marked by
the immunization proceeding to the humoral
variety, because of saturation of shock organs with
antibodies with sufficient overflow into body
fluids to then protect these organs.
The following experience indicates that a
bacterial antigen may produce reactions similar
to those produced by "allergens."
Mrs. G. L. suffered from sinus infection characterized by pain over the eyes and discomfort of the
cheeks, teeth, and ears since October, 1941. There
was a purulent discharge from the nose. Cultures
made in October, 1942, revealed only N. catarrhalis.
Six injections of an autogenous vaccine were given
intracutaneously from October to December 1942.
Within 26 hours after injections, the previous sites of
inoculation flared. She remained well from December
1942 till October 1943 when the symptoms recurred.
Her vaccine was given, causing no flares at the sites of
previous inoculations, and there was no change in her
condition. A new culture of the nasal discharge now
revealed staphylococcus albus in pure culture. Anew
autogenous vaccine was given intracutaneously on
November 3, 1943. No flares occurred but she
complained of being dizzy on November 4 and 5.
After this, smaller doses were given at intervals of from
two to four weeks. No focal reactions occurred but
the sites of two previous staphylococcus inoculations
always flared within two days of the time of injection.
These sites could be recognized by carefully choosing
skin areas for injection and by making recognizable
patterns with divided doses. Only once did the
regular train of events fail to occur. This was when
the two previous sites of inoculation flared while
she was having an upper respiratory infection.
I t appears that the skin has become a shock
organ reacting both to injected antigen and to the
bacteria concerned with infection.
PRACTICAL APPLICATION'S
Injections for immunization should, in general,
be kept at minimal levels to avoid stimulating
shock organs other than at the site of injection.
Intracutaneous injections are usually preferable
to the subcutaneous route because the skin
readily lends itself to immunization, and, further,
an intracutaneous injection actually involves the
reticulo-endothelial system, which is known to be
an important factor in immunization. Sabin9
recounts the experience that injections of certain
dyes intracutaneously actually demonstrate involvement of the lymphatics.
However, it is not always advantageous to immunize the skin. For example, in poison ivy
immunization, cutaneous injection would actually
aggravate the condition, and it is therefore important to avoid contact of antigen with the skin.
In this type of immunization, intramuscular
injections are given.
The rationale of the treatment of nasal allergy
by the instillation of antigens into the nose is
open to question. Simply increasing the immunity of the nasal mucous membrane without producing a corresponding humoral immunity might
render the nose more vulnerable to bacterial
products. Also, the action of oral vaccines should
be studied further in the light of modern immunology. It would be interesting to know if users of
oral vaccines have a greater susceptibility to
gastrointestinal infections, particularly appendicitis, than non users.
In the treatment of pollenosis and other allergic
manifestation it has been my experience that a
good prognosis was assured by large reactions at
the sites of inoculation, flaring of other sites, or
urticaria involving new sites if the original shock
81
DESENSITIZATION IN ALLERGY
organ could be spared from reacting. On the
other hand, a poor prognosis was indicated, when,
due to accident or otherwise, injections often
produced focal reactions.
Rackemann 10 has noted the paradox that a
horse sensitive patient may be successfully treated
with horse dander extract administered by the
physician, and yet constant exposure to horses
fails to maintain this "desensitization." I t is
obvious that the place of administration of the
antigen is the important factor in treatment.
SUMMARY
The present theory of the mechanism of desensitization in the treatment of allergic diseases is
admittedly inadequate. This theory explains
desensitization as the neutralization of antibodies
by the injection of small quantities of antigen.
In this discussion I have attempted to show
that desensitization which implies removal of
immunity can be used properly to describe the
phenomenon which follows anaphylactic shock.
However, in the treatment of allergic diseases
in man, the purpose of the treatment is to increase
the immunity at the site of injection, usually the
skin and portions of the reticulo-endothelial
system, without stimulating the already immune
tissues which we are trying to protect. The
injected tissues develop local immunity by the
production of fixed cellular antibodies; and as this
immunity approaches that in the original shock
organ, the latter is increasingly spared the unfavorable antigen-antibody reactions. Thus the
process is one of simple immunization, utilizing,
first of all, the expedient of the shifting of the
shock organ to one that
munologic conflict, with
humoral immunity with
organs.
The understanding of
practical value in the
conditions.
is better suited to imthe ultimate hope of
insulation of all shock
this mechanism is of
treatment of allergic
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(1) ALEXANDER, H. L.: Synopsis of Allergy. St.
Louis, C. V. Mosby Co. 1941, p. 51.
(2) TUFT, Louis: Clinical Allergy. Phila., W. B.
Saunders Co. 1937, p. 34.
(3) BESREDKA, A.: DU mficanisme de l'anaphylaxie
vis-a-vis du s6rum de cheval. Compt. rend.
Soc. de biol., 63: 294-296, 1907.
(4) ARTHUS, M.: Injections r£p6t§es de sSrum de
cheval chez le lapin. Compt. rend. Soc. de
biol., 65: 817, 1903.
(5) OPIE, EUGENE L.: Anaphylactic shock caused
by antibody in animals sensitized by antigenreversed passive anaphylaxis. J. Exper. Med.,
43: 469, 1926.
(6) SHWARTZMAN, G.: Studies on Bacillus Typhosus
toxic substances; phenomenon of local skin
reactivity to B. typhosus culture filtrate.
J. Exper. Med., 48: 247, 1928.
(7) TOPLEY AND WILSON: Principles of Bacteriology
and Immunity. 2 ed. Baltimore, Williams &
Wilkins Co., 1941, p. 913.
(8) KAHN, R. L.: Tissue Immunity. Springfield,
111. Charles C. Thomas, 1936, p. 599.
(9) SABDJ, F. R.: Contributions of Charles Denison
and Henry Sewall to medicine. Science, 86:
357, 1937.
(10) RACKEMANN,
FRANCIS M.:
Clinical Allergy.
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