PHYSIOLOGICAL
Publisbcd
THE AMERICAN
VOLUME 32
copyright
OCTOBER
the Department
SOCIETY,
INC.
1952.
NUMBER 4
on Lymphatic
Tissue
F. DOUGHERTY
of Anatomy,
University
of Utah College of iMedicine
Salt Lake City, Utah
LTHOUGH IT IS usual to introduce a paper dealing with lymphatic tissue by
calling attention to our lack of knowledge concerning this tissue, the author
wishes to take a more positive approach. He has found it impossible to
present more than a few of the vast number of facts available in the literature concerning the hormonal control of lymphatic tissue. The material reviewed will be confined to the influence of hormoneson the involution and growth of lymphatic tissue
and on the structure and number of circulating lymphocytes. The functional significance of hormonally induced acute involution which involves such problems as the
role of lymphatic tissue in the synthesis and release of certain serum proteins and
also its role in the bodily economy have been recently reviewed elsewhere(185).
INVOLUTION
OF LYMPHATIC
TISSUE
Hammar in Igo5 (77) observed an extensive decreasein the size of the thymus
during inanition and contrasted this acute type of atrophy to the gradual involution
of lymphatic tissue which occurs during aging. He proposed the term ‘accidental
involution’ to describe this abrupt decreasein lymphatic tissue weight. Since Hammar’s initial description of this phenomenon, there have been numerous reports of
other conditions producing acute thymic involution. Although many of these stimuli
are pathological in nature, certain physiological stimuli produce acute involution.
The term ‘acute involution’ will be used here to denote the responseof lymphatic
tissue to either physiological or pathological stimulation since the term ‘accidental
involution’ implies a pathological change.
Age Involution. Limitation of spaceforbids an analysis of all factors responsible
for the involution of lymphatic organs which begins about puberty and continues
throughout life. A brief discussionof this phenomenon, referred to here as ‘age involution,’ is necessaryto serve as a foundation for a contrast between this and the
acute type of involution.
Hammar (78, 80) has made the most thorough analysis of age involution among
many speciesof animal and man. Hellman (85), using quantitative methods, found
that the rapid prepubertal gain followed by loss of lymphatic organ weight during
aging was a reflection of the increase and subsequentdecreaseof lymphocytes in
these organs. Andreasen (2, 3) provided further evidence that these changesin lymphatic organs are a reflection of their cell content sincehe found a continuous decline
in nucleic acid phosphorus during age involution which paralleled the decline in
weight.
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Although the spleens of rats (2) and humans (86) continue to increase in weight
following puberty, the lymphatic t .issue of this organ undergoes the usual age involution (86, 76). In contrast to the thymus, splenic wh ite pulp and Peyer’s patches,
the other lymphatic organs of humans and rabbits (go), rats (19, 2, 141), mice
(Santisteban and Dougherty, unpublished) and guinea pigs (2) do not begin age
involution until sometime after puberty. It should be emphasizedat this point that
the lymphatic tissue growth pattern does not follow a curve which merely reflects
changesin body weight during aging but exhibits a type of growth unique among the
tissuesof the body (152).
The influence of hormoneson age involution has been incompletely studied. On
the basisof the endocrinological observations to date, it is apparent that none of the
hormones known to moderate lymphatic organ mass is solely responsiblefor age
involution. Although ablation of gonads (19-21,
139, 141) or adrenals (141,
47) of
prepubertal, pubertal or aging animals results in an increasedamount of lymphatic
tissue, there is no change in the time of onset of age involution or rate of loss of
lymphatic tissue weight.
Age involution of lymphatic tissue presents many unique and as yet poorly
understood aspects of the general phenomenon of aging. The gradual depletion of
lymphocytes from lymphat ic organ.smay be due to an increasingrate of their removal
from these organs rather than to an inhibition of lymphocytopoiesis, since the actual
rate of mitosis is as rapid in aged as in young animals (3).
Acute Involution Produced by Gonadal Hormones. The alterations in lymphatic
tissue resulting from the administration of androgensor estrogensto unoperated or
castrated animals of both sexeshave been extensively studied. Androsterone, testosterone and testosterone propionate produce atrophy of the thymus in intact or castrate animals (I IO, 139, 107, 19, 106). Lesscommonly available androgenic hormones
such as androsterone, 5-androstenediol etc. were also found to decreasethe size of
the thymus in intact or castrate rats (162, 163, 139). Androsterone and testosterone
propionate were the most effective thymolytic androgensin unoperated or castrate
rats (139). After assaying a large number of steroid compounds, Selye (159) came to
the conclusion that all hormonally active steroids will produce thymic involution if
they are administered for a sufficient period of time.
Estrogenic hormoneshave been found to induce acute involution of the thymus
in puppies (6), and in prepubertal rats (66, 17, 153, 139, 19-21, 127). Large amounts
of progesteroneproduced an atrophy of the thymus of rats (164), whereasmoderate
dosesof this compound when administered daily for 20 to 30 days to rats had no such
effect (17).
Placental and urinary extracts from pregnant women administered to rats
resulted in thymic atrophy (14% 53). This acute involution of the thymus was not
due to a nonspecific stress stimulus since heated urine did not produce involution
(14% 104)
Prolan (IO R. U.) when administered daily for 9 days (33) or gonadotrophic
hormone (50 R. u.), for 65 days (53) produced extensive atrophy of the thymus in
prepubertal or adult rats. Gonadotrophic hormoneshad no effect in castrate rats (53).
Few investigators have studied the effects of these hormones on lymphatic
structures other than the thymus. Reinhardt et al. (143) noted that testosterone
propionate and estradiol dipropionate produced only moderate atrophy of lymph
nodes. Administration of pregnancy urine to rats did not causeinvolution of submaxillary and cervical lymph nodes although it produced marked involution of the
thymus (105).
Otto ber Ig5.z
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A major question concerning the action of the sex hormones on the thymus is
whether administration
of these steroid compounds produces acute involution or
merely enhances the rate of age involution. Chiodi (19) investigated this problem
in male and female prepubertal rats which were castrated at the time of maximal
thymic weight and then given testosterone propionate or estrone daily for II days.
Although the amount of hormone administered was sufficient to affect the accessory
sexual structures, only minimal thymic involution was found in the treated animals.
On the basis of this experiment, Chiodi concluded that the involution produced by
gonadal hormones is of the acute type rather than being an accelerated age involution.
Acute Involution
Produced
by Adrenocortical
Hormones.
Selye (157) first
demonstrated thymus atrophy in rats following administration of adrenocortical
extracts. This observation was substantiated by Carriere et al. (18). Ingle (93) found
that moderate involution of the thymus could be produced by adding large amounts
of cortin to the drinking water of intact rats. Later (95, 94), it was found that daily
injections of 17-hydroxy-1 I-dehydrocorticosterone acetate (Compound E acetate)
were more effective in producing thymus involution than similar treatment with
II-desoxycorticosterone acetate (DCA). Wells and Kendall (184) found that corticosterone acetate (Compound A) was more active than corticosterone and that
neither desoxycorticosterone nor DCA produced any lymphatic tissue involution in
the dosesused.They also found that there waslittle atrophy of the thymus following
administration of Cortin when the preparation contained smallamountsof compounds
A or B. Ingle (94) has pointed out that those hormones which produce thymic involution also increase the muscle work capacity of adrenalectomized animals. On
the other hand, Cortin, which is most effective in maintaining life of adrenalectomized
animals, has only a slight thymolytic effect (184).
Desoxycorticosterone or DCA, when given in large doses,will produce thymic
atrophy (94, 162). Dougherty (unpublished data) found that absorption of 60 pg.
daily (from pellets) for 26 to 30 days produced marked thymic involution in intact
mice, although the lymph nodesincreasedin size during this period. A slight involution of the thymus of hypophysectomized or adrenalectomized animals treated with
DCA was reported by Rapela (141).
An analysis of the older literature indicates that corticosterone and its derivatives, dehydrocorticosterone and compound E of Kendall are the most effective adrenal cortical steroids in the production of acute lymphatic tissue involution. Of
these compounds the most active seemedto be compound E (cortisone). DCA is
thymolytic in intact animals but is only moderately, if at all, effective in adrenalectomized animals. Even large dosesof this compound do not decreasethe massof
the lymph nodesof intact mice.
Money et al. (I 27) compared the effects of various steroid and other hormoneson
lymphatic tissuesof intact rats. Quantitative comparisonsof the degree of activity
of these hormones were not made. The compounds tested were ACTH, cortisone,
compound A (I I-dehydrocorticosterone), compoundS (I 7-a-hydroxy-1 I, 2 I-acetoxydesoxycorticosterone), Compound L (I 7 (p)-hydroxy-progesterone), desoxycorticosterone,dihydrocortisone (I 7-ar-hydroxy-2 I-acetoxypregnane-3, I I, ao-trione), pregnenolone, testosterone, progesterone and various estrogenic compounds. ACTH,
cortisone, Compounds A, S and L, pregnenolone, testosterone, DCA and estrogens
all produced thymic atrophy. Only ACTH, cortisone and compound A had any effect
on lymph nodes.
Various steroid hormones were studied in the author’s laboratory (Santisteban
and Dougherty, unpublished). Graded dosesof hormones were given to adrenal-
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ectomized mice of the same age and sex. Weights of thymi and lymph nodes were
plotted against the log dose and straight lineal regression lines were obtained (fitted
by method of least squares). The dose response curve for cortisone was used as the
standard of reference. There is a highly significant inverse relationship between
cortisone dosage and thymus and lymph node weight (7 varied from .285-.330).
Potency ratios for various steroid hormones showed that compound F (17 hydroxycorticosterone) was the most effective with respect to lymphatic organ in involution.
Cortisone, compound B and compound A were successively less potent. Compounds
L and S produced no involution of thymus and lymph nodes even when the graded
dosages were increased above those for cortisone. Desoxycorticosterone
glucoside
produced a slight but significant increase in weight of the thymus.
These experiments demonstrate a high degree of correlation between lymphatic
tissue weights and the quantity of certain steroid hormones administered. Further,
it is evident that there is synergistic activity between positions C-II and C-17 (C-II
hydroxy being more potent than the c-17 hydroxy position). The lack of lymphocytolytic activity of compound L demonstrates the importance of unsaturation of
Ring A for lymphocytolytic activity.
There are many reports that acute involution of the thymus follows administration of crude ACTH (23, 128, 31, 54, 27, 28, 129, 135) as well as the highly purified preparations (39, 91, 171, 170, 141).
Continuous daily injection of ACTH for 15 days into mice resulted in the maintenance of extreme involution all lymphatic tissue except the spleen (39). Splenic
atrophy has also been found recently with more potent preparations of ACTH (36).
Thus, it has been demonstrated that acute involution can be maintained by chronic
treatment with ACTH.
Since ACTH is not effective in adrenalectomized animals (31, 28, 39, 170, 141),
it can be assumedthat the acute involution produced by this hormone is due to an
increased secretion of adrenocortical steroids. Rapela (141) found that ACTH
produced thymic atrophy in castrate, thyroidectomized and/or hypophysectomized
rats, thus eliminating the possibility that ACTH stimulates sufficient gonadal or
thyroidal secretion to causeacute involution.
Role of Other Hormones in Production of Acute Involution. Acute involution of
the thymus or other lymphatic organs did not result from administration of either
prolactin (39) or growth hormone (61). Although no studies are available concerning
the administration of parathormone, ablation of the parathyroid glands of rabbits
did not alter thymus size (122).
The acute involution of lymphatic organs produced
by administration of single dosesof thyroxine and insulin is, apparently, mediated
by the pituitary adrenocortical stimulation produced by these hormones (reviewed
by Dougherty and White, 45).
Interrelationship of Hormones Producing Acute Involution. An answer to the
question of whether the gonadal hormones produce acute involution of lymphatic
tissue directly or whether their action is mediated by pituitary adrenocortical
hormones was approached by injecting gonadal hormones into adrenalectomized
animals. Schacher et al. (153) tested a large number of different compounds,someof
which had sex hormonal activity, and others, although closely related chemically,
which had no effect on the sex organs.Theseauthors found that only those compounds
having definite sexhormonal activity produced lymphatic tissueinvolution in adrenalectomized rats. Estrogens were far more potent than androgens.The dosagesof hormoneswhich were required to produce atrophy of lymphatic organswere considerably
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greater than the amounts required to stimulate the accessory sex organs. The above
observations have been amply confirmed (165, 141).
The increase in lymphatic organ weight following castration can be prevented
by the administration of adrenocortical hormones (I I 2). DCA produced involution
of the thymus of adrenalectomized (94, 141) or hypophysectomized
(141)
but not
castrate rats (141).
In summary, it is apparent from the data cited that acute involution is produced
by enhanced endogenous secretion or administration of a wide variety of androgenic,
estrogenic and adrenocortical steroid hormones. Adrenocortical preparations are most
potent in this regard. The effects of gonadal hormones do not seem to be entirely
mediated by increased pituitary adrenocortical secretion. The comparative effectiveness of other than adrenocortical hormones has not been investigated by methods
which yield accurate quantitative information, nor is there a sufficient amount of
information to allow a comparison of the rates and extent of involution among the
various lymphatic organs induced by hormonal means. It is well established, however,
that the thymus undergoes involution more rapidly and extensively than lymph
nodes.
Mechanism of Production of Acute Involution. Since lymphatic organs (with
exception of the spleen) are composed mostly of lymphocytes, and since acute involution is due to a diminution of these cells, the hormones which produce acute
involution must act by depressing the rate of production, increasing the rate of release
or by increasing the rate of destruction of lymphocytes. Which of these three possibilities might be an explanation of hormonally mediated acute involution was extensively investigated in mice, rats and rabbits treated with ACTH or adrenal
cortical extracts (41, 43, 188). Following a single injection of ACTH the earliest
change in lymphatic tissue was a marked edema, which occurred within I hour and
persisted for 6 hours. During the stage of edema the lymphocytes diminished in
numbers and exhibited marked degenerative changes. There was a cessation of mitosis
of small and medium-sized lymphocyte and a development of reaction centers in the
lymph nodes. Later, (6-g hours) numerous macrophages were observed which were
filled with nuclear debris derived from disintegrating
lymphocytes.
Mitosis of
lymphocytes was resumed at this time and there was also a resumption of heteroplastic development from reticular lymphocytes. These latter cells showed no degenerative alterations with amounts of adrenocortical hormones which destroyed the
smaller lymphocytes. Histiocytes underwent various morphological alterations but
showed no signs of degeneration.
The most profound degenerative alterations were found in the small and mediumsized lymphocytes. These destructive changes, grouped under the term ‘dissolution
of lymphocytes’, began with cytoplasmic budding and eventually resulted in pycnosis
and karyorrhexis of the cells (lymphocytolysis).
The observation of lymphocytolysis
in vivo stimulated several investigators to
ascertain whether or not this phenomenon was due to a direct or indirect action of
adrenocortical steroids on lymphocytes. Robertson (147) and Delaunay et al. (34)
were unable to demonstrate lymphocytolysis in vitro with adrenal cortical extracts or
I I-dehydrocorticosterone. Others, however, have reported lysis of lymphocytes in
vitro using various adrenal cortical extracts (154, 83, 56). Hechter and Johnson (83)
found that lymphocytolysis occurred in vitro when tissue homogenateswere added to
lymphocytes and adrenocortical extract. They suggestedthat a co-factor present in
the tissuewas essentialfor lymphocytolysis. Herlant (88) found that when an amount
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of ACE which did not produce lymphocytolysis in adrenalectomized animals was
combined with a stress stimulus, definite lymphocyte destruction occurred in vice.
He concluded that the hormone acts asa ‘conditioning factor’ for someother lymphocytolytic agent.
In vitro lysis of lymphocytes by adrenocortical steroids which are lymphocytolytic in viva was demonstrated in tissueculture (84) and in cell suspensions(I 54-156).
Schrek (155) found that cortisone but not DCA produced lymphocytolysis. This
author has also designedan assay method for adrenal cortical hormones based on
the lymphocytocidal action of these hormones (156).
The progressive changesoccurring during the lysis of lymphocytes have been
followed in the author’s laboratory by using the phasemicroscopeand photographing
the samelymphocytes at intervals following the addition of cortisone to a suspension
of living cells. Other evidence has been obtained indicating that lymphocyte budding
is produced in vitro by both compound F and cortisone (Frank and Dougherty, unpublished). Thus, there is much evidence in favor of a direct lytic action of certain
adrenocortical steroids on lymphocytes.
The edema fluid in lymph nodes of hormone-treated animals was laded with
cytoplasmic fragments, aptly termed hyaline bodies by Downey and Weidenreich
(48). On the basis of these findings, Dougherty and White (43) suggestedthat the
lymphocyte representeda cellular cite of action of C-II-oxy adrenocortical steroids,
and that the dissolution of lymphocytes by cytoplasmic shedding is a secretory
mechanism.Williamson (191) also suggestedthat budding of lymphocytes is a manifestation of secretion.
The increasein numbers of fixed and free macrophagesin the lymphatic organs,
lungs and livers of mice treated with ACTH suggestedthe possibility that adrenocortical hormonesmight be stimulating the entire fixed phagocytic system (43). The
experimental evidence of Gordon and Katsch (68) and Timiras (179) confirm and
extend this finding.
The alterations described above for ACTH administration into intact animals
are also seen after administration of single injections of aqueous adrenal cortical
hormone (Wilson), Lipo adrenal cortical extract (Upjohn), compound E, compound
F (Kendall) or corticosterone but not DCA into intact or adrenalectomized
animals (4.3).
The observations of several investigators (39, 193, 5, II, 13) demonstrate that
lymphatic tissueatrophy can be maintained for long periodsby continuous treatment
with large amounts of ACTH or cortisone.
Although the rapid loss of lymphatic organ weight which characterizes acute
involution may be attributed to lymphocytolysis, and to a lesserextent inhibition
of mitosis, it is unlikely that the atrophy of lymphatic tissue maintained by chronic
treatment with ACTH or adrenocortical hormonesis due solely to lymphocytolysis
(43). Lymphocytolysis, although it did occur, was not extensive during the period
of maintained atrophy (193, II). Baker et aZ. (II) found that although the lymphatic
organs contained lymphocytes with pycnotic nuclei there was only a small amount of
karyorrhexis after a prolonged period of ACTH treatment. These authors suggested
that due to the absenceof many mitotic figures, the capacity of ACTH to maintain
lymphatic organs in an atrophic state was due to a suppressionof lymphocytopoiesis.
Dougherty (36) confirmed that histological observations of Baker et ah, in mice
given large dosesof ACTH, cortisone or compound F for periods as long as 17 days.
This author found that when hormone treatment was discontinued that lymphatic
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tissue rapidly regenerated. Changes during the period of regeneration were similar
to those found following single injections of ACTH, i.e. rapid resumption of differentiation of lymphocytes from reticular lymphocytes and mitosis of mature lymphocytes. Also, pycnotic lymphocytes appeared to revert to a more normal appearance
following cessation of hormone treatment.
The focus of attention on lymphocytolysis
as an explanation of the lymphopenic
response in the blood after hormone administration appears to have obscured the
fact that adrenocortical secretions not only produce lymphocyte dissolution but also
inhibit heteroplastic and homoplastic lymphocytopoiesis.
Although the mechanism of the acute involution produced by gonadal hormones
has not been as thoroughly investigated as that for adrenocortical hormones, Chiodi
(19) suggested that estrogens exert their moderating action on lymphatic tissue by
continuously destroying lymphocytes. This suggestion is strengthened by the fact
that the mitotic rates during regeneration of lymphatic tissue previously depleted by
starvation were the same in estrone-treated and nontreated animals (20).
Acute Involution Following Stress Stimuli. Selye (158) first demonstrated that
several noxious stimuli which produce an alarm reaction also bring about acute
involution of the thymus and-lymph nodes in intact, but not adrenalectomized
animals. Acute lymphatic tissue involution was, therefore, included as an integral
part of the alarm reaction. However, Selye also demonstrated that the alarm reaction is potentiated in adrenalectomized animals in which lymphatic tissue involution does not occur. According to Selye’s original and recently emphasized concept
(I~I),
stress is a stereotyped response to a wide variety of stimuli (stressors), and
thymico lymphatic involution was considered to be an indirect result of stress mediated by corticoids. The fact that acute involution accompanies the alarm reaction
in intact animals does not mean that it should be considered a pathological phenomenon. Rather, acute involution as a response to the alarm reaction represents a
general lymphatic tissue response produced by increased pituitary adrenocortical
secretion which may occur in many adaptive physiological, as well as externally
induced stressful circumstances. Thus, the functional importance of acute involution
may be that it is a protective mechanism with respect to harmful effects of stress.
Although sex steroids also produce acute involution, enhanced pituitary-gonadal
secretion does not apparently mediate the involution induced by stress stimuli since
it does not occur in adrenalectomized animals having intact gonads (194) and thymic
involution occurs in ACTH-treated
gonadectomized animals (54, 19).
The fact that stressors of a wide variety induce pituitary adrenocortical mediated
acute involution is now so well known and accepted that it does not seem essential
to enumerate the various stimuli producing this phenomenon. Agents causing this
type of acute involution have been reviewed by Dougherty and White (45) and by
Selye (160). The investigations included below are those which are of physiological
importance to the organism in adapting to variations in the external and internal
environment and which are not necessarily accompanied by an alarm reaction.
The histological changes in lymphatic organs of intact animals following single
subjection to stressors are similar to those described for ACTH and adrenocortical
steroids (43, 188, 185, II). The effects on lymphatic organs of prolonged subjection
of animals to stressful stimuli are not, however, strictly comparable in all instances
to prolonged over-dosage with ACTH or adrenocortical extracts. Dougherty and
White (45) emphasized that stressful stimuli which produce a rapidly occurring
acute involution may, if the stress is continued, result in an increase of lymphatic
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organ mass. Thus, when attention is focused on the reaction of lymphatic tissue itself
and not on the increased adrenocortical secretion, it is apparent that various stressors
induce direct as well as an-adrenocortical responses of lymphatic organs. The responses to the following adaptive stimuli are illustrative.
Alterations in the External Environment. The lymphatic tissue of mice exposed
to heat for 5 minutes underwent extensive acute involution followed by hypertrophy
(32). Both fasted and fed rats exposed to cold for a period of 68 hours showed a reduction in the size of their thymi, spleens, cervical and mesenteric lymph nodes
(143)*
Inanition and Malnutrition.
Early investigations concerning the effects of inanition on lymphatic tissue were reviewed by Jackson (96) and more recently by
Andreasen (2). All of the earlier investigators who studied the effects of inanition on
the various organs concluded that during starvations the lymphatic structures and
the liver lose more weight in proportion to body weight than any other organ (82, 2,
143).
The alterations in the microscopic structure of lymphatic organs during starvation, described by Jackson (96), are similar to those described for acute involution
following adrenocortical stimulation.
White and Dougherty (189) studied the relation of various endocrine secretions
to the extensive loss in lymphatic tissue weight in mice induced by inanition and
found that acute involution produced by starvation is mediated in large part by
adrenocortical secretions. Suppression of lymphocytopoiesis is probably in large part
responsible for the maintained involution following starvation since adrenalectomizing starved animals results in an almost immediate increase in mitotic figures, weight
of lymphatic tissue and number of circulating lymphocytes (38).
Thyroid and gonadal hormones play a role in moderating the weight loss of
lymphatic tissue during starvation. White and Dougherty (189)
found that the
amount of lymphatic tissue protein lost during starvation was increased in thyroidectomized-starved as compared to intact-starved mice. Thyroxine did not accelerate
acute involution in adrenalectomized mice but it did diminish muscle nitrogen. The
loss of protein from both lymphatic organs and muscle was checked completely by
adrenalectomizing and thyroidectomizing
the starved animals. These authors suggested that whereas acute involution mediated by adrenocortical secretions yielded
protein for metabolic use, muscle protein was not diminished by adrenal, but rather
by thyroid secretions. The fact that Szego and White (178) found that the degree
of lymphatic tissue loss was less in gonadectomized than in intact-starved rats demonstrated that gonadal hormones partially mediate acute involution due to starvation.
The mediation by sex steroids was not as great as by adrenocortical steroids. Adrenalectomizing starving animals at any time during the period of fast arrested involution
of lymphatic organs. The rate of reconstitution of depleted lymph,atic tissue of previously fasted and refed animals was greater in adrenalectomized than intact mice.
These data suggest that lymphatic tissue of adrenalectomized animals has priority
over other tissues for endogenous or exogenous protein (62).
The acute involution following malnutrition is probably also mediated by pituitary adrenccortical secretion. The nutritional requirements for lymphocyte growth
are extremely important since this tissue is one of the most rapidly growing tissues
of the body and represents a source of rapidly available protein (189). However, the
nutritional requirements are difficult to assess due to the acute involution produced
by pituitary adrenocortical mediated effects of inanition. Stoerck (176) has considered
this fact in his experiments and found that pyridoxine deficiency induces a greater
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loss of thymus weight (in proportion to body weight loss) than vitamin B-complex
and thiamin deficiencies. Calcium deficiency has quite an opposite effect. Since
involution occurred in pyridoxine-deficient
adrenalectomized animals, it may be
assumed that this vitamin is required for lymphocytopoiesis
and that the lymphatic
tissue atrophy was not an adrenocortical mediated result of inanition. Aminopterin,
a folic acid antagonist, also induces acute involution (183,35).
Aminopterin, however,
did not produce acute involution in adrenalectomized mice even when doses were
given which killed the animals after I week of treatment (35). Again, although it
would appear that the effect of aminopterin on lymphatic tissue was entirely adrenocortical mediated, it has been suggested that this folic acid antagonist, in addition to
enhancing adrenocortical secretion, actually inhibits lymphocyte production directly
since the alterations in lymphatic tissue which follow adrenalectomy were prevented
by aminopterin treatment of the adrenalectomized mice (35).
Altered Physiological Conditions : Pregnancy and Lactation. Acute involution
of the thymus during pregnancy has been noted by many observers in almost every
species of animal and in man (reviewed by Chiodi, 19). Maximal thymic atrophy of
humans is found within 2 months after the onset of pregnancy (IS). Hammar (79)
weighed the thymi of pregnant women who died quickly following accidents or
poisoning and found an atrophy of the thymus at various stages of pregnancy. Chiodi
(19) found that 1ymphatic organs other than the thymus also underwent acute
involution during pregnancy.
The acute involution of the thymus which occurs during pregnancy is maintained during lactation (75). Only those lactating rats which maintained their
normal body weight were autopsied in order to rule out possible effects of inanition.
By varying either the number of suckling offspring or cutting the galacophores to
some of the nipples, Gregoire demonstrated that the weight of thymi of lactating
mothers varied inversely with the amount of milk secreted.
Estrogens do not seem to be entirely responsible for the decrease in size of the
lymphatic organs during lactation since gonadectomizing lactating females does not
eliminate the involution (75). Estrogenic hormones, however, may play some indirect
role since gonadectomy results in a further increase of the already enlarged adrenals
of lactating animals (75). It is unlikely that prolactin is responsible for induction of
acute involution of lactation since administration of the hormone did not result in
any striking changes in the size of lymphatic organs (39).
Substances Producing Acute Involution Directly. There are several types of
stimuli which are known to produce acute involution in the absence of the adrenal
gland. These agents, however, also act as stressors and cause enhanced adrenocortical
secretion (45).
Numerous authors have suggested that x-rays produced indirect effects on lymphatic tissue which were variously believed to be due to circulating toxins, deposition
of necrotic lymphocytes in tissues distant from exposed areas or to be mediated by
humoral means (36). Hormonal mechanisms responsible for the distant effects of
x-rays were investigated by Leblond and Segal (III).
Irradiation of the hind quarters
of partially shielded rats produced generalized lymphatic organ involution in unoperated but not in adrenalectomized animals although the thymi in both groups of
animals were affected by direct radiation.
In order to determine the amount of radiation necessary to stimulate adrenocortical secretion and produce atrophy of lymphatic organs, both unoperated and
adrenalectomized mice were irradiated with dosages extending from I0 to 200 r (44).
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GROWTHOF LYMPHATICTISSUE
It is difficult to evaluate the influence of hormoneson the growth of a tissue in
which the cells have as rapid a rate of multiplication and disposition as the lymphocytes. As White (186) has pointed out, in addition to hormones, nutritional, genetic,
and probably other factors play important roles in lymphatic tissue growth. The
problem is further complicated by the fact that undoubtedly any one of thesefactors
modify the effects of others. Analyses of hormonal factors influencing lymphocytopoiesisand disposition of lymphocytes have not as yet beenmade. Most of our knowledge concerning hormonal influences on lymphatic tissue growth is derived from investigations of changesin weight of lymphatic organsfollowing various experimental
procedures. Interpretation of such data with respect to cellular dynamics is indirect,
difficult to interpret and often times misleading. The term growth is used here to
denote increasesin massof lymphatic organsas compared to different baseline values
under different experimental conditions of investigation.
Effect of Gonadal Hormones.
Chiodi (19) has reviewed the early literature on
this subject. Thymus enlargement occurs after gonadectomy of either sex in almost
every speciesof domestic and experimental animal as well as man. Although many
authors believed that gonadectomy slowed the rate of age involution, Chiodi (19)
called attention to the fact that gonadectomy of animals at any time of life including
senility resulted in increasedthymus weights and that castration of either sex did not
produce a significant delay in the time of onset or rate of age involution of the enlarged thymi and lymph nodes when compared to those of rats of the same age.
Similar findings were reported by Plagge (139) and Rapela (141). These investigators
concludedthat gonadal secretionsexert a constant moderating influence on the growth
of lymphatic organs throughout life.
Gonadal hormones were thought to destroy lymphocytes rather than inhibit
mitosis since there was an accelerated rate of destruction of these cells in intact as
compared to gonadectomized animals (19). On the other hand, Gregoire (74) observed that the rate of reconstitution of lymphocytes after irradiation was greater in
gonadectomized than in intact rats.
Effect of Adrenocortical
Hormones.
The effect of adrenalectomy is similar to
gonadectomy in that both operations result in an increase in absolute weight of
lymphatic organs. This observation has been reported for almost every speciesof
animal and for humans with adrenal cortical insufficiency (reviewed by Rapela, 141).
Earlier authors favored the possibility that adrenalectomy delayed the onset and rate
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Acute involution of lymphatic tissueoccurred in both groups of animals with dosages
of x-rays from 25 to 200 r. The smallestdose(IO r) which was effective in intact mice
had only minimal effects on lymphatic tissue in the adrenalectomized animals. All
of the above dosesof x-rays, however, produced stimulation of adrenocortical secretion as judged by depletion of either adrenocortical sudanophilic material or total
adrenocortical cholesterol. Hypersecretion of adrenocortical hormones induced by
x-rays has also been demonstrated in rats (137).
Several chemical agents also produce lymphatic tissue involution directly.
Administration of chloroethyl vesicants (nitrogen mustards) resulted in acute lymphatic organ involution in either intact or adrenalectomized animals (103, 101).
However, Kindred (103) suggestedthat since the nitrogen mustards also produce
depletion of adrenocortical sudanophilic material, that a portion of their lymphocytolytic activity may be mediated by hormonesof the adrenal cortex.
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of age involution. Jaffe (97, 98) and later Rapela (141) followed the changes in weight
of lymphatic organs of animals adrenalectomized at different periods of life and concluded that although the lymphatic organs of operated animals increased in size as
compared to unoperated controls, the time of onset and rate of lymphatic tissue loss
during age involution was not altered by adrenalectomy. It was concluded that
adrenocortical secretions exert a constant moderating influence on lymphatic tissue
throughout life.
Several investigators reported that ablation of gonads and adrenals results in a
greater increase of lymphatic tissue than does either operation alone (122, 19, 141).
A comparison of the effects of gonadal and adrenocortical secretionsrevealed that
adrenocortical hormones exert the greater moderating influence, and that the secretions of the two glands have similar but independent effects on lymphatic tissue.
Stoerck (175) reported that the thymus weight, to body weight ratio of castrated
or adrenalectomized animals did not differ from that ratio found in well-nourished
control animals which grew at an optimal rate. Woodbury and Dougherty (47)
weighed thymi and lymph nodes of mice which were deprived of their adrenals at
various age intervals during the prepubertal, pubertal and postpubertal times of
life. Adrenalectomy at any period was followed by an increasein lymphatic organ
weight but the time of onset and rate of age involution were not altered. The ratio
of the thymus weight to body weight of the adrenalectomized animals at each age
interval did not differ significantly from that of intact mice of the sameage. On this
basisit was concludedthat adrenalectomy doesnot result in a true increasein thymus
weight, although there was a slight increase in some of the lymph nodes. These
results further indicate that in the absenceof various degreesof acute involution, i.e.
in adrenalectomized animals, the mean lymphatic organ weight increasesbut does
not exceed to any extent the maximum values found in a seriesof intact control
animalskept under optimal conditions of minimum stress(175). Boyd (14) recognized
the importance of acute involution and called attention to the fact that in order to
prove excessivegrowth of human lymphatic tissue it must be shown that the lymphatic organs exceed the maximum values of well-nourished healthy individuals of
the sameage.
The concept of homeostasisimplies that any mean physiological value is the
resultant of opposing forces, someof which tend to increase and others to decrease
this value. Thus, adrenocortical and gonadal hormonescounterbalance through their
moderating effects those influenceswhich tend to increasethe amount of lymphatic
tissue. Since there is no progressiveincreasein lymphatic tissue in adrenalectomized
or gonadectomized animals (35, 38, 175, IS), it may be assumedthat the removal of
these moderating influences is not followed by an enhancement of those factors
which tend to increaselymphatic tissue.
True hyperplasia, as defined here, implies that lymphatic organ massis greater
than that found in animalsin which one or all moderating influencesare not operating.
In order to prove the existence of true hyperplasia as measuredby increasein mass,
the lymphatic organ weight of experimental animals must be greater than that found
in adrenalectomizedor gonadectomized controls.
Effect of Purified Steroid Hormones. Investigations of growth promoting effects
of steroid hormonesare few and in most casesthe weights of lymphatic organs were
not compared to standards which would indicate whether or not true hyperplasia
was produced. DCA produced enlargement of the thymus and lymph nodes when
administered for a long period of time (159, 16, 162). Selye (159) suggestedthat
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this is an example of ‘dissociated adaption,’ i.e. the effect of the hormone on the
thymus was lost. Prolonged administration of DCA decreased the size of the adrenal
cortex (159, 141) and thus a state of adrenal cortical insufficiency may account for
the increasedamount of lymphatic organ mass.Since there was inadequate comparison to control animals, it is not known whether the enlarged thymi were truly
hyperplastic.
Money et al. (127) reported that among a large number of hormones given to
intact rats only progesteroneincreasedthe size of the thymus. Natural and synthetic
estrogens,testosterone,pregnenoloneand compoundL increasedthe sizeof mesenteric
nodes.Here again the comparisonto intact control animals alone (in which there was
a wide variation) prevents any interpretation of the data concerning capacity of any
of the hormones to produce true growth. The finding that compound L increased
mesentericnode size is of interest becauseit occurred in spite of adrenal enlargement
and thymic involution. Data in the author’s laboratory (Santisteban and Dougherty)
indicate that compound L produces true hyperplasia of lymph nodes but not thymi
in adrenalectomized-treated animals.
Effect of Growth Hormone on Lymphatic Tissue. Growth hormone was found to
increase the size of the thymus of intact and hypophysectomized animals (61, 114,
57). It was suggestedthat growth hormone might have a specific thymotrophic
action since hypophysectomized growth hormone treated animals had larger thymi
but not lymph nodes and spleensthan operated control animals given the same
amount of food (123, 141). Feldman (57) compared the weights of thymi of hypophysectomized controls, hypophysectomized growth hormone treated and intact
nontreated control animals. He concluded that growth hormone treatment increases
the size of the thymus, but examination of his protocols doesnot support this conclusion. Growth hormone treatment, however, increasedthe weights of lymph nodesas
compared to either intact or hypophysectomized controls.
Greenbaum and Young (69) found that after adjusting the daily food intake of
adult intact rats treated with growth hormone (I mg/day) for 23 days to the same
amount consumedby control animals, the spleensof treated animals exhibited isometric growth. Szegoand White (177) concluded that growth hormone did not effect
the composition and weight of lymphatic tissue of starved adrenalectomized and
intact mice. The weight of lymphatic tissue of adrenalectomized fed mice given
growth hormone was not increased (177).
The thymi, lymph nodesand spleensof intact rats treated with growth hormone
daily for 350 to 465 days were reported to be no larger (weights not given) than those
of nontreated rats of similar age (130). The same authors found that prolonged
growth hormone treatment of hypophysectomized rats resulted in larger lymph nodes,
thymi and spleensas compared to those of hypophysectomized nontreated controls
(131)
Experimental evidence is conflicting and further work is necessaryto clarify the
influence of growth hormone on lymphatic tissue. However, administration of this
hormone partially prevents the involution of the thymus of hypophysectomized
animals and apparently increasesthe size of the lymph nodesof hypophysectomized
animals as compared to intact controls. Since growth hormone does not increase
lymphatic tissueof intact or adrenalectomized animals it is apparent that it doesnot
produce a true hyperplasia. Many authors have reported that the thymi of hypophysectomized rats are smaller than those of intact animals of comparable age (173,
8, 58, 141, 143, 57). The spleensof operated animals also were reported to be smaller
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57) but not the mesenteric lymph nodes (143).
Examination of the protocols
indicate that Feldman (57) found a significant increase of lymph node weight and
although statistical comparison was not made, an extensive increase of thymic
weight in hypophysectomized as compared to control groups. Increasesin weight of
thymi and lymph nodes of hypophysectomized rats were reported by Richter and
Wislocki (146).
The discrepanciesin these results emphasizethe importance of taking into consideration the methods of analysis. For example, when the weight of the lymphatic
organswasexpressedin amounts per IOO gm. of final body weight there was an actual
increased amount of lymphatic tissue. One may assume,therefore, that lymphatic
tissue does not lose weight to as great an extent as does the total body following
hypophysectomy. On the other hand, if the lymphatic organ weight is expressedin
terms of IOO gm. initial body weight, an actual lossamounting to at least 20 per cent
was found (141). If the data for hypophysectomized animalsgiven by several authors
are expressedin terms of IOO gm. body weight of control nontreated intact animalsof
the same age and sex, it is even more apparent that involution of the thymus and
spleen, but not lymph nodes, is characteristically found in the absence of the
hypophysis.
By synthesizing the results obtained by thesevarious methodsof expressingdata,
it is apparent that lymphatic organs composea greater proportion of the total mass
of hypophysectomized animals but this amount is lessthan that composingthe lymphatic organ proportion of body weight of intact animals. The weight of lymph
nodes of hypophysectomized animals is maintained at the proportion of the total
weight of intact animals to a greater extent than that of other lymphatic organs.
Effect of Thyroid Hormone. The slight loss of lymphatic tissue weight due to
thyroidectomy in rats was eliminated by the daily administration of thyroxine (I&).
Marine et al. (122) found that the rate of age involution in young rabbits was accelerated following thyroidectomy and that- ablation of the thyroids and gonads
eliminated the increase in size of the thymus expected in castrates. Instead of an
increasein weight as expected following gonadectomy alone, ablation of the thyroid
of previously castrated rats was followed by involution (19). The rate of age involution of the thymi of the doubly operated animals was greater than the rate of the
lossof body weight.
The expected increaseof weight of the thymi of adrenalectomized rabbits and
rats was diminished but not completely prevented when the animals were also thyroidectomized (I 2 2, 141). Thyroidectomy of previously gonadectomized-adrenalectomized rats resulted in an increased size of the thymus and lymph nodesof operated as compared to intact control animals of the sameage (141).
Dessicated thyroid fed to various speciesof experimental animals induced enlargement of lymphatic tissue (early work reviewed by Marine, 122), Low (116), and
Houssay, (unpublished work quoted by Rapela, 141). Reinhardt (143) found that
feeding of dessicatedthyroid increasedthe weight of the lymph nodesand spleenbut
did not alter the weight of the thymus. Houssay (141) reported that an increasein
thymus weight was produced by certain dosesof dessicatedthyroid, and that doses
larger or smaller than the optimal amount were ineffective. Andreasen (I) reported
that hypertrophy of the thymus of animals fed dessicatedthyroid did not regularly
occur and was present only in emaciated animals. These findings were confirmed by
Gregoire (70). Marder ( IIS) recently reported that administration of thyroxine induced a slight but significant increaseof lymphatic tissueof intact mice.
(143,
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Thyroxine when given to castrate rats did not increase the weight of the thymus
to a greater extent than castration alone (144).
The lymph nodes and thymi of
thyroxine-treated
hypophysectomized
animals were larger per IOO gm. final body
weight than intact nontreated controls (57).
Apparently Gregoire is the only investigator who has studied the role of thyrotrophic hormone in the regulation of lymphatic tissue growth (70-73). The thymi of
chicks and thymi and lymph nodes of rats given graded doses of thyrotrophic
hormone sufficient to produce graded increases in thyroid size were not enlarged as
compared to those of normal growing prepubertal controls. However, the lymphatic
organs of animals which lost body weight during hormone treatment were greatly
enlarged. Gregoire also compared the alterations in the size of thymi and lymphatic
organs of intact and adrenalectomized rats given thyrotrophic
hormone (71). He
found that in spite of a profound body weight loss, the thymi and lymph nodes of the
adrenalectomized thyrotrophic hormone treated rats underwent an absolute increase
in mass greater than that following adrenalectomy alone (true hyperplasia), whereas
the thymi of intact treated animals did not change in weight.
In addition to experimental procedures described above, other authors applied
different technics to the study of lymphatic tissue growth. Various ablation procedures in a member or both members of pairs of parabiotic rats were performed by
Rapela (141). It is unfortunate that the results of these excellent experiments cannot
be fully treated here. In general, Rapela’s results confirm the findings that gonadal
and adrenocortical secretionsmoderate lymphatic tissue growth. The role of the thyroid in maintaining the size of the thymus was also investigated. Thyroidectomized
rats were joined to thyroidectomized and adrenalectomizedrats. The thymus weights
were lessin the animals having intact adrenals than in the doubly operated animals.
The effects of hormones on the growth of lymphatic tissue were also investigated by first producing acute involution of lymphatic organs and then determining
the rate of their reconstitution to normal levels. Gregoire (72) determined the rate of
return to normal weight of lymphatic tissuesof rats made atrophic by whole body
x-irradiation. He compared the rates of reconstitution of the lymphatic tissue of
adrenalectomized, adrenalectomized and castrated nontreated and adrenalectomized
and castrated rats given thyrotrophic hormone to those found for intact x-irradiated
animals. The rate of reconstitution was faster in the adrenalectomized than in the
intact treated rats and still more rapid in the adrenalectomized and gonadectomized
irradiated animals. The most rapid rate of reconstitution was found in gonadectomized-adrenalectomized irradiated rats given thyrotrophic hormone. The lymphatic tissue of intact irradiated animals treated with thyrotrophic hormone did
not grow faster than that of the intact irradiated control group.
Marine (119-121) and Wanser (182) on the basisof human and animal investigation suggestedthe possibility that the hyperplastic lymphatic organs found in
Grave’s diseasewere the result of an underlying deficiency in gonadal and adrenocortical secretions accompanied by an excessive thyroid secretion. Gregoire (71)
concurred with this suggestionand also pointed out that hypersecretion of thyroid
hormone alone doesnot result in an extensive hyperplasia of lymphatic tissue. This
may account for the absenceof a lymphocytosis and lymphatic tissue hyperplasia
in simple hyperthyroidism as contrasted to the enlarged lymphatic organs found in
most casesof ‘toxic’ hyperthyroidism (reviewed by Sloan, I 72). In this respect, Boyd
(14), who reported on a large seriesof human diseases,found that the only human
disease(with the exception of lymphomas) in which a true hyperplasia of lymphatic
tissue independent of the lossof body weight is found, is in toxic hyperthyroidism.
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HORMONAL
EFFECTS ON BLOOD LVMPHOCYTES
A lymphocytosis following adrenalectomy has been reported in cats (195, 24),
rats (166, 29, 187), and mice (187). Other investigators did not find a lymphocytosis
in adrenalectomized cats (113, 181) or in adrenalectomized rats (25). The slight
lymphocytosis of adrenalectomized mice was not entirely due to hemoconcentration
and its extent dependedon the animal speciesstudied (187). The presenceof a slight
but significant lymphocytosis in Addison’s diseasehas been reported many times
(I339 32, 89, Id
Hyper-adrenal cortical secretion, on the other hand, depressesblood lymphocyte
levels. Mice which received daily injections of adrenocorticotrophic hormone for a
period of 15 days had slight but significantly decreasednumbers of circulating
lymphocytes (187). A sustained drop in lymphocytes has been reported following
chronic administration of ACTH or cortisone to rats and rabbits (rg3), to mice
(140, 102), to hypophysectomized rats (7), or adrenalectomized rats (67). A study of
the blood picture in Cushing’ssyndrome revealed that the deviation of blood lymphocytes is the opposite of that found in panhypopituitarism or Addison’s disease(32).
‘Lymphopenic
Response.’ Dougherty and White in 1943reported that a sudden
decreasein circulating lymphocytes occurred following administration of ACTH (40).
The sameauthors also found that adrenal cortical extracts and purified preparations
of compoundsE and F when given to several speciesof animals alsoproduced lymphopenia (42). This rapidly occurring lymphopenia became maximum within 3 to g
hours (depending on the preparation used and the speciesstudied) and was followed
by a return to normal lymphocyte levels within approximately 24 hours. This phenomenon, i.e. sudden lymphopenia and rapid reconstitution to normal numbers of
blood lymphocytes was named the ‘lymphopenic response’ by Dougherty and
White (4 5).
The specificity of this reaction was demonstrated by the fact that ACTH did
not produce lymphopenia in adrenalectomized animals (39). Only the so-calledglucocorticoids produce a lymphopenic response.When given in a wide variety of doses
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It must be emphasized again that measurements of changes in mass of lymphatic
organs do not necessarily reflect the rate of production and destruction of lymphocytes. Although a given hormone may enhance lymphocytopoiesis
(either hetero- or
homoplastic), other hormones may enhance the rate of destruction with the result
that no change in weight would necessarily occur. It seems clear, however, that certain
endocrine secretions (adrenocortical and gonadal) exert only a moderating influence
and that their absence allows but does not in itself lead to proliferation of lymphocytes. There may be other as yet unknown mechanisms which moderate lymphatic
tissue, but, of the two so far investigated, adrenocortical hormones appear to be the
more influential. Among the hormones which have been thought to have stimulating
influences, it appears that thyroid hormone exerts a greater effect (as measured by
increase in mass) than growth hormone. An analysis of the data so far presented indicates that the most important hormonal secretions which, through their respective
counterbalancing effects, maintain lymphatic tissue within the normal range characteristic of a particular age are thyroid, adrenocortical and gonadal hormones. The
existence of interrelationships of the opposing effects of these hormones is emphasized
by the fact that hypersecretion of thyroid hormone does not produce any great
increase in lymphatic organ weight unless moderating influences are simultaneously
diminished. The weight of lymphatic organs at any one time reflects the relative relationship existing between stimulating and moderating influences.
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DCA does not affect the numbers of circulating lymphocytes (41). This phenomenon
has been reproduced many times by the administration of ACTH to animals (145,
192) and humans (89, 59, 87, ISI). Dosageswhich elicited lymphopenia in normal
subjects were ineffective in patients with Addison’s disease(89, 59).
The lymphopenic responsewas also elicited in humans following injection of
adrenal cortical extracts (41, 30, Sg) and compound F (60) although desoxycorticosteronewas ineffective.
Nelson and co-workers (134) found that administration of cortisone, cortisone
acetate, compound F and compound F acetate to normal human subjects was followed by increasedblood levels of I 7-hydroxycorticosteroids which was accompanied
by a lymphopenia. Cortisone acetate given intramuscularly causedinconstant changes
in steroid levels and number of blood lymphocytes, and compound F acetate given
by this route was ineffective. When these hormones were given intramuscularly in
alcoholic solutions, increasedblood levels of I 7-hydroxycorticosteroids and lymphopenic responsesoccurred. Compound S (free alcohol or acetate) was ineffective when
given either orally or intramuscularly. These investigators found that whereas the
maximum elevation of blood corticoids was at I hour, the maximum lymphocyte
changesoccurred 4 to 8 hours after administration, (at which time blood hormone
levels were normal or below normal). These investigators have been the first to demonstrate the closerelationship between the blood level of hormone and number of blood
lymphocytes.
Although Nelson et al. note1 decreasedmonocytes, alterations in monocyte numbers were not as consistently observed as was the lymphopenia. Tompkins (180)
reported that a monocytopenia was as constant as a lymphopenia in rabbits
given ACE.
There are only a few investigations concerning the effects of nonadrenocortical
hormones of the numbers of circulating lymphocytes. An increase in the absolute
number of blood lymphocytes of hypophysectomized rats was reported by Crafts
(25).
However, no alterations in the number of circulating lymphocytes have been
found in humanswith various types of pituitary deficiencies(30).
Neither gonadectomy nor the administration of testosteronepropionate produced
any significant changesin the level of blood lymphocytes (26). Large dosesof estrogens produced both agranulocytosis and lymphopenia in dogs (46). Prolactin did
not produce an acute lymphopenia nor did it alter the level of blood lymphocytes
when administered daily for 15 days to mice (187).
An absolute lymphopenia was reported in patients following thyroidectomy
(174), and thyroidectomy was followed by a decreasein circulating lymphocytes in
rabbits (167) and rats (25).
An increase in circulating lymphocytes follows the
administration of thyroid hormone to animals, and a lymphocytosis in thyrotoxic
patients has been reported by many authors. Bistrom (12) has reviewed the reports
on this subject and supplied further evidence that a lymphocytosis is consistently
present in thyrotoxic patients. Contrary to earlier reports, other investigators did
not find alterations in blood lymphocytes in hyper- or hypothyroid patients (9) or
in dogs given thyrotrophic hormone or dessicatedthyroid (169).
Although it has been shown that blood lymphocyte levels are not necessarily
and consistently correlated with the size of lymphatic organs (4), it is apparent that
the lymphopenic responsereflects the increase of blood I 7-hydroxycorticosteroids
and is a peripheral indication of acute lymphatic tissue involution.
‘Lymphopenic Response’and Stress. The acute involution of lymphatic tissue
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which follows many varieties of stress has its blood counterpart in the ‘lymphopenic
response.’ Thus, the lymphopenic response may accompany adaptive physiological
alterations such as pregnancy, lactation, or certain emotional stimuli in animals and
man
(5% 64, 55, 90, 13% 125).
The lymphopenic response has also been produced by subjection of animals to
variations in the external environment. A rapidly occurring lymphopenia followed by
lymphocytosis was observed in mice subjected to extreme heat for a period of 5
minutes (132). Decreasesin blood lymphocytes were also produced by exposing rats
to cold (gg, 81) and reduced oxygen tension (124, I 17).
Starvation also induced a lymphopenia in rats (168). The lymphopenia produced
by inanition in mice could be eliminated by adrenalectomizing the fasting animalsat
any time during a 4-day starvation period (62). The lymphopenic responsewhich
resulted from feeding dextrose to rats did not occur in adrenalectomized animals
(61). Aminopterin produced an adrenocortical mediated lymphopenic responsein
mice but as was the casewith the lymphatic organs when it was given to adrenalectomized mice, it prevented the expected lymphocytosis (35).
A large number of drugs, bacterial products, tissue metabolites, and disease
states were also found to produce adrenocortical mediated lymphopenic responses
(reviewed by Dougherty and White, 45, and by Selye, 160).
Several hormones,which apparently do not have direct effects on lymphocytes,
produce adrenocortical mediated lymphopenic responses.Administration of epinephrine has been shown to produce a typical lymphopenia in unoperated but not in
adrenalectomized rats (65) and in humans (125, 190, 149). The fact that epinephrine
produced lymphopenia in normal human subjects but not in patients with Addison’s
diseasehas been used clinically to differentiate between primary adrenocortical and
pituitary insufficiency in this disease(142). Although attention has been called to
the fact that the eosinopenia produced by epinephrine provides a better clinical
method for testing pituitary adrenal cortical secretion, it is not within the scopeof
this review to compare the eosinopenicand lymphopenic responses.
The lymphopenic responseproduced by single injections of Pitressin in mice or
rats was abolished by adrenalectomizing or hypophysectomizing the animals (45).
Although gonadal hormones may produce involution of lymphatic tissues in the
absenceof the adrenal cortex, thesehormonesare incapable of mediating the lymphopenic responseto stressors.
A group of stimuli which include x-rays, (44), urethane (so) and nitrogen
mustards ( IOI, 103) are all capable of producing lymphopenia in adrenalectomized
animals. Since each of these stimuli, however, hasbeen shownto alsoincreaseadrenal
cortical secretion (101, 45), it is probable that someof their effects on blood lymphocytes (as well as on lymphatic tissue) are hormonally mediated.
The duration of the lymphopenia is related to the amount of adrenal cortical
steroids secreted, the period over which accelerated adrenal cortical secretion continues and the rate of restoration of lymphocytes to the blood. Since nonspecific
stimuli produce varying degreesof adrenocortical secretion (qo),
it is not expected
that all stimuli should produce the same degree and duration of lymphopenia.
Quantitative studiesof the relationship between hormone doseand degreeof lymphopenia similar to those for eosinophilresponseshave not been made. In order to maintain animals in a lymphopenic state, adrenocortical hormonesmust be administered
at closely spacedintervals (109).
Mechanism of Production cf Lymphopenia. The decreasein blood lymphocytes
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could be due to an inhibition of mitosis, decreased delivery to the circulation or rapid
destruction of cells in tissue and blood. After examining these three possibilities, it
was suggested (43) that since lymphocytolysis
in the tissue precedes a fall in blood
lymphocytes that this mechanism was of greater significance than inhibition of mitosis
in the production of the lymphopenic response. It was also suggested that lymphocytolysis occurs in blood and nonlymphatic tissues (43). Recent evidence, vide supra,
that there is a direct lymphocytolytic effect of adrenal cortical steroids on lymphocytes supports this point of view. Lymphocytolysis could also account for the decreaseddelivery of lymphocytes to the circulation from the thoracic duct following
ACTH and epinephrine (192, 92). Hungerford and co-workers (92) showed that
ACTH decreasedthoracic duct lymphocytes in hypophysectomized but not in adrenalectomized animals. Epinephrine was also effective in hypophysectomized rats.
Pitocin, STH, ACE, cortisone and DCA did not reduce the number of thoracic duct
lymphocytes in any group of animals studied. Other investigators also found ACE
ineffective in reducing thoracic duct lymphocytes (I~I).
This difference in action between ACTH and purified adrenal cortical steroids
emphasizesthe fact that reduced delivery of lymphocytes to the blood is not the
solemechanismby which the lymphopenic responseis produced. These results provide further support for the theory that lymphocytes are destroyed in the blood by
adrenocortcial secretions. On the other hand, the lymphopenia which is maintained
by continuous hormone treatment may be partially dependent upon inhibition of
mitosis.
The lymphopenic response following several stress stimuli differs from that
produced by adrenocortical hormonesin that there is an immediate increasein blood
lymphocytes (phaseI>, followed by a lymphopenia (phase 11) and finally a reconstitution to normal levels (reviewed by Michael, I 25). The lymphopenic responseto
epinephrine, electroshock and other stimuli follow this type of curve and have been
discussedin detail by Michael (I 25), Michael and Brown (I 26) and Samuels(149).
Phase I was attributed to epinephrine secretion which produced splenic contraction and thus a discharge of lymphocytes into the circulation (I 25). However,
phase I has been observed in splenectomized animals and humans (reviewed by
Michael, 125). It is also possible that epinephrine administration or discharge by
increasing the tissuerequirement for blood steroidsproducesa decreasein circulating
adrenocortical steroids which in turn would result in a concomitant increasein blood
lymphocytes (I IS). This suggestion is strengthened by the observations that the
degree of lymphocytosis of stressedadrenalectomized mice given graded dosesof
cortisone is inversely proportional to the hormone dosage (108)
and also by the
finding of Dougherty and Frank (37) that the lymphopenia produced by administering compound F to adrenalectomized mice could be abolished by the concomitant
administration of epinephrine.
Phase II is not dependent upon adrenal medullary dischargesince lymphopenia
occurs in animals with denervated adrenals subjected to emotional stimuli (22).
However, there is evidence that ACTH and epinephrine may have synergistic action
since when these two hormoneswere given together a greater reduction of thoracic
duct lymphocytes occurred than following administration of either compound alone
(92). The lymphocytosis of phase I wasalsoenhancedby simultaneousadministration
of compound F and epinephrine (37).
The responsesof lymphatic tissue to other than
‘Lymphocytotic
Response.’
adrenocortical effects (an-adrenocortical) of stressorswould be masked in intact
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EFFECT
OF
HORMONES
ON
LYMPHATIC
TISSUE
397
The author expresses his gratitude
to Jean H. Dougherty,
M.D. for her invaluable
assistance in
reviewing
the literature
and aiding in preparation
of the manuscript.
Thanks are also due Dr. and
Mrs. George Santisteban
for the complete translation
of the monographs
and papers of the Argentine investigators
cited.
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