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Immune system of the spontaneously hypertensive ratII. Morphology and function

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THE ANATOMICAL RECORD 237:236-242 (1993)
Immune System of the Spontaneously Hypertensive Rat:
II. Morphology and Function
Department of Anatomy and Cell Biology (E.S.P., V.H.G.), Department of Pathology and
Oncology (G.W.W.), University of Kansas Medical Center, Kansas City, Kansas
The spontaneously hypertensive rat (SHR) is a stress-sensitive animal which exhibits moderate immune dysfunction that has been
implicated in the onset of hypertension. In this study, we examined the
morphology of SHR thymus and spleen and further characterized the immune deficiency using Wistar-Kyoto (WKY) and Fisher 344 (F-344)rats for
comparison. The adult SHR thymus does not display the increase in medullary volume typically noted with aging and the volume density of the
marginal zone is decreased in the spleen. In vivo tritiated-thymidine incorporation is also decreased in the spleen of unstimulated SHR. In mixed
lymphocyte reactions (MLR),the proliferative response of SHR splenocytes
is significantly decreased relative to controls, WKY and F-344. Addition of
interleukin-1 (IL-1), interleukin-2 (IL-2),or indomethacin to the MLR cultures does not increase proliferation. The proliferative response to T cell
receptor monoclonal antibody (mAb-TCR)or interleukin-2 (IL-2)are similarly impaired in the SHR. The depressed proliferative T cell response is
reversed by prolactin. It is suggested that the SHR is a valuable model for
the study of immune deficiency. o 1993 Wiley-Liss, Inc.
Key words: Thymus, Spleen, Spontaneously hypertensive rat, Interleukin
2, T Lymphocyte
The SHR is a widely used animal model of hypertension. Depressed immune function relative to other rat
strains has been demonstrated using polyclonal mitogens, rosette formation with sheep red blood cells,
plaque forming assays, allograft rejection, and footpad
swelling (Takeichi et al., 1980, 1981). The impairment
of mitogen-induced proliferation is age dependent
(most notable at 12 weeks of age) and appears to be
suppressed, a t least in part, by a subpopulation of
mononuclear cells (Pascual e t al., 1992). The immunological deficit has been implicated in the etiology of the
increased blood pressure however the exact mechanism
has not been elucidated. Thymic transplants and other
immunological manipulations alleviate hypertension
in SHR (Ba et al., 1982; Khrabi et al., 1984; Norman et
al., 1985; Strausser, 1983). The SHR also exhibits abnormalities in antibody mediated immune responses
(Takeichi e t al., 1981). The observations of immunologic abnormalities in both SHR and humans with essential hypertension has generated interest in the interrelationship between altered immune function and
hypertension (see Dzielak, 1992; and Mugge and Lopez,
1991, for review).
The SHR is stress-sensitive and exhibits increased
sympathetic neural input to a number of organs (Donohue e t al, 1988; Gattone et al., 1990). This enhanced
innervation has also been implicated in the development of hypertension. Renal denervation (Norman et
al., 1985) and systemic sympathectomy (Yamori e t al.,
1985) prevent the onset of hypertension. We previously
demonstrated increased sympathetic innervation of
thymus and spleen in the SHR at time points (e.g., 12
weeks of age) that appear to be related to the immune
deficit (Purcell and Gattone, 1992). Since sympathetic
innervation is believed to modulate some aspects of
immune responsiveness (see Felten et al., 1988, for review), the SHR provides a potential model of neurally
mediated immune suppression.
In the present study, we examined thymic and
splenic morphology and combined those observations
with assays of T cell function in order to further characterize the immune dysfunction of the SHR. We demonstrate unusual morphological characteristics of SHR
thymus and spleen that may be related to immune
function. We also report impairment of T cell proliferative capacity including a virtual lack of response to
the important lymphokine, IL-2.
Adult, male SHR and WKY rats obtained from
Taconic Farms (Germantown, NY) were used for the
initial MLR studies. Colonies of SHR, WKY, and F-344
Received March 9, 1993; accepted J u n e 7, 1993.
Address reprint requests to Vincent H. Gattone, 11, Department of
Anatomy and Cell Biology, University of Kansas Medical Center,
3901 Rainbow Blvd., Kansas City, KS 66160-7400.
rats were also established and maintained in the Animal Care facility at the University of Kansas Medical
Center from breeding stock obtained from Charles
River Labs (Wilmington, MA). Blood pressure was
measured for SHR and WKY rats using tail pleismography (IITC Inc., Woodland Hills, CA) prior to experimental use. Rats were anesthetized with sodium pentobarbital, the vascular systems flushed with perfusate
and thymi and spleens removed. Extraneous tissue was
dissected away from the organs and they were weighed.
Organ weight was evaluated and compared relative to
body weight since different strains can have slightly
different body growth development and terminal
Morphometric Analysis
Organs were perfusion-fixed with 4% paraformaldehyde in 0.1M phosphate buffer, embedded in paraffin,
sectioned at 10 pm, and every tenth section was placed
on slides and stained with hematoxylin and eosin. Grid
point counting was used for morphometric analysis by
projecting all of these tissue sections of thymus onto a
grid and noting the number of intersections in cortex
and medulla. Random fields from each of several sections through each spleen were photographed at 50 x .
Prints were overlayed with a grid and intersections in
the periarteriolar lymphoid sheath (PALS), marginal
zone (MZ), red pulp (RP), and other regions (i.e., vasculature and capsule) were determined. Counts were
performed on coded specimens.
In Vivo Proliferation Assay
Twenty-four-week-old rats received 1.0 pCi/g body
weight of tritiated-thymidine (6.7 Ci/mmol, ICN Radiochemicals, Irvine, CA; administered i.p.). After one
hour, rats were anesthetized with sodium pentobarbital. Spleen and a section of intestine (positive control)
were removed and immersion-fixed in 10% neutral
buffered formalin, and blocked in paraffin. Sections
were cut a t 10 pm and mounted on gelatin-subbed
slides. The slides were dipped in NTB-3 autoradiographic emulsion (Eastman Kodak, Rochester, NY)
and exposed in the dark at 4°C for 6 weeks. Following
development in D-19, slides were lightly counterstained with hematoxylin and eosin. The number of
labeled nuclei within a 0.2 mm2 reticule was then
noted. On coded slides, seven random fields were
counted per zone (PALS, MZ, and RP) from each section
and three sections approximately l m m apart were examined per rat. Results are expressed a s the number of
labeled nuclei per square mm SEM.
0.0003% 2-mercaptoethanol. Cells were cultured for 72
h at 37°C in 5% carbon dioxide.
Cytokine Stimulation
Spleen cells were cultured with (or without) recombinant human IL-1 alpha (10 ng/ml, Immunex, Inc.,
Carson City, NV) and/or recombinant human interleukin-2 (50 IU/ml) or as indicated below. To determine if
a prostenoid was responsible for depressed immune responsiveness, 10 pl of indomethacin (3 ng/ml, Sigma,
St. Louis, MO) was added to a subset of selected wells.
Assessment of IL-2 receptor functionality was tested by
supplementing that sera with additional exogenous
prolactin (leuteotropic hormone, 1 IU/ml, Sigma, St.
Louis), a co-factor.
Anti-TCR-Induced Stimulation
Monoclonal anti-TCR antibodies (Bioproducts for
Science, Indianapolis, IN) were added to some culture
wells to produce a final concentration of 1:1,000 as a
form of immune stimulation not requiring antigen recognition.
In Vitro Proliferation Assays
Cells were pulsed with 1 pCi tritiated-thymidine per
well for 24 h under the culture conditions as described
above. Cells were harvested and 3H-thymidine uptake
measured by liquid scintillation counting. Results for
each rat and experimental condition represent the
mean cpm from six wells. Stimulation indices were calculated for each rat a s the average cpm under stimulated conditions divided by the average cpm without
Statistical Analysis
Data were evaluated by analysis of variance
The thymic weight (as a percentage of body weight)
was not significantly different between the SHR and
WKY a t any time point examined. The F-344 thymus
was smaller in the newborn and at one week after
birth, but was larger a t the 12-week time point (Fig. 1).
The thymic medullary/cortical volume ratio was similar between SHR and WKY during the suckling period.
The relative compartment volumes (ratio of mm3 medulla/mm3 cortex) remained essentially constant after
3 weeks in the SHR while there was a n increase in the
medullary component in the WKY with maturation. As
a result there was a significant difference (P < 0.01) in
the thymic morphology of adult animals (Figs. 2, 3).
Mixed Lymphocyte Reaction
The medullary/cortical volume ratio from F-344 rats
Animals were euthanized by carbon dioxide asphyx- was not significantly different from that of the WKY,
iation. Spleens were aseptically removed into RPMI but was different from that of the SHR (F-344,0.823 2
1640 medium, rinsed twice, then physically dissociated 0.078 vs. SHR, 0.513 t 0.019, mean 2 SEM, 12 week).
The splenic weight (expressed a s a percentage of toin medium and passed through a sterile gauze. Cells
were counted and viability was determined by trypan tal body weight) of the WKY was markedly increased
blue exclusion. Stimulator cells were irradiated (2,500 over both SHR and F-344 during the suckling period
rads). Cells were plated in 96 well culture plates, 200 (weeks 1-3, Fig. 4). The SHR and F-344 were compapl/well a t a density of 2.5 x 106/ml responder cells rable a t most time points (Fig. 4). Although the relawith or without 5 x 105/ml stimulator cells. Spleno- tive sdenic size was not different in adult rats. the
cytes were cultured in RPMI 1640 with 10% fetal calf volume density (Vv) of white pulp, specifically the marserum, 1%glutamine, 1% nonessential amino acids, 1% ginal zone (MZ), was reduced in the SHR (Figs. 5, 6).
sodium pyruvate, 1% penicillin/streptomycin, and The splenic morphology in the F-344 was not signifi-
rn SHR
ma F-344
F-344 spleen cells similarly challenged SHR (Fig. 7).
However, SHR splenocytes functioned normally as
stimulator cells. Addition of IL-1 and/or IL-2 as well as
indomethacin did not significantly increase the proliferative response of SHR splenocytes.
0.40 Proliferative T cell responses to mAb-TCR were
quantitatively similar to those seen with the MLRs.
a 0.30
Proliferation of SHR splenocytes was low relative to
the WKY (Stimulation indices of 0.83 ? 0.233 and 2.17
k 0.203 respectively, P 5 0.01, n = 3 for each strain).
O 0.20
When stimulated directly with 50 units per ml of IL-2
the proliferative response of SHR splenocytes was
again significantly depressed as compared to the WKY
and F-344 (Fig. 8). Increasing the concentration of IL-2
to 100 IU/ml and 150 IU/ml did not significantly in0
crease 3H-thymidine incorporation by the SHR culAGE IN WEEKS
tures (data not shown). Although prolactin was not mitogenic added alone, coadministration with IL-2 (50 IU/
Fig. 1. Relative thymic weight in newborn, 1-, 2-, 3-,12-,and 24- ml) resulted in a marked increase in proliferation of
week-old SHR, WKY, and F-344rats. Data expressed as organ weight
as a percentage of total body weight (BW). N = 5, 5,3,4,3,4,5,7,3, SHR splenocytes yielding a stimulation index of 3.96 5
9,13,3,4,5, 3,5, 5,4,respectively.
Blood pressure measurements for 12 and 24 week old
SHR and WKY rats indicated th a t SHR were hypertensive at both 12 and 24 weeks (SHRNKY 12 week:
189 2 14.0/102 ? 3.5; 24 week:192 ? 7.7/135 5.5).
Age in Weeks
Fig. 2. Thymic medullarykortical ratios at various developmental
time points in SHR and WKY rats. The relative volume of thymic
medulla is reduced in the adult SHR (* indicates P 5 0.01) Each point
represents data from 4-5 rats.
cantly different from that seen in the WKY, but was
different from t hat of the SHR (Vv MZ; F-344, 35.5 *
3.89 vs. SHR, 18.5 2.32, P < 0.05, 12 week).
Splenocyte proliferation in vivo, as reflected by tritiated thymidine uptake, was significantly (P 5 0.025)
reduced in the SHR compared to the WKY (76.0 ? 7.7
vs. 182.4
30.8 labeled nuclei/mm2, respectively).
Analysis of variance indicated a significant difference
in spenocyte proliferation in all regions of the SHR
spleen (SHR/WKY: periarterial lymphoid sheathPALS, 94.2 * 20.6D92.4 ? 10.5; MZ, 62.1 ? 16.4D21.5
2 49.0; red pulp-RP, 71.4
11.4/233.3 2 32.9 labeled
The in vitro Droliferative resDonse to a n antigenic
challenge in a MLR was minimal when SHR sdenocytes were challenged with irradiated WKY spleen
cells as compared to the normal response of WKY or
The present study confirms a deficit in SHR immune
responsiveness compared to other ra t strains. Additionally, this study describes immune organ differences associated with decreased immune function and a lack of
responsiveness to the cytokine IL-2. These data provide
important new information about the immune deficit
in the SHR. The lack of responsiveness to IL-2 is especially pertinent, we feel this inability may be causally
related to the immune deficit of the SHR.
The striking similarity in relative thymic weight,
especially between the SHR and WKY, clearly separates the immune disorder in the SHR from those found
in the nude mouse or DiGeorge syndrome where the
thymus fails to develop (Kretschmer et al., 1968).However, the typical increase in relative medullary volume
with maturation does not occur in the SHR. This is
particularly surprising because the SHR is stress-sensitive and has increased corticosterone secretion
(Zamir et al., 1983) which would be expected to produce
increased medullary and decreased cortical volume.
Thymic transplants and thymosin fraction 5 restore
immune function in the SHR and alleviate the hypertension (Ba et al., 1982, Takeichi et al., 1985). Thymic
humoral factors are important for the development of
normal immune function (Trainin, 1974) and are presumably produced in the medulla. Therefore, the lack
of thymic medullary development in the SHR may play
a n important role in the immune deficit.
The decreased medullary/cortical ratio in the SHR
suggests a n alteration in the maturation process of thymocytes. Since sympathetic innervation influences
thymocyte maturation (Singh and Owen, 1976), it is
possible that the hyperinnervation previously noted in
SHR thymus (Purcell and Gattone, 1992) may contribute to this abnormality. The decrease in relative medullary volume is necessarily accompanied by an increase in relative cortical volume. The cortical increase
may reflect decreased clonal deletion which is a n im-
Fig. 3.Photomicrographs of thymus stained with hematoxylin and eosin from 12-week-old rats. There
is a reduction in the relative size of the medulla (m) as compared to the cortex (c) in the thymus of SHR
(a)as compared to WKY (b). x 45.
s m
A g e in Weeks
Fig. 4. Relative splenic weight in newborn, 1-, 2-, 3-, 12- and 24week-old SHR, WKY, and F-344 rats. The relative weight of the WKY
spleen is increased during the suckling period compared to the other
two strains (* indicates P 5 0.05). Data expressed as a percentage of
total body weight (BW). N = 5 , 5 , 3 , 5, 5, 4 , 5 , 7, 3,9, 1 3 , 3 , 4 , 5 , 3, 3,
3, 3, respectively.
Fig. 5.Volume density of splenic marginal zone a t various developmental time points in SHR and WKY rats. The volume density of MZ
increases with age in WKY rats, but decreases in the SHR (* indicates
P 5 0.01). Each point represents data from 4-5 rats.
portant mechanism in the induction of self-tolerance
(Kappler et al., 1987). Interestingly, the SHR is reported to exhibit autoimmunity (Takeichi e t al., 1981a,
1988). Dossiblv related to decreased clonal deletion.
The ;olurne density of splenic red pulp is significantly increased in SHR due to the reduced volume of
the white pulp. The actual mass of of the red pulp is,
however, comparable between the species since the absolute weight of WKY spleen is larger. Accordingly,
the noted decrease in the volume density of white pulp
in SHR sDleen is even more Dronounced when the
smaller absolute organ size is coisidered. For example,
Fig. 6. Photomicrographs of spleen stained with hematoxylin and eosin from 12-week-old rats. The
marginal zone between the marginal sinus (arrowhead) and border of the red pulp (arrow) is decreased
in the SHR (a) as compared to the WKY (b).x 110.
the calculated mass of SHR marginal zone (volume
density x organ weight) is only about one fourth that
of the WKY (0.087 and 0.338 gramdspleen, respectively). The relative lack of marginal zone implies decreased immunological responsiveness in vivo which is
further supported by the decrease in 3H-thymidine uptake by spleen. These data, along with the previous
findings on delayed skin graft rejection in the SHR
(Takeichi e t al., 1980), imply that immune function is
impaired in the intact SHR and is not merely an artifact of in vitro assays.
The earlier concanavalin A and phytohemagglutinin
stimulation studies (Takeichi et al., 1980, 1981)
showed a n impaired proliferative response of SHR lymphocytes. We chose to examine lymphocyte responses
using the MLR because it requires specific recognition
of a Class I1 MHC mismatch rather than polyclonal
stimulation. The SHR failed to properly respond to
such a challenge when stimulated by WKY or F-344
splenocytes. The addition of IL-1 or IL-2 did not enhance this response. Therefore, these data suggest that
the impairment of function is not due to decreased production of these key lymphokines. The lack of improvement following the addition of indomethacin strongly
suggests that the proliferation is not impaired due to
the production of inhibitory arachidonic acid metabolites such as prostaglandin E2 which has been reported
to be increased in SHR (Strausser, 1983). Stimulation
of lymphocyte proliferation by mAb-TCR simulates antigen-induced proliferation without requiring a n antigen recognition step by the cells. The impaired proliferative response of SHR splenocytes to mAb-TCR
suggests that the immune defect involves more than
the presentation or recognition of antigen.
The lack of proliferative capacity of SHR lymphocytes
in response to IL-2 stimulation appears to be a n important characteristic of this immune deficit. It is unclear
a t present why this impairment exists. IL-2 could normally reverse anergy induced by lack of co-factor with
TCR stimulation (Kang et al., 1992). We found the SHR
splenocytes were equally unresponsive to IL-2 at doses
up to 150 IU/ml. Pascual et al. (1992) provide evidence
that factors produced by the adherent cells (presumably
macrophages) impair the proliferation of SHR splenocytes. PgE2 is often implicated in immune suppression
mediated by macrophages, but our data on indomethacin-treated MLRs suggest that this is not the primary
suppressor factor in the SHR. Pascual et al. (1993) have
recently described nitric oxide as a suppressor of splenocyte proliferation in the SHR.
24 1
Fig. 7. Crossed mixed lymphocyte reaction. The proliferative response of SHR splenocytes challenged with irradiated WKY splenocytes is significantly less (* indicates P 5 0.05) than that of WKY
splenocytes responding to SHR stimulator cells. Results of the analogous experiment between SHR and F-344 rats showed a similarly
depressed response. Each bar represents data from 3 rats.
excluded as playing a role in the impaired IL-2 responsiveness. However, the concentration of prolactin used
in our study greatly exceeds the physiological circulating levels found in rat.
Beta-adrenergic agonists decrease IL-2 receptor expression (Feldman et al., 1987). We previously reported
I a n increased sympathetic innervation of thymus and
spleen in the SHR, especially a t important time points
in immune function (Purcell and Gattone, 1992). The
sympathetic nervous system is thought to modulate
immune function via beta-adrenoceptor mediated increases in CAMP in lymphocytes (see Felten e t al.,
1988, for review). Therefore, it is possible that the enhanced sympathetic innervation of the SHR spleen and
thymus contributes to its immune dysfunction.
In summary, we confirmed earlier reports of a n immunological deficit in the SHR. Morphological alterations exist in the immune organs which may correlate
Fig. 8. Proliferative response to interleukin-2 by splenocytes from
SHR, WKY and F-344 rats. The stimulation index of the SHR is with the dysfunction. The SHR exhibit a decreased proliferative response both in vivo and in vitro as comsignificantly reduced compared to both WKY and F-344 (* indicates P
5 0.05). N = 5, 5, 3, respectively.
pared to the WKY and F-344 r a t strains. The lack of
proliferation of SHR splenocytes in response to direct
IL-2 can be reversed by the addition of prolactin indiProlactin increases IL-2 receptor expression cate that SHR splenocytes have the capability to pro(Mukherjee et al., 1990) and prolactin translocated to liferate under appropriate conditions. While the prethe nucleus is required for IL-2 responsiveness (Clev- cise mechanisms responsible for this impairment
enger et al., 1991). The recovery of IL-2 responsiveness remain to be elucidated, likely contributors may inby addition of exogenous prolactin to SHR splenocyte clude: lack of thymic humoral factors, macrophage-decultures suggests that the defect may be in receptor rived immunosuppression (nitric oxide), neuroimmuexpression. While prolactin levels are not reduced in nomodulation, decreased IL-2 receptor expression and
the SHR (McMurty et al., 19801, prolactin cannot be impaired prolactin metabolism in lymphocytes.
Thanks to Dr. Robert Klein for his critical review of
this manuscript. This work supported by National Institute of Mental Health Grant MH 46511.
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morphology, spontaneous, hypertension, immune, ratio, system, function
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