(Circulation. 1997;96:2247-2253.)
© 1997 American Heart Association, Inc.
Articles |
Regulation by Differential Development of Th1 and Th2 Cells in Peripheral Tolerance to Cardiac Allograft Induced by Blocking ICAM-1/LFA-1 Adhesion
From the First Department of Internal Medicine, Shinshu University School of Medicine (M.I., J.S., S.Y., Yoshikazu Yazaki, S.H., Y.O., M.S.), and The Third Department of Internal Medicine, University of Tokyo (K.M., Yoshio Yazaki), Japan.
Correspondence to Mitsuaki Isobe, MD, The First Department of Internal Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390 Japan. E-mail isobemi{at}gipac.shinshu-u.ac.jp
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Abstract |
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Background Specific immune tolerance to cardiac allografts is induced by anti–ICAM-1 and anti–LFA-1 MAbs. Although the expression of the Th1 cytokines IL-2 and IFN-
is shown
to increase in association with acute rejection, the roles of
cytokines in the induction of peripheral tolerance
by anti–ICAM-1 and anti–LFA-1 MAbs are not yet known. Methods and Results BALB/c hearts were transplanted into C3H/He mice. The MAbs to ICAM-1 and LFA-1 were injected for 3 days after transplantation in some recipients, and others were treated with FK506. IL-2 concentration in the supernatant of splenocytes from MAb-treated mice that were mix-cultured with donor splenocytes was lower than in normal controls. The expression of Th1 cytokines, detected by Northern blot assay, was enhanced in grafts or spleens of nontreated mice, whereas Th2 cytokines were expressed in the spleens of MAb-treated mice. No cytokine expression was enhanced in mice treated with FK506. Also, the induction of tolerance was prevented by the administration of rIL-2 in vivo in 5 of 7 mice, which were rendered tolerant.
Conclusions These data provide evidence that impairment of IL-2 production is critically involved in this tolerance induction and suggest that predominance of Th2 over Th1 cells is essential for tolerance induction by antiadhesion therapy.
Key Words: cytokines • interleukins • glycoproteins • immunology • transplantation • immune system • rejection
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Introduction |
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Antigen-specific transplantation tolerance induction is one of the major goals of transplantation immunology. It has been reported that specific tolerance to murine cardiac allografts can be induced by a short-term administration of MAbs to ICAM-1 and LFA-1.1 2 The primary cardiac allografts as well as the second skin graft from the donor strain are accepted indefinitely. Immune reactions to other antigens remain unaffected, as demonstrated by normal rejection of skin from third-party strains. However, the molecular mechanism of this unique tolerance is not yet understood. Experiments in vitro showed that incomplete signaling derived from a costimulatory receptor in the presence of signals from T-cell receptors causes alteration in IL-2 production, which leads to clonal inactivation of T cells.3 It is possible that this mechanism is involved in the transplantation tolerance induced by blocking ICAM-1/LFA-1 adhesion, because LFA-1 is shown to produce costimulatory signals that lead to T-cell activation.4
Development of immature helper (Th0) cells into mature Th1 cells is an
important factor in determining the kinetics of cytokine
production that lead to acute immunological
rejection.5 6 7 Th1 cells produce IL-2 and IFN-, which
primarily mediate cellular immunity and have been shown to be
associated with mouse islet allograft rejection.8 In
contrast, Th2 cells produce IL-4 and IL-10, which promote antibody
responses, and have been implicated in allograft
tolerance.9 10 11 12 Suppression of Th1 cytokines by the
Th2 cells may be related to the induction of tolerance, because Th1
cells and Th2 cells mutually suppress each other's subsets. However, a
lack of preferential Th1/Th2 cytokine gene expression in a
model of transplantation tolerance by anti–
/ß T-cell receptor MAb
has been reported.13 The absence of differences in Th1 or
Th2 expression in spontaneously accepting versus rejecting liver
transplant recipients is also demonstrated.14 Furthermore,
the IL-2 gene is shown to be induced in both tolerant and untreated
animals to similar levels in a model of donor-specific presensitization
to rat renal allografts.15 It is therefore likely that
preferential use of cytokines is different depending on the
models and organs transplanted.
To clarify the mechanism of tolerance induction through anti–ICAM-1/LFA-1 therapy, we characterized the cytokine profile using quantitative and semiquantitative analysis of cytokine gene expression, immunohistochemistry, and lymphocyte culture as well as in vivo studies. We found that production and transcription of Th2 cytokines were detected in the mice treated with the MAbs, whereas Th1 cytokines were suppressed. Also, exogenously administered rIL-2 prevented the induction of tolerance to cardiac allografts in the majority of the mice. A significant difference was observed in cytokine profiles in allografted mice treated with FK506.
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Methods |
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Anti–ICAM-1 and anti–LFA-1 MAbs
The MAbs for tolerance induction used in this study, KBA (IgG2a)16 and YN1/1.7 (IgG2b),17 are rat MAbs to mouse CD11a (
-chain of LFA-1) and ICAM-1,
respectively.1 These MAbs were kindly provided by Prof Ko
Okumura, Juntendo University, Tokyo, Japan. Ascites produced in nude
mice was applied to a protein-G column for one-step purification as
described before.18
Heterotopic Cardiac Transplantation and Induction of
Tolerance
Male BALB/c (H-2d) and C3H/He (H-2k)
mice (4 to 6 weeks old, 20 to 25 g) were obtained from Japan
Charles River Laboratories (Tokyo). Donor hearts were heterotopically
transplanted into recipient mice by microsurgical technique as
described earlier.18 19 C3H/He or BALB/c hearts were
transplanted into C3H/He recipients as isograft controls or as
allografts, respectively. Recipient mice were treated with daily doses
of 50 µg each of anti–ICAM-1 and anti–LFA-1 MAbs for 3 consecutive
days starting immediately after the allograft
transplantation.1 FK506 (Fujisawa Pharmaceutical Co) was
injected at a dose of 1 mg/kg IM daily in 15 allograft
recipients that did not receive MAb injection. This treatment was
started on the day of surgery and continued until they were killed.
Isografts (n=9), allografts from nontreated mice (n=15), allografts
from MAb-treated mice (n=21), and allografts from FK506-treated mice
(n=15) were removed at days 1 to 11.
Mixed Leukocyte Culture and Determination of IL-2
Concentration
C3H/He recipients transplanted with BALB/c hearts were treated
with 50 µg each of KBA and YN1/1.7 for the first 3 days after
transplantation. Spleen cells from the recipients were washed three
times after lysis of red blood cells in 175 mmol/L ammonium
chloride. These splenocytes were mix-cultured for 4 days with
irradiated splenocytes of BALB/c mice in a 96-well culture plate (model
3072, Falcon). Culture medium was RPMI 1640 containing 10% FCS and 1%
gentamicin. Four sets of triplicated assay plates were prepared.
Culture supernatant collected four times at 24-hour intervals was
subjected to ELISA to determine IL-2 concentration (Intertest-2X,
Genzyme). Experiments were repeated three times, and data are indicated
as the mean±SD of three independent experiments.
Immunohistochemistry
Cardiac allografts and spleens were removed and kept frozen.
Serial sections (6 to 8 µm) were cut and dipped in cold acetone
for 10 minutes. The sections were rehydrated in PBS and incubated with
5% normal goat serum to avoid nonspecific reaction. They were
incubated with biotinylated primary antibodies against IFN-, IL-2,
IL-4, and IL-10 (PharMingen) for 12 hours at 4°C. Antibody-biotin
conjugate was detected with an avidin-biotin–horseradish peroxidase
complex (Nichirei) used according to the manufacturer's instructions.
Enzyme activity was detected with diaminobenzidine (0.5 mg/mL)
with 0.05% NiCl in 50 mmol/L Tris buffer, pH
7.5.20
The number of positive cells per 10 microscopic fields under x100
magnification was counted in each section by two independent observers.
Four animals in each group were killed for this experiment. The total
number of IFN-– and IL-2–producing cells was considered as being
the number of Th1 cells and that of IL-4– and IL-10–producing cells
as Th2 cells. The entire tissue section was examined to exclude any
bias relating to a nonrandom distribution of positive cells. Standard
hematoxylin-eosin stain was also performed.
RT-PCR
Total mRNA (5 µg in 5 µL DEPC-H2O) was reverse
transcribed in a 25-µL reaction volume containing buffer
(mmol/L: Tris-HCl 10 [pH 8.3], KCl 50, MgCl2 1.5),
2 mmol/L DTT, 1.2 µg of oligo (dT) primer, 50 U RNase
inhibitor, and 200 U Moloney murine leukemia virus reverse
transcriptase (Perkin-Elmer) for 15 minutes at 42°C. cDNA (5 µL)
was analyzed in a 50-µL reaction containing buffer (as
above), 0.2 mmol/L (each) dNTPs, 0.4 µmol/L
primers, and 1.25 U Taq polymerase (Perkin-Elmer). Samples
were amplified with the following parameters: 94°C, 1
minute; 55°C to 60°C, 2 minutes; 72°C, 1 minute; and 25 to 40
cycles. Primers for IFN-, IL-2, IL-4, and IL-10 were synthesized as
described.21 As a control for the presence of
PCR-detectable cDNA, cDNA preparations were analyzed for GAPDH.
Products were analyzed by electrophoresis on 1.5% agarose
gels followed by ethidium bromide staining.
Northern Blot Assay
Total RNA was prepared with Isogen (Wako Pure Chemicals).
Cytokine transcripts were evaluated as follows: total RNA from
heart grafts and spleens was size-fractionated in a 1.5% agarose gel
(0.37 mol/L formaldehyde) and blotted to nylon membranes
(Hybond-N+, Amersham). The mouse cDNA probes (for IL-2, IL-4, IL-10,
and IFN-) were kindly provided by Prof Takashi Yokota, University of
Tokyo, Japan. The membranes were prehybridized and hybridized overnight
at 42°C (50% deionized formamide, 5xSSC, and 1xPE [50
mmol/L Tris-HCl, pH 7.5, 0.1% sodium pyrophosphate, 1% SDS,
0.2% polyvinylpyrrolidone, 0.2% Ficoll, and 5 mmol/L
EDTA]), 150 µg/mL denatured salmon sperm DNA with
[32P]dCTP and washed twice in 2xSSC/0.1% SDS for 5
minutes at 22°C. The filters were exposed to Kodak X-Omat AR film.
Radioactivity was quantified by an image analyzer system
(BAS2000, Fuji). The ratio of the radioactivity of the mRNA signal for
cytokines to background radioactivity was calculated.
Administration of rIL-2
Mice treated with the MAbs were injected with rIL-2 (kindly
provided by Shionogi Pharmaceutical Co), dissolved in RPMI 1640
supplemented with 10% FCS, and administered by osmotic pumps (model
1007D, Alzet) at a constant rate for 7 days. rIL-2 was administered
during the course of MAb treatment beginning on the day of
transplantation or on day 50 after tolerance induction. The graft beat
was checked daily by palpation by two independent observers. The
complete loss of graft beat was interpreted as rejection. The procedure
was verified by histochemical examination of hematoxylin-eosin–stained
sections.
Statistics
Comparison of survival rates was performed by a Kaplan-Meier
survival model. A value of P>.05 was considered
nonsignificant in comparisons between multiple groups of data. All data
were expressed as the mean±SD.
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Results |
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Graft Survival
The beat of the allografts that received no immunosuppressive treatment decreased daily, and all grafts stopped beating by day 9. However, the isografts and allografts with MAbs or FK506 treatment kept beating as long as observation continued.
IL-2 Production
Serial determinations of IL-2 concentration in the supernatant of
mixed lymphocyte culture are shown in Fig 1
. Splenocytes taken from mice treated
with MAbs responded to donor-strain allostimulation, and IL-2
concentration peaked at 72 hours (229±38 pg/mL, n=3); however,
the concentration was significantly lower than that of normal mice
(517±99 pg/mL, n=3, P<.05). In contrast, IL-2 in
the supernatant of splenocytes from mice with rejecting cardiac
allografts peaked at 
24 to 48 hours and then decreased gradually (72
hours, 89±64 pg/mL). The chronological pattern of IL-2
production in vitro in MAb-treated mice at 9 days and 55 days
was similar.
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Hematoxylin-Eosin Staining
The cardiac allografts without immunosuppression showed various
extents of mononuclear cell infiltration and myocyte damage starting at
day 3. These histological changes increased gradually
after transplantation. Mononuclear cell infiltration in the allografts
from MAb-treated or FK506-treated mice at day 7 was less than that in
the nontreated allografts (data not shown).
Immunohistochemistry
Widespread and dense distribution of IFN-– and IL-2–producing
cells was observed in the allografts from nontreated mice, but cells
were present with less frequency in the MAb- or FK506-treated
allografts (Fig 2). The number of
IFN-–producing cells peaked on day 5 and gradually declined,
whereas that of IL-2–producing cells gradually increased in the
allografts from nontreated mice. In contrast, IL-4– and
IL-10–producing cells were invariably present in the cardiac
interstitium of MAb-treated mice. The ratio of Th2 cells to Th1 cell
population in nontreated animals was always greater than that of
MAb-treated mice during the course of observation (Table 1).
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RT-PCR
mRNA encoding the cytokines IL-2, IL-4, IL-10, and IFN-
was present in the cardiac allografts but not present in the
isografts. On day 7, an intense signal corresponding to IFN- and
IL-2 was detected in the nontreated allografts but not in the
allografts treated with the MAbs after 30 cycles of PCR. In contrast,
IL-4 and IL-10 mRNAs were present on day 7 in allografts with MAb
treatment as well as in nontreated allografts after 40 cycles of PCR.
However, differences in Th2 cytokine transcription between
treated and nontreated allografts could not be detected by this method
(Fig 3). These experiments were repeated
three times with consistent results.
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Northern Blot Assay
IFN- and IL-2 mRNAs were detected in allografts from nontreated
mice, but the transcript was suppressed in the isografts and allografts
of MAb-treated and FK506-treated mice. The IL-4 transcript was enhanced
in the spleens from mice with MAb treatment, but the transcript was
reduced in the isografts and allografts from nontreated and
FK506-treated mice (Fig 4). The
experiment was repeated twice with consistent results. IL-10
transcripts could not be detected in any of the grafts and spleens by
this method.
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Administration of rIL-2
Isograft beat was not affected by an injection of rIL-2. Five of 7
mice treated with a total of 100 000 U rIL-2 rejected cardiac
allografts within 25 days (Table 2).
These allografts showed typical histological features
of acute rejection. One of the 5 mice treated with 25 000 U rIL-2
rejected the allograft at day 20, whereas the other 4 mice accepted
allografts indefinitely. In contrast, an administration of rIL-2
beginning on day 50 after tolerance induction did not affect the
allograft beat. Once established, tolerance could not be abrogated by
exogenous rIL-2 (Fig 5).
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), whereas 1 of 5 mice treated
with 25 000 U rIL-2 rejected allograft (
). In contrast,
administration of rIL-2 to isografted mice (
) and to allografted
mice starting on day 50 (
) did not affect graft beat. |
Discussion |
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Adhesion molecules play important roles in immune responses to transplanted organs. Significant induction of adhesion molecules such as ICAM-1, VCAM-1, and E-selectin in association with acute cardiac rejection is reported.22 23 Specific tolerance is achieved by a short-term administration of anti–ICAM-1 and anti–LFA-1 in a mouse heterotopic cardiac allograft model.1 Similar immunosuppression is also induced by blocking VCAM-1/very late antigen–424 or CD28/B725 26 adhesion.
Cell adhesion mediated by the LFA-1/ICAM-1 system is an essential part of various T-cell functions in vitro. Costimulatory signals mediated by CD28, LFA-1, or very late antigen–4 are required for T-cell activation and clonal expansion.4 27 T-cell receptor–mediated stimulation in the absence of a costimulatory signal can lead to T-cell inactivation.3 28 The continuous stimulation with alloantigens in the absence of the LFA-1–mediated costimulatory signal by blocking LFA-1/ICAM-1 interaction is postulated to lead to the induction of this specific tolerance. One of the important clues to follow in the investigation of this assumption could be to evaluate IL-2 production in the tolerant mice, because a lack of IL-2 transcription is involved in clonal anergy induced by an absence of costimulatory signals in vitro.3
Differential development of immature helper cells (Th0) into mature Th1 or Th2 cells is an important factor in determining the kinetics of cytokine production and immune responses to rejection.29 30 Many investigators have reported the characteristics of the Th1/Th2 cytokine profile in a variety of experimental models.9 10 11 12 13 14 The absence of differences in Th1 or Th2 expression in spontaneously accepting versus rejecting liver transplant recipients is also demonstrated14 ; however, the results are not consistent. It is possible that the roles of cytokines may differ depending on the methods used to induce tolerance and on the organs transplanted. Also, the majority of investigators use the RT-PCR technique to quantify cytokine mRNA of transplanted organs. RT-PCR is a sensitive approach to detect mRNA, yet it involves difficulty in quantification. We addressed this problem by using Northern blot assay to quantify Th1/Th2 cytokine mRNA.
The results of Northern blot assay and RT-PCR clearly demonstrated that Th1 mRNA expression was enhanced in the rejected grafts but was reduced in the grafts from MAb-treated mice. RT-PCR revealed a clear difference in Th1 cytokine mRNA expression between rejecting and tolerant spleens while showing equal amplification of their Th2 cytokines. Northern blot assay was performed because subtle changes in cytokine mRNA expression may not be detectable by RT-PCR. The results showed relatively intense IL-4 mRNA transcription in the tolerant spleen compared with mice with other treatments. Transcription of this Th2 cytokine in the spleen was weak in mice treated with FK506, and that in the mice with rejecting cardiac allografts showed an intermediate intensity. Enhanced IL-4 expression in the mice treated with MAbs could be responsible for regulating the Th development from Th0 to Th2.
The effects of cyclosporine on cytokine expression
have been investigated in detail. It is noteworthy that Th2
cytokine expression between FK506 and antiadhesion therapy
differed. Cyclosporine selectively blocks
IL-2,31 IFN-, IL-4, and IL-10 transcripts in the
transplanted grafts.10 FK506 also acts on IL-2
production by T cells and on expression of IL-2
receptors.32 However, the effect of FK506 on Th2
cytokine production remains uncertain at present.
The difference in IL-4 mRNA expression between FK506 and MAb treatment
observed in the present study indicates the differences among
mechanisms of immunosuppression.
Immunohistological studies showed that
IFN-–expressing cells were located in the area of mononuclear cell
infiltration in the rejected grafts. IL-2– as well as
IFN-–positive cells were present in the rejected grafts and
were located mainly near damaged muscles. This localization is most
closely related to destruction of myocytes. Conversely, IL-4– and
IL-10–expressing cells were more frequently observed in the tolerant
than in the rejected allografts. The total numbers of infiltrating
cells were different between rejected and tolerant grafts, so that the
ratio of Th2 (IL-4+IL-10) to Th1 (IL-2+IFN-) was a valuable
indicator of altered Th development. The ratio was significantly
greater in the tolerant grafts than in the rejected grafts. The
observation that IL-2 production in response to in vitro
stimulation is reduced in MAb-treated mice also suggests that an
impairment of IL-2 production is involved in the induction of
tolerance by antiadhesion therapy. Interestingly, lymphocytes from
tolerant mice produced a certain amount of IL-2 in response to donor
allostimulation in vitro. Mechanisms of this response should be studied
further.
In 5 of 7 graft recipients, treatment with exogenous IL-2 effectively interfered with development of allograft tolerance that results from blocking LFA-1/ICAM-1 adhesion in vivo. These data further support the idea that IL-2 production is impaired during the tolerance induction. In contrast, administration of rIL-2 starting on day 50 after tolerance induction did not affect allograft beat. Tolerance, once established, could not be abrogated by exogenous IL-2. These observations suggest that induction and maintenance of tolerance may be driven by different molecular mechanisms.
Using immunohistochemical studies, Sayegh et al12 reported similar changes in Th1/Th2 cytokines in their model of tolerance induction to rat kidney allografts by CD28/B7 blockade. A distinctive difference in costimulation between CD28 and LFA-1 has been reported. Costimulation with ICAM-1 is required for activation of resting T cells, whereas costimulation with B7 is necessary for restimulation of activated T cells.33 34 It is therefore reasonable to assume that costimulatory signals through LFA-1 are involved in the initiation of immune responses, and CD28 gives the costimulation necessary to sustain proliferation of antigen-primed T cells. Also, recent investigations suggest that LFA-1 and CD28 transduce signals through different phosphorylation cascades.35 36 It is of interest that blockade of two different adhesion molecules, LFA-1 and CD28, leads to similar immune reactions to transplanted organs. Although the function and signaling pathway for T-cell clonal expansion differ, the absence of costimulatory signals from CD28 and LFA-1 could result in a similar outcome: suppression of Th1 cells and preservation of Th2 cells. It has been shown that stimulation of Th0 cells in the absence of costimulation could anergize Th1 clones, whereas IL-4 production by Th2 was spared.37 It is possible to assume that through such mechanisms, antigen-specific Th2 clones are expanded while Th1 clones become inactivated.
It is clear from our experiments that the cytokine profile is significantly altered in tolerant mice compared with mice that reject cardiac allografts. The impairment of IL-2 production and the activation of Th2 cytokines are involved in tolerance induction by blocking of ICAM-1/LFA-1 adhesion, as demonstrated by the in vivo and in vitro studies. It is noteworthy that immunosuppression by FK506 did not enhance the Th2 transcript. These findings certainly expand our knowledge of immune system reaction to transplanted organs and will lead to the development of new modes of specific immunosuppression. Further experiments are needed to clarify the role of Th2 activation in inducing specific immune tolerance for the clinical treatment of transplantation.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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We would like to thank Misako Horii for excellent technical assistance and Prof Takashi Yokota for providing the mouse cDNA for IL-2, IL-4, IL-10, and IFN-
. We are also indebted to Prof Ko Okumura
of Juntendo University for providing the MAbs. We are grateful to Drs
Takumi Takeuchi, Hiroki Kurihara, Masayuki Nomura, Gen Suzuki, Takashi
Yokota, Ken-ichi Arai, Toshio Nishikawa, and Hideo Nariuchi for
valuable discussions. This study was supported by a grant-in-aid from
the Ministry of Education, Science, and Culture; the Ichiro Kanehara
Foundation; the Ryoichi Naito Foundation for Medial Research; the Cell
Science Research Foundation; and the Institute for Adult Diseases,
Asahi Life Foundation. Received January 16, 1997; revision received April 24, 1997; accepted April 28, 1997.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
-
Isobe M, Yagita H, Okumura K, Ihara A.
Specific acceptance of cardiac allograft after treatment with
anti-ICAM-1 and anti-LFA-1. Science. 1992;255:1125-1127.
[Abstract/Free Full Text]
-
Isobe M, Ihara A. Tolerance induction against
cardiac allograft by anti-ICAM-1 and anti-LFA-1 treatment: T cells
respond to in vitro allostimulation. Transplant
Proc. 1993;25:1079-1080.[Medline]
[Order article via Infotrieve]
-
Mueller D, Jenkins M, Schwartz R. Clonal
expansion versus functional clonal inactivation: a costimulatory
outcome of T cell antigen receptor occupancy. Annu Rev
Immunol. 1989;7:445-480.[Medline]
[Order article via Infotrieve]
-
van Seventer GA, Shimizu Y, Horgan KJ, Shaw S.
The LFA-1 ligand ICAM-1 provides an important costimulatory signal for
T cell receptor-mediated activation of resting T cells.
J Immunol. 1990;144:4579-4586.[Abstract]
-
Mosmann TR, Coffman RL. Th1 and Th2 cells:
different patterns of lymphokine secretion to different functional
properties. Annu Rev Immunol. 1989;7:143-173.
-
Klamus SM, Falco DA, Villanueva JC, Rabkin J,
Tomlanovich SJ, Vincenti F, Amend WJC, Melzer J, Garovoy MR, Roberts
JP, Ascher NL, Matinez OM. Cytokine and T cell receptor
gene expression at the site of allograft rejection.
Transplantation. 1992;53:151-156.[Medline]
[Order article via Infotrieve]
-
Romball CG, Weigle WO. In vivo induction of
tolerance in murine CD4 cell subsets. J Exp Med. 1993;178:1637-1644.
[Abstract/Free Full Text]
-
O'Connell PJ, Pacheco SA, Nickerson PW, Muggia RA,
Bastos M, Kelley VR, Strom TB. Unmodified pancreatic islet
allograft rejection results in the preferential expression of certain T
cell activation transcripts. J Immunol. 1993;150:1093-1104.[Abstract]
-
Dallman MJ, Larsen CP, Morris PJ.
Cytokine gene transcription in vascularised organ grafts:
analysis using semiquantitative polymerase chain
reaction. J Exp Med. 1991;174:493-496.
[Abstract/Free Full Text]
-
Takeuchi T, Lowry RP, Konieczny B. Heart
allografts in murine systems: the differential activation of Th2-like
effector cells in peripheral tolerance.
Transplantation. 1992;53:1281-1294.[Medline]
[Order article via Infotrieve]
-
Binder J, Hancock WW, Wasowska B, Gallon L, Watschinger
B, Sayegh MH, Brock J, Lehmann M, Volk HD, Kupiec WJ.
Donor-specific transplantation unresponsiveness in sensitized rats
following treatment with a nondepleting anti-CD4 MAb is associated with
selective intragraft sparing of Th2-like cells.
Transplant Proc. 1995;27:114-116.[Medline]
[Order article via Infotrieve]
-
Sayegh MH, Akalin E, Hancock WW, Russell ME, Carpenter
CB, Linsley PS, Turka LA. CD28-B7 blockade after alloantigenic
challenge in vivo inhibits Th1 cytokines but spares
Th2. J Exp Med. 1995;181:1869-1874.
[Abstract/Free Full Text]
-
Hofmann WJ, Dufter C, Terness P, Thies J, Post S, Otto
G, Otto HF, Geisse T, Gaweco AS. Lack of preferential Th1/Th2
cytokine gene expression patterns in both alpha/beta
T-cell-tolerant and -rejecting rat cardiac allografts.
Transplant Proc. 1995;27:232-234.[Medline]
[Order article via Infotrieve]
-
Thai NL, Fu F, Qian S, Sun H, Gao L, Wang SC, Demetris
AJ, Woo J, Thomson AW, Duquesnoy RJ, Fung JJ. Cytokine
mRNA profiles in mouse orthotopic liver transplantation: graft
rejection is associated with augmented TH1 function.
Transplantation. 1995;59:274-281.[Medline]
[Order article via Infotrieve]
-
Dallman MJ, Shiho O, Page TH, Wood KJ, Morris
PJ. Peripheral tolerance to alloantigen results from
altered regulation of the interleukin 2 pathway. J Exp
Med. 1991;173:79-87.
[Abstract/Free Full Text]
-
Nishimura T, Yagi H, Hashimoto Y. The role of
lymphokine-activated cell-associated antigen, II: distribution
and correlation with cell cycle. Cell Immunol. 1987;107:24-31.[Medline]
[Order article via Infotrieve]
-
Takei F. Inhibition of mixed lymphocyte response
by a rat monoclonal antibody to a novel murine lymphocyte activation
antigen (MALA-2). J Immunol. 1985;134:1403-1407.[Abstract]
-
Isobe M, Narula J, Strauss HW, Khaw BA, Haber E.
Imaging the rejecting heart: in vivo detection of MHC class II antigen
induction. Circulation. 1992;85:738-746.
[Abstract/Free Full Text]
-
Isobe M, Haber E, Khaw BA. Early detection of
rejection and assessment of cyclosporine therapy by
indium-111 antimyosin imaging in mouse heart allografts.
Circulation. 1991;84:1246-1255.
[Abstract/Free Full Text]
-
Bogen SA, Fogelman I, Abbas AK. Analysis
of IL-2, IL-4, and IFN- producing cells in situ during immune
responses to protein antigens. J Immunol. 1993;150:4197-4205.[Abstract]
-
Morgan CJ, Pelletier RP, Hernandez CJ, Teske DL, Huang
E, Ohye R, Orosz CG, Ferguson RM. Alloantigen-dependent
endothelial phenotype and lymphokine mRNA
expression in rejecting murine cardiac allografts.
Transplantation. 1993;55:919-923.[Medline]
[Order article via Infotrieve]
-
Taylor PM, Rose ML, Yacoub MH, Pigott R.
Induction of vascular adhesion molecules during rejection of human
cardiac allografts. Transplantation. 1992;54:451-457.[Medline]
[Order article via Infotrieve]
-
Tanio JW, Basu CB, Albelda SM, Eisen HJ.
Differential expression of the cell adhesion molecules ICAM-1, VCAM-1,
and E-selectin in normal and posttransplantation
myocardium: cell adhesion molecule expression in human
cardiac allografts. Circulation. 1994;89:1760-1768.
[Abstract/Free Full Text]
-
Isobe M, Suzuki J, Yagita H, Okumura K, Yamazaki S,
Nagai R, Yazaki Y, Sekiguchi M. Immunosuppression to cardiac
allografts and soluble antigens by anti-VCAM-1 and anti-VLA-4
monoclonal antibodies. J Immunol. 1994;153:5810-5818.[Abstract]
-
Lenschow DJ, Zeng Y, Thistlethwaite JR, Montag A, Brady
W, Gibson MG, Linsley PS, Bluestone JA. Long-term survival of
xenogeneic pancreatic islet grafts induced by CTLA4Ig.
Science. 1992;257:789-792.
[Abstract/Free Full Text]
-
Turka AL, Linsley PS, Lin H, Brady W, Leiden JM, Wei
RQ, Gibson ML, Zheng XG, Myrdal S, Gordon D. T cell activation
by the CD28 ligand B7 is required for cardiac allograft rejection in
vivo. Proc Natl Acad Sci U S A. 1992;89:11102-11105.
[Abstract/Free Full Text]
-
Altmann D, Hogg N, Trowsdale J, Wilkinson D.
Cotransfection of ICAM-1 and HLA-DR reconstitutes human
antigen-presenting cell function in mouse L cells.
Nature. 1989;338:512-514.[Medline]
[Order article via Infotrieve]
-
Geppert TD, Davis LS, Gur H, Wacholtz MC, Lipsky
PE. Accessory cell signals involved in T-cell
activation. Immunol Rev. 1990;117:5-66.[Medline]
[Order article via Infotrieve]
-
Cher DJ, Mosmann TR. Two types of murine helper
T cell clones, II: delayed-type hypersensitivity is mediated by Th1
clones. J Immunol. 1987;138:3688-3694.[Abstract]
-
Fong TAT, Mossman TR. Alloreactive murine CD8+ T
cell clones secrete the Th1 pattern of cytokines.
J Immunol. 1990;144:1744-1752.[Abstract]
-
Calne RY, Rolles K, White DJG, Thiru S, Evans DB,
McMaster P, Dunne DC, Craddock GN, Henderson RG, Aziz S, Lewis
P. Cyclosporine-A initially as the only
immunosuppressant in 34 recipients of organs: 32 kidneys, 2 pancreases,
2 livers. Lancet. 1979;2:1033-1036.[Medline]
[Order article via Infotrieve]
-
Todo S, Fung JJ, Demetris AJ, Venkataramanan R, Startzl
TE. Early trials with FK506 as primary treatment in liver
transplantation. Transplant Proc. 1990;22:13-16.[Medline]
[Order article via Infotrieve]
-
Damle NK, Klussman K, Linsley PS, Aruffo A, Ledbetter
JA. Differential regulatory effects of intercellular adhesion
molecule-1 on costimulation by the CD28 counter-receptor B7.
J Immunol. 1992;149:2541-2548.[Abstract]
-
Damle NK, Klussman K, Leytze G, Myrdal S, Aruffo A,
Ledbetter JA, Linsley PS. Costimulation of T lymphocytes with
integrin ligands intercellular adhesion molecule-1 or vascular cell
adhesion molecule-1 induces functional expression of CTLA-4, a second
receptor for B7. J Immunol. 1994;152:2686-2697.[Abstract]
-
Kanner SB, Grosmaire LS, Ledbetter JA, Damle NK.
Beta 2-integrin LFA-1 signaling through phospholipase C-gamma 1
activation. Proc Natl Acad Sci U S A. 1993;90:7099-7103.
[Abstract/Free Full Text]
-
Rudd CE, Janssen O, Cai YC, Silva AD, Raab M, Prasad
KV. Two-step TCR zeta/CD3-CD4 and CD28 signaling in T cells:
SH2/SH3 domains, protein-tyrosine and lipid kinases.
Immunol Today. 1994;15:225-234.[Medline]
[Order article via Infotrieve]
-
Gajewski TF, Lancki DW, Stack R, Fitch FW.
`Anergy' of TH0 helper T lymphocytes induces downregulation of TH1
characteristics and a transition to a TH2-like
phenotype. J Exp Med. 1994;179:481-491.
[Abstract/Free Full Text]
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