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Is Critical for Long-Term Allograft Survival Induced by Blocking the CD28 and CD40 Ligand T Cell Costimulation Pathways1
The Carlos and Marguerite Mason Transplantation Research Center,
*
Renal Division, Department of Medicine and
Department of Surgery, Emory University School of Medicine and Veterans Affairs Medical Center, Atlanta, GA 30033;
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, WA 98121; and
§
Pathology and Laboratory Medicine, Veterans Affairs Medical Center and State University of New York, Buffalo, NY 14215
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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production hinders long-term
acceptance of transplanted organs. To test this hypothesis, we compared
survival of skin and heart allografts in wild-type
(IFN-+/+) mice to that in IFN- gene knockout
(IFN--/-) mice. We found that perioperative blockade
of the CD28 and/or CD40 ligand T cell costimulation pathways induces
long-term skin and heart allograft survival in IFN-+/+
recipients but fails to do so in IFN--/- mice or in
wild-type mice treated with IFN--neutralizing Ab at the time of
transplantation. In vitro studies showed that endogenously produced
IFN- down-regulates T cell proliferation and CTL generation in MLCs.
These actions of IFN- were not mediated by TNF-
production or
Fas-Fas ligand interactions. In vivo studies revealed exaggerated
expansion and, subsequently, impaired deletion of superantigen-reactive
T lymphocytes in IFN--/- mice injected with
staphylococcal enterotoxin B. Taken together, our findings indicate
that IFN- does not hinder but instead facilitates induction of
long-term allograft survival possibly by limiting expansion of
activated T cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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is an
immunoregulatory cytokine secreted by activated T lymphocytes and NK
cells (1, 2). It enhances Ag presentation by up-regulating MHC
expression and promotes cellular immunity by activating macrophages, NK
cells, and Th1 lymphocytes (1, 2). It is therefore postulated that
IFN- mediates acute transplant rejection while IFN-
neutralization favors long-term engraftment. This hypothesis is
supported by studies demonstrating increased IFN- expression in
acutely rejected cardiac, renal, and pancreatic islet cell allografts,
and diminished IFN- expression in long-term surviving transplants
(3, 4, 5). Moreover, IFN- administration has been shown to precipitate
acute rejection in animals previously rendered tolerant to donor
Ags (6).
Other studies, however, provided evidence that IFN- is not essential
for acute rejection. For example, in vivo neutralization of IFN-
failed to prolong survival of fully allogeneic skin grafts in rhesus
monkeys or MHC class I disparate skin grafts in mice (7, 8). We
recently demonstrated that IFN- gene-knockout
(IFN--/-)3 mice reject
fully allogeneic, vascularized cardiac transplants at the same rate as
wild-type (IFN-+/+) recipients (9). Furthermore, Dalton
et al. observed increased proliferation and CTL activity among
IFN--/- splenocytes stimulated with allogeneic cells
suggesting that endogenously produced IFN- down-regulates alloimmune
responses in vitro (10).
In this study, we tested the hypothesis that induction of long-term
allograft acceptance is facilitated in the absence of IFN- by
comparing survival of skin and heart allografts between
IFN-+/+ and IFN--/- recipient mice
treated with inhibitors of T cell costimulation. Blocking B7-CD28 and
CD40-CD40L T cell costimulation pathways in rodents leads to long-term
graft survival and in some cases donor-specific tolerance (5, 11, 12, 13).
We report that, contrary to the hypothesis, induction of long-term
allograft survival by T cell costimulation blockade is dependent on
IFN- expression. We also provide evidence that endogenously produced
IFN- limits expansion of activated T cells, a mechanism by which
this cytokine could facilitate long-term acceptance of transplanted
organs.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Male C3H/He (H-2k), C3H/He-FasLgld,
BALB/c (H-2d), C57BL/6 (H-2b), and
IFN--/- C57BL/6 mice were purchased from The Jackson
Laboratory, Bar Harbor, ME. IFN--/- BALB/c mice were
provided by Dr. David W. Pascual (Montana State University, Bozeman,
MT) with permission from Drs. D. Dalton and T. Stewart (Genentech,
South San Francisco, CA) (10). All IFN--/- mice were
bred at Emory University (Atlanta, GA)/Veterans Affairs Medical Center
animal facility in microisolators supplied with sterile food and water.
Inactivation of IFN- gene function in these animals was confirmed by
performing IFN--specific ELISA (Genzyme, Cambridge, MA) on
splenocyte supernatants collected at 0, 24, 48, 72, and 96 h after
Con A stimulation (3 µg/ml) (9).
Reagents used in vivo
Human rCTLA4Ig, which blocks B7-CD28 T cell costimulation
pathway (11), was provided by Dr. Peter S. Linsley (Bristol-Myers
Squibb Pharmaceutical Research Institute, Seattle, WA). Anti-mouse gp39
Ab (MR1), which blocks CD40-CD40L interaction (14), was provided
by Drs. Christian P. Larsen and Thomas C. Pearson (Emory University
School of Medicine). Neutralizing, monoclonal, hamster anti-mouse
IFN- Ab was purchased from Genzyme, Boston, MA. Reagents were
diluted in endotoxin-free PBS (Life Technologies, New Haven, CT) and
sterile filtered before use.
Transplantation procedures
Fully allogeneic (MHC class I and class II disparate) BALB/c
tail skin grafts were transplanted to the dorsal trunk area of 6- to
8-wk-old male IFN--/- and IFN-+/+
C57BL/6 recipients (13). Mice either were left untreated or received
250 µg of human CTLA4Ig plus 250 µg MR1 i.p. on days 0, 2, 4, and 6
post-transplantation. Skin rejection was defined as >90% graft
necrosis. Skin allograft survival greater than 50 days was considered
long-term survival. Fully allogeneic, vascularized, heterotopic heart
transplantation was performed as described (15) using 8- to 10-wk-old
male C3H/He donors and 6- to 8-wk-old male IFN--/- and
IFN-+/+ BALB/c recipients. Mice were either left
untreated or received 200 µg human CTLA4Ig i.p. on the second day
post-transplantation. A separate group of IFN-+/+
recipients treated with CTLA4Ig also received 500 µg hamster
anti-mouse IFN--neutralizing mAb (Genzyme) i.p. 3 days before
and 4 days after transplantation. Rejection was identified by loss of
palpable cardiac contractions at which time the recipient was killed
and the allograft removed for analysis. Cardiac allograft survival for
longer than 100 days was considered long-term survival. All procedures
conformed to IACUC standards. Statistical analysis of survival data was
performed using the Mann-Whitney U test.
Histopathology
Formalin-fixed, paraffin-embedded cardiac allograft tissue removed at the time of rejection was stained with hematoxylin and eosin or with periodic acid-Schiff and examined by a pathologist (F. K. Baddoura) who was unaware of recipients’ identity. Acute cellular rejection was graded according to the International Society for Heart Transplantation criteria (16).
Reverse transcription-PCR
Cardiac allograft and spleen tissue, resected at time of
rejection, was snap-frozen in liquid nitrogen. RNA was extracted in
guanidinium salt solution and purified by the CsCl gradient method
(17). Five micrograms of total RNA were reverse transcribed using
oligo(dT) primers and Superscript reverse transcriptase according to
the manufacturer’s instructions (Life Technologies). Ten percent of
cDNA was then subjected to 30 cycles of PCR amplification in a
Perkin-Elmer Thermocycler 480 (Perkin-Elmer, Foster City, CA) using
mouse IFN--specific primer pairs (3). Fifteen percent of each PCR
reaction was electrophoresed on 2% SeaKem LE agarose gels (American
Bioanalytical, Natick, MA) and stained with ethidium bromide. RT-PCR
controls included "no RNA" (blank) and "no reverse
transcriptase" reactions.
Mixed leukocyte reaction
Mouse splenocytes were enriched for T lymphocytes by applying to
nylon wool columns (Polysciences, Warrington, PA) (18). One-way primary
MLR was performed by incubating 4 x 105
IFN-+/+ or IFN--/- BALB/c
(H-2d) T cells with 2.5 x 104
mitomycin-treated C3H/He (H-2k) splenocytes in complete
RPMI 1640 medium (10% heat-inactivated FCS, 2 mM
L-glutamine, 1% nonessential amino acids, 1% sodium
pyruvate, 10 mM HEPES buffer, 50 µM 2-ME, 100 U/ml penicillin, and
100 µg/ml streptomycin) (Life Technologies) at 37°C and 5%
CO2 using 96-well round-bottom plates (Corning, New York,
NY). After 3 to 6 days, 0.25 µCi [3H]TR was added to
each well (total well volume, 200 µl) and cells were harvested 6
h later. Net [3H]TR uptake was determined by
subtracting uptake in control wells (responder and stimulator cells
cultured separately) from that in MLR wells. Proliferative responses of
C3H/He and C3H/He-FasLgld T lymphocytes to BALB/c
stimulators were studied in a similar fashion. Mouse rIFN-,
neutralizing anti-mouse IFN- mAb, and neutralizing polyclonal
rabbit anti-mouse TNF- antiserum used in MLR experiments were
obtained from Genzyme.
CTL assay
Splenocytes from IFN-+/+ or
IFN--/- BALB/c mice were stimulated with
mitomycin-treated C3H/He splenocytes as described in the previous
section. Five days later, nonadherent cells were harvested and assayed
for cytotoxic activity by incubating with either 1 x
105 LK35.2 (H-2d,k) or P815 (H-2d)
target cells (American Type Culture Collection, Rockville, MD) for
2.5 h (19). Target cells were preloaded with Calcein-AM (Molecular
Probes, Eugene, OR) and calcein release was measured in a LS50B
Luminescence Spectrometer (Perkin-Elmer) (20). Experiments in which
spontaneous calcein release was greater than 30% of maximum release
were rejected. Allospecific cytotoxic activity was calculated according
to the following formula: % specific lysis = 100 x [(test
release - spontaneous release)/(maximum release -
spontaneous release)].
Superantigen-induced T lymphocyte expansion and deletion
IFN-+/+ and IFN--/- BALB/c male
mice (6 to 8 wk old) were immunized with either PBS (Life Technologies)
or 50 µg of Staphylococcus enterotoxin B (SEB) (Sigma)
i.p. on day 0. To study SEB-induced T cell expansion, mice were killed
on day 3 and spleen cell suspensions were analyzed by single color flow
cytometry using an Ab to Vß8.1Vß8.2 (biotin conjugated) followed by
streptavidin-cychrome. To study SEB-induced T cell deletion, mice were
immunized with either PBS or 50 µg SEB i.p. on day 0 followed by
either PBS or 25 µg SEB i.p. on day 3. Mice were killed on day 10 and
spleen cell suspensions were analyzed by two-color flow cytometry using
Abs to murine CD4 (FITC conjugated), CD8 (phycoerythrin conjugated),
and either Vß6 (biotin conjugated) or Vß8.1Vß8.2 (biotin
conjugated) followed by streptavidin-cychrome. All flow cytometry
reagents were purchased from PharMingen (San Diego, CA).
Statistical analyses
Differences in allograft survival were analyzed using the Mann-Whitney U test. All other statistical comparisons were performed using analysis of variance (ANOVA, Fisher, and Scheffé tests).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mean survival time (MST ± SE) of tail skin allografts
transplanted to untreated IFN--/- mice (11 ± 1
days; n = 3) was comparable with that in untreated
IFN-+/+ recipients (8 ± 1 days; n
= 3). In contrast, administration of human rCTLA4Ig and MR1 Ab induced
long-term skin allograft survival in 60% of IFN-+/+
recipients (MST = 56 ± 10 days; n = 7) but
failed to do so in the IFN--/- group (MST =
18 ± 2 days; n = 7) (Fig. 1
A) (p
= 0.004, Mann-Whitney U test). Similarly, CTLA4Ig treatment
resulted in long-term cardiac allograft survival in 25% of
IFN-+/+ mice (MST >51 ± 15 days;
n = 8) but in none of the IFN--/-
recipients (MST = 16 ± 2 days; n = 8) (Fig. 1B) (p = 0.007, Mann-Whitney
U test). CTLA4Ig also failed to induce long-term cardiac
allograft survival in IFN-+/+ mice treated with
IFN--neutralizing Abs around the time of transplantation (MST =
10 ± 1 days; n = 3) (Fig. 1B)
(p = 0.01, Mann-Whitney U test, when
compared with CTLA4Ig-treated IFN-+/+ recipients who did
not receive neutralizing Abs). Histologic examination performed at the
time of cessation of heart beat confirmed that allograft failure
resulted from acute cellular rejection. Routine histopathologic
staining did not reveal differences between hearts rejected by
IFN-+/+ or IFN--/- recipients. In both
groups, grade III to IV cellular rejection characterized by mononuclear
cell infiltrate, myocardial cell necrosis, and disruption of myocardial
architecture was observed. RT-PCR analysis confirmed absence of IFN-
mRNA expression in cardiac allograft and spleen tissue removed from
IFN--/- mice at the time of rejection (Fig. 2).
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To investigate the response of IFN--/- T
lymphocytes to allogeneic stimulation, we measured their proliferation
and CTL activity in primary, one-way MLR. As shown in Figure 3A, IFN--/- T
cells had significantly higher [3H]TR uptake than
IFN-+/+ T lymphocytes (p <
0.05, ANOVA). This difference was apparent between the third and sixth
days of the MLR. Addition of mouse rIFN- significantly reduced
[3H]TR uptake by IFN--/- responders
while IFN--neutralizing Ab significantly increased
[3H]TR uptake by IFN-+/+ responders
(Fig. 3A) (p < 0.05, ANOVA).
TNF- neutralization did not block IFN--mediated suppression of
[3H]thymidine uptake in either IFN-+/+ or
IFN--/- MLRs (Fig. 3B)
(p > 0.05, ANOVA). Moreover,
C3H/He-FasLgld responders, which lack functional FasL,
displayed the same increase in [3H]TR uptake as C3H/He
responders when IFN--neutralizing Ab was added to the MLR (Fig. 3C) (p > 0.05, ANOVA). We also
observed that allospecific CTL activity was significantly greater in
cultures in which IFN- was either absent or neutralized with mAb
(Fig. 4). Enhanced
[3H]thymidine uptake and increased CTL activity in
IFN--/- MLR were not due to increased IL-2 secretion
(Fig. 5). In fact, IL-2 production was
higher in IFN-+/+ MLRs. As expected, IFN- was present
in supernatants of IFN-+/+ MLRs (1.5 ng/ml at 48 h)
but was absent in IFN--/- MLRs. IL-4 was below
detection limit of the assay (<5 pg/ml) in either culture.
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in clonal T cell expansion and deletion
Injecting SEB superantigen into mice causes rapid proliferation
followed by death of T cells bearing Vß8 TCR (21). We therefore
compared SEB-induced clonal expansion and deletion of
Vß8+ T cells in IFN-+/+ mice to that in
IFN--/- mice. Percent change in Vß8+
cells was calculated in reference to control mice that received PBS. As
shown in Figure 6A, expansion
of Vß8+ splenocytes 3 days after a single SEB injection
was significantly greater in the IFN--/- group.
Moreover, percent deletion of Vß8+ T cells
(CD4+ or CD8+) 7 days after rechallenge with
SEB was lower in IFN--/- mice suggesting that a
greater number of Vß8+ T cells persisted in the absence
of IFN- (Fig. 6B). Small compensatory changes in the
non-SEB-reactive Vß6 subset were observed in both experiments (Fig. 6, A and B, bar graphs).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. Surprisingly, we
found that T cell costimulation blockade induces long-term acceptance
of skin and heart allografts in wild-type recipients but fails to do so
in IFN--/- mice or in wild-type mice treated with
IFN--neutralizing Ab. These findings indicate that IFN- is
required for successful induction of long-term allograft survival. Our
results are consistent with other experimental systems in which
endogenous IFN- was found to have immunosuppressive actions. For
example, (IFN-R-/-) mice were more susceptible to
collagen-induced or Staphylococcus aureus-induced arthritis
than their wild-type counterparts (22, 23, 24). Similarly,
IFN-R-/- mice were hypersensitive to
anti-CD3-induced cytokine release syndrome (25), and
IFN--/- or IFN-R-/- mice had
exaggerated mortality following induction of experimental allergic
encephalomyelitis (26, 27). IFN- production also accounted for the
generalized immunosuppression that accompanies murine graft-vs-host
disease (28).
We also addressed in this report the mechanisms by which IFN- could
contribute to long-term allograft acceptance. We found that IFN- is
an endogenous inhibitor of T cell proliferation and CTL generation in
primary MLRs. It also inhibited superantigen-induced clonal expansion
of Vß8+ T lymphocytes in vivo. These observations suggest
that IFN- regulates immune responses by limiting expansion of
activated T lymphocytes. In fact, previous studies have shown that
exogenous IFN- suppresses proliferation of several cell types
including T cell lines (2, 10, 29). It has also been proposed that
IFN- promotes death of activated T lymphocytes, particularly cloned
Th1 cells (30). We found, however, that IFN--induced inhibition of
[3H]TR uptake in MLRs is not mediated through
TNF--TNF-R or Fas-FasL cell death pathways and was not
accompanied by preferential decrease in Th1-derived cytokines. Others
also failed to demonstrate a pro-apoptotic effect of IFN- in primary
T cell cultures (31, 32, 33). Additional mechanisms by which IFN- could
exert immunosuppressive effects include stimulation of macrophage
hydrogen peroxide and nitric oxide production, which in turn inhibit T
cell proliferation (34, 35). It has also been suggested that IFN-
contributes to T cell anergy by inducing MHC class II molecules on
nonprofessional APCs (36) or by enhancing "natural suppressor cell"
activity (37).
Although endogenous IFN- appears to limit T cell proliferation in
unmodified MLRs, accelerated acute allograft rejection was not observed
in untreated IFN--/- mice (9). It is possible that the
immunoregulatory functions of IFN- are masked by the extreme
magnitude and plurality of the cytokine response observed in unmodified
allograft recipients. Discrepancies between in vitro and in vivo
findings relating to acute allograft rejection have been demonstrated
in other cytokine gene knockout mice (38, 39). For example, unmodified
IL-2 gene knockout mice acutely reject pancreatic islet cell and
cardiac allografts (our unpublished observations) despite near absence
of T cell proliferation in a primary MLR (39).
We also demonstrated in this study that administration of
IFN--neutralizing Ab to wild-type recipients prevents induction of
long-term allograft survival. This indicates that failure to achieve
allograft acceptance in IFN--/- mice did not result
from overcompensation by a redundant cytokine system such as TNF-,
which could have developed during embryogenesis of these mice. In fact,
we did not detect immunoreactive TNF- in sera from
IFN--/- recipients, and TNF- production by
allostimulated IFN--/- splenocytes was similar to that
by IFN-+/+ splenocytes (our unpublished observations).
Studies which examined the role of exogenous IFN- in transplantation
tolerance have yielded conflicting results. Paineau et al. found that
administration of rIL-2 shortened cardiac allograft survival in
cyclosporin-treated rats when given alone but failed to do so when
given with rIFN-, leading the authors to suggest that IFN- has
immunosuppressive effects (40). The same group, however, reported later
that rat rIFN-, given 1 wk after a tolerizing regimen of donor blood
transfusions, abolished tolerance to allografts transplanted between
congenic rat strains (6). Chen et al. also demonstrated that rIFN-
counteracts neonatal tolerance induction in mice (41). Exogenous
IFN-, therefore, could promote or hinder long-term allograft
survival depending on time of administration and tolerance
model studied.
The mechanisms by which perioperative T cell costimulation blockade
leads to long-term allograft survival or transplantation tolerance are
not known. It has been proposed that CTLA4Ig promotes Th1 to Th2 immune
deviation and thus protects against allograft rejection (5). We
observed in this study that CTLA4Ig-induced long-term allograft
survival is not facilitated but, instead, hindered by the absence of
IFN-. Moreover, IL-4-/- mice, which are deficient in
Th2 cytokine production, accepted heart allografts indefinitely when
treated with CTLA4Ig (38). Taken together, these data strongly suggest
that immune deviation is not a principal mechanism by which CTLA4Ig
induces long-term allograft survival. Using a TCR transgenic model,
Judge et al. demonstrated that CTLA4Ig suppresses immune responses
partly by inhibiting expansion of Ag-reactive cells (42). Our results
extend this observation by providing evidence that endogenous IFN-
facilitates CTLA4Ig-induced long-term allograft survival possibly by
down-regulating proliferation of activated T cells. In addition to
limiting lymphocyte expansion, costimulation blockade also induces a
state of ignorance or anergy in residual Ag-reactive T cells (13, 42, 43). Larsen et al. proposed that silencing of donor-specific T
lymphocytes in mice treated with inhibitors of B7-CD28 and CD40-CD40L
interactions is an active process requiring signaling through the TCR
because concomitant cyclosporin A administration resulted in premature
rejection of skin grafts (13). Cyclosporin A suppresses synthesis of
cytokines such as IFN-, which are secreted by activated T cells
(44). We demonstrated in this study that IFN- is critical for
achieving long-term allograft survival, further suggesting that
tolerance induction depends on stimulation of T lymphocytes by
alloantigen. These observations are pertinent to testing CTLA4Ig and
MR1 in clinical transplantation in which the majority of patients are
treated with cyclosporin A.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Fadi G. Lakkis, Emory University School of Medicine and Veterans Affairs Medical Center, Research 151N, 1670 Clairmont Road, Atlanta, GA 30033. E-mail address:
3 Abbreviations used in this paper: IFN--/-, IFN- gene knockout; IFN-+/+, wild-type strain; SEB, staphylococcal enterotoxin B; MST, mean survival time; L, ligand (as in CD40L).
Received for publication August 13, 1997. Accepted for publication November 4, 1997.
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plays a critical down-regulatory role in the induction and effector phase of myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. J. Immunol. 157:3223.[Abstract]
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J. Yang, A. Reutzel-Selke, C. Steier, A. Jurisch, S. G. Tullius, B. Sawitzki, J. Kolls, H.-D. Volk, and T. Ritter Targeting of Macrophage Activity by Adenovirus-Mediated Intragraft Overexpression of TNFRp55-Ig, IL-12p40, and vIL-10 Ameliorates Adenovirus-Mediated Chronic Graft Injury, whereas Stimulation of Macrophages by Overexpression of IFN-{gamma} Accelerates Chronic Graft Injury in a Rat Renal Allograft Model J. Am. Soc. Nephrol., January 1, 2003; 14(1): 214 - 225. [Abstract] [Full Text] [PDF]
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M. Sho, A. Yamada, N. Najafian, A. D. Salama, H. Harada, S. E. Sandner, A. Sanchez-Fueyo, X. X. Zheng, T. B. Strom, and M. H. Sayegh Physiological Mechanisms of Regulating Alloimmunity: Cytokines, CTLA-4, CD25+ Cells, and the Alloreactive T Cell Clone Size J. Immunol., October 1, 2002; 169(7): 3744 - 3751. [Abstract] [Full Text] [PDF]
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 A. Rabinovitch, W. L. Suarez-Pinzon, A.M. J. Shapiro, R. V. Rajotte, and R. Power Combination Therapy With Sirolimus and Interleukin-2 Prevents Spontaneous and Recurrent Autoimmune Diabetes in NOD Mice Diabetes, March 1, 2002; 51(3): 638 - 645. [Abstract] [Full Text] [PDF]
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P. Reddy, T. Teshima, M. Kukuruga, R. Ordemann, C. Liu, K. Lowler, and J. L.M. Ferrara Interleukin-18 Regulates Acute Graft-Versus-Host Disease by Enhancing Fas-mediated Donor T Cell Apoptosis J. Exp. Med., November 12, 2001; 194(10): 1433 - 1440. [Abstract] [Full Text] [PDF]
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A. C. Wiseman, B. A. Pietra, B. P. Kelly, G. R. Rayat, M. Rizeq, and R. G. Gill Donor IFN-{gamma} Receptors Are Critical for Acute CD4+ T Cell-Mediated Cardiac Allograft Rejection J. Immunol., November 1, 2001; 167(9): 5457 - 5463. [Abstract] [Full Text] [PDF]
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P. F. Halloran, L. W. Miller, J. Urmson, V. Ramassar, L.-F. Zhu, N. M. Kneteman, K. Solez, and M. Afrouzian IFN-{{gamma}} Alters the Pathology of Graft Rejection: Protection from Early Necrosis J. Immunol., June 15, 2001; 166(12): 7072 - 7081. [Abstract] [Full Text] [PDF]
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Y. Yan, S. Shastry, C. Richards, C. Wang, D. G. Bowen, A. F. Sharland, D. M. Painter, G. W. McCaughan, and G. A. Bishop Posttransplant Administration of Donor Leukocytes Induces Long-Term Acceptance of Kidney or Liver Transplants by an Activation-Associated Immune Mechanism J. Immunol., April 15, 2001; 166(8): 5258 - 5264. [Abstract] [Full Text] [PDF]
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D. K. Bishop, S. C. Wood, E. J. Eichwald, and C. G. Orosz Immunobiology of Allograft Rejection in the Absence of IFN-{{gamma}}: CD8+ Effector Cells Develop Independently of CD4+ Cells and CD40-CD40 Ligand Interactions J. Immunol., March 1, 2001; 166(5): 3248 - 3255. [Abstract] [Full Text] [PDF]
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P. F. Halloran, M. Afrouzian, V. Ramassar, J. Urmson, L.-F. Zhu, L. M. H. Helms, K. Solez, and N. M. Kneteman Interferon-{{gamma}} Acts Directly on Rejecting Renal Allografts to Prevent Graft Necrosis Am. J. Pathol., January 1, 2001; 158(1): 215 - 226. [Abstract] [Full Text] [PDF]
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K. Shimizu, U. Schonbeck, F. Mach, P. Libby, and R. N. Mitchell Host CD40 Ligand Deficiency Induces Long-Term Allograft Survival and Donor-Specific Tolerance in Mouse Cardiac Transplantation But Does Not Prevent Graft Arteriosclerosis J. Immunol., September 15, 2000; 165(6): 3506 - 3518. [Abstract] [Full Text] [PDF]
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C. Lawson, A. M. McCormack, D. Moyes, S. Yun, J. W. Fabre, M. Yacoub, and M. L. Rose An Epithelial Cell Line That Can Stimulate Alloproliferation of Resting CD4+ T Cells, But Not After IFN-{gamma} Stimulation J. Immunol., July 15, 2000; 165(2): 734 - 742. [Abstract] [Full Text] [PDF]
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A. S. Diamond and R. G. Gill An Essential Contribution by IFN-{gamma} to CD8+ T Cell-Mediated Rejection of Pancreatic Islet Allografts J. Immunol., July 1, 2000; 165(1): 247 - 255. [Abstract] [Full Text] [PDF]
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Y. Watarai, S. Koga, D. R. Paolone, T. M. Engeman, C. Tannenbaum, T. A. Hamilton, and R. L. Fairchild Intraallograft Chemokine RNA and Protein During Rejection of MHC-Matched/Multiple Minor Histocompatibility-Disparate Skin Grafts J. Immunol., June 1, 2000; 164(11): 6027 - 6033. [Abstract] [Full Text] [PDF]
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M. R. Nicolls, M. Coulombe, H. Yang, A. Bolwerk, and R. G. Gill Anti-LFA-1 Therapy Induces Long-Term Islet Allograft Acceptance in the Absence of IFN-{gamma} or IL-4 J. Immunol., April 1, 2000; 164(7): 3627 - 3634. [Abstract] [Full Text] [PDF]
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 J. Koglin, T. Glysing-Jensen, S. Gadiraju, and M. E. Russell Attenuated Cardiac Allograft Vasculopathy in Mice With Targeted Deletion of the Transcription Factor STAT4 Circulation, March 7, 2000; 101(9): 1034 - 1039. [Abstract] [Full Text] [PDF]
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Y. TAKEI, T. N. SIMS, J. URMSON, and P. F. HALLORAN Central Role for Interferon-{gamma} Receptor in the Regulation of Renal MHC Expression J. Am. Soc. Nephrol., February 1, 2000; 11(2): 250 - 261. [Abstract] [Full Text] [PDF]
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A. Schwarting, G. Tesch, K. Kinoshita, R. Maron, H. L. Weiner, and V. R. Kelley IL-12 Drives IFN-{gamma}-Dependent Autoimmune Kidney Disease in MRL-Faslpr Mice J. Immunol., December 15, 1999; 163(12): 6884 - 6891. [Abstract] [Full Text] [PDF]
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A. McI. Mowat, M. Steel, A. J. Leishman, and P. Garside Normal Induction of Oral Tolerance in the Absence of a Functional IL-12-Dependent IFN-{gamma} Signaling Pathway J. Immunol., November 1, 1999; 163(9): 4728 - 4736. [Abstract] [Full Text] [PDF]
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R. S. Liwski and T. D. G. Lee Nematode Infection Enhances Survival of Activated T Cells by Modulating Accessory Cell Function J. Immunol., November 1, 1999; 163(9): 5005 - 5012. [Abstract] [Full Text] [PDF]
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G. H. Ring, Z. Dai, S. Saleem, F. K. Baddoura, and F. G. Lakkis Increased Susceptibility to Immunologically Mediated Glomerulonephritis in IFN-{gamma}-Deficient Mice J. Immunol., August 15, 1999; 163(4): 2243 - 2248. [Abstract] [Full Text] [PDF]
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Ali. A Ashkar and B. A. Croy Interferon-{gamma} Contributes to the Normalcy of Murine Pregnancy Biol Reprod, August 1, 1999; 61(2): 493 - 502. [Abstract] [Full Text]
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T. A. Judge, Z. Wu, X.-G. Zheng, A. H. Sharpe, M. H. Sayegh, and L. A. Turka The Role of CD80, CD86, and CTLA4 in Alloimmune Responses and the Induction of Long-Term Allograft Survival J. Immunol., February 15, 1999; 162(4): 1947 - 1951. [Abstract] [Full Text] [PDF]
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A. Bushell, M. Niimi, P. J. Morris, and K. J. Wood Evidence for Immune Regulation in the Induction of Transplantation Tolerance: A Conditional but Limited Role for IL-4 J. Immunol., February 1, 1999; 162(3): 1359 - 1366. [Abstract] [Full Text] [PDF]
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D. Matesic, A. Valujskikh, E. Pearlman, A. W. Higgins, A. C. Gilliam, and P. S. Heeger Type 2 Immune Deviation Has Differential Effects on Alloreactive CD4+ and CD8+ T Cells J. Immunol., November 15, 1998; 161(10): 5236 - 5244. [Abstract] [Full Text] [PDF]
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M. D. Sharma, M. Leite de Moraes, F. Zavala, C. Pontoux, and M. Papiernik Induction and Inhibition of CD40-CD40 Ligand Interactions: A New Strategy Underlying Host-Virus Relationships J. Immunol., November 15, 1998; 161(10): 5357 - 5365. [Abstract] [Full Text] [PDF]
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A. N. Schweitzer and A. H. Sharpe Studies Using Antigen-Presenting Cells Lacking Expression of Both B7-1 (CD80) and B7-2 (CD86) Show Distinct Requirements for B7 Molecules During Priming Versus Restimulation of Th2 But Not Th1 Cytokine Production J. Immunol., September 15, 1998; 161(6): 2762 - 2771. [Abstract] [Full Text] [PDF]
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Z. Dai, B. T. Konieczny, F. K. Baddoura, and F. G. Lakkis Impaired Alloantigen-Mediated T Cell Apoptosis and Failure To Induce Long-Term Allograft Survival in IL-2-Deficient Mice J. Immunol., August 15, 1998; 161(4): 1659 - 1663. [Abstract] [Full Text] [PDF]
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A. Schwarting, T. Wada, K. Kinoshita, G. Tesch, and V. Rubin Kelley IFN-{gamma} Receptor Signaling Is Essential for the Initiation, Acceleration, and Destruction of Autoimmune Kidney Disease in MRL-Faslpr Mice J. Immunol., July 1, 1998; 161(1): 494 - 503. [Abstract] [Full Text] [PDF]
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T. Wekerle, M. H. Sayegh, J. Hill, Y. Zhao, A. Chandraker, K. G. Swenson, G. Zhao, and M. Sykes Extrathymic T Cell Deletion and Allogeneic Stem Cell Engraftment Induced with Costimulatory Blockade Is Followed by Central T Cell Tolerance J. Exp. Med., June 15, 1998; 187(12): 2037 - 2044. [Abstract] [Full Text] [PDF]
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A. Schwarting, K. Moore, T. Wada, G. Tesch, H.-J. Yoon, and V. R. Kelley IFN-{gamma} Limits Macrophage Expansion in MRL-Faslpr Autoimmune Interstitial Nephritis: A Negative Regulatory Pathway J. Immunol., April 15, 1998; 160(8): 4074 - 4081. [Abstract] [Full Text] [PDF]
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 K.-i. Seino, K. Fukao, K. Muramoto, K. Yanagisawa, Y. Takada, S. Kakuta, Y. Iwakura, L. Van Kaer, K. Takeda, T. Nakayama, et al. Requirement for natural killer T (NKT) cells in the induction of allograft tolerance PNAS, February 27, 2001; 98(5): 2577 - 2581. [Abstract] [Full Text] [PDF]
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) mice treated with CTLA4Ig and MR1 on
days 0, 2, 4, and 6 after transplantation. Rejection was defined as
greater than 90% graft necrosis. B, Cardiac allograft
survival (C3H/He, H-2k to BALB/c, H-2d) in
IFN-
) was also
treated with IFN-
,
IFN-
BALB/c (H-2d) MLR by measuring calcein
released from LK35.2 (H-2d,k) target cells. •,
IFN-
