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*
Department of Medicine, Harvard Medical School, Division of Immunology, Beth Israel Deaconess Medical Center, Boston, MA 02215;
LeukoSite, Inc., Cambridge, MA 02142; and
Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, FL 33101
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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c of IL-2 receptor, a shared essential signaling component by
receptors for IL-2, IL-4, IL-7, IL-9, and IL-15, prolonged the survival
of islet allografts in DKO mice. Hence, a T cell dependent allograft
rejection enabled by rapamycin-sensitive signals or signals mediated by
binding of the c chain occurs in the absence of both IL-2 and IL-4.
Non-T cell-derived TCGFs, especially IL-7 and IL-15, may play an active
role in supporting allograft rejection. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-2 has often been portrayed as of central importance to activation
and clonal expansion of alloreactive T cells. Under some circumstance,
however, IL-4 is more vigorously expressed than IL-2 during allograft
rejection (4, 5). Recently, IL-2, IL-4, IL-7, IL-9, and IL-15, all
TCGFs, albeit not all T cell products, have been shown to utilize the
same IL-2 receptor chain (also known as the common or c
chain) as an essential signal transducing component in their multichain
receptor complexes (6). The importance of c chain in TCGF-mediated T
cell growth is underscored by the findings that mutations of this
protein in mice or humans result in severe combined immunodeficiency
(7, 8), an immunodeficiency that is far more profound than that
manifested by IL-2 or IL-2 receptor 
ß-chain knockout mice
(9, 10, 11).
Although IL-2, IL-4, IL-7, IL-15, and to lesser extent IL-9, exhibit
remarkable functional redundancy in T cell growth, the mechanisms
involved in their de novo expression during immune activation and their
precise cellular origin appear to be distinct, and therefore, the
precise role of each TCGF in mediating allograft rejection is
uncertain. IL-2 and IL-4 are derived primarily from activated
CD4+ and CD8+ T cells whereas IL-9 is produced
mainly by CD4+ Th2 cell clones and certain primary lymphoma
cells (12, 13, 14). IL-7 is derived from stromal cells and plays an
important role in T cell maturation, proliferation, and differentiation
(15). IL-15 is a product of activated macrophages, muscle cells,
keratinocytes, renal epithelial cells, and endothelial cells (16).
IL-15 binds to a heterotrimeric receptor complex that shares both the
ß- and the -chains with the IL-2 receptor (6); therefore, IL-15
exerts several IL-2-like activities including stimulation of
proliferation of activated T cells and NK cells, activation of CTL
function, and IFN- and TNF- expression (16).
We hypothesized that the expression of non-T cell-produced TCGFs in the
local milieu of organ transplants may impose an unacknowledged barrier
to the acquisition of transplantation tolerance (17). To test for the
overriding importance of IL-2 and IL-4 in allograft rejection and to
define possible alternative TCGFs in supporting the allograft rejection
process, we have bred IL-2-/- and IL-4-/-
double knockout mice (DKO). In the present study, we examined if fully
MHC-mismatched islet allografts could be rejected in the absence of
both IL-2 and IL-4, two potent T cell-derived TCGFs, by using DKO mice
as allograft recipients. We also determined the effect of treatment
with anti-CD3, rapamycin, or anti-c mAbs (c blockade) on
islet allograft rejection in DKO mice. We found that vigorous T
cell-dependent islet allograft rejection can be executed in the absence
of both IL-2 and IL-4, and non-T cell-derived TCGFs, especially IL-7
and IL-15, may be actively involved in supporting the IL-2- and
IL-4-independent allograft rejection process.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RPMI 1640 medium, FCS, and penicillin-streptomycin were
purchased from BioWhittaker (Walkersville, MD). Recombinant murine
IL-2, IL-4, IL-7, IL-9, and IL-15 were obtained from PharMingen (San
Diego, CA). Rapamycin was kindly provided by Wyeth-Ayerst (Princeton,
NJ) and prepared in carbomethycellulose as suggested by the company.
The B cell hybridoma producing a hamster anti-mouse CD3 mAb (2C11)
was kindly provided by Dr. J. Bluestone (University of Chicago,
Chicago, IL). Two blocking mAbs (4G3 and 3E12) against the common c
chain of cytokine receptors were used as previously reported (18).
Treatment with 4G3 and 3E12 in vivo does not result in leukopenia or
enhancement of leukocyte clearance from the circulation (18).
Animals
Male DBA/2J (H-2d) and Ola129 (H-2b) mice (8 to 10 wk old) were obtained from The Jackson Laboratory (Bar Harbor, ME) and housed under standard conditions. IL-2-/- and IL-4-/- mice (C57BL/6 x OLA129, H-2b) were created by targeted gene disruption as previously described (9, 19). IL-2-/- and IL-4-/- DKO were created by crossing IL-2+/- and IL-4-/- mice, and the double mutant mice were selected by PCR-based genotyping. DKO mice used as transplantation recipients were homozygous for the disrupted genes. All IL-2-/- and IL-4-/- DKO animals were housed under pathogen-free conditions. Ola129 mice were used as wild type (wt) controls. (C57BL/6 x Ola129)F1 mice were used as donors for the syngeneic transplants.
Islet transplantation
Islet transplantation was performed as previously described (4). Donor pancreata were perfused in situ with 3.5 ml type IV collagenase (2 mg/ml, Worthington Biochemical Corp. Freehold, NJ) through the common bile duct. The pancreata were harvested after perfusion and incubated at 37°C for 40 min. Islets were released from the pancreata by gentle vortex and further purified on discontinuous Percoll gradients. Briefly, the crude islet preparation was resuspended in 4 ml 25% Percoll, layered on top with 2 ml 23%, followed by 2 ml 21% and 2 ml 11% Percoll gradients. After centrifugation at 1800 rpm for 10 min, the islets were harvested from 21/11% gradient interface. Islets were washed twice in HBSS, and 300 to 400 islets were transplanted under the renal capsule of each recipient rendered diabetic by a single i.p. injection of streptozotocin (225 mg/kg, Sigma, St. Louis, MO). Allograft function was monitored by serial blood glucose measurements. Primary graft function was defined as a blood glucose under 200 mg/dl on day 3 posttransplantation, and graft rejection was defined as a rise in blood glucose exceeding 300 mg/dl following a period of primary graft function.
Immunohistochemistry
The left kidney containing the islet graft was removed from the recipients at various times after transplantation and embedded in OCT compound (Tissue TCK, Miles Scientific, Elkhart, IN), snap frozen in liquid nitrogen, and sectioned with a cryostat. Serial frozen sections (6 µm) were mounted on Superfrost/Plus glass slides (Fisher Scientific, Pittsburgh, PA) and fixed either in cold acetone for immunohistochemistry or in methanol for hematoxylin and eosin staining. For cell surface Ag staining, sections were blocked sequentially with normal mouse serum, avidin/biotin, and quenched with 1% H2O2 in 0.02% sodium azide for 60 min. After washing in balanced salt solution, the slides were incubated overnight at 4°C with rat anti-mouse CD4 (GK1.5), CD8 (53–6.7), or control mAb (PharMingen), followed by incubation with biotin-labeled goat anti-rat IgG (PharMingen) at room temperature for 30 min. After sequential washing in balanced salt solution, the slides were further incubated with avidin-horseradish peroxidase (PharMingen). The color reaction was developed by diaminobenzidine (DAB) 0.5 mg/ml. For intragraft cytokine staining, acetone-fixed cryostat sections were stained by immunoperoxidase method using rat mAbs against mouse IL-7 (AB-407-NA, R&D, Minneapolis, MN), IL-9 (D8402E8, PharMingen), and IL-15 (G277–3588, PharMingen) as previously described (20). Control sections were stained with isotype-matched control Abs as well as Abs absorbed with respective cytokines before staining. Sections were briefly counterstained with hematoxylin and mounted for examination.
RNA extraction
The tissue samples were homogenized, and total cellular RNA was extracted using a Qiagen RNA isolation kit (Qiagen, Chatsworth, CA) according to manufacturer’s instructions. RNA was reverse transcribed into cDNA in a 40-µl reaction mixture containing First strand buffer (10 mM Tris-HCl, 15 mM KCl, 0.75 mM MgCl2), 10 mM dNTP mix, 100 mM DTT, 5 units of RNase inhibitor (RNasin, Pharmacia, Piscataway, NJ; 31 U/µl), BSA (1 µg/µl), random primers (500 µg/ml), and 200 units of Moloney murine leukemia virus (MMLV) reverse transcriptase (Life Technologies, Grand Island, NY). The reaction mixture was incubated at 37°C for 1 h, terminated by heat inactivation at 65°C for 10 min, and stored at -20°C.
Quantitative reverse transcriptase assisted PCR
Quantitative RT-PCR (QRT-PCR) was performed as previously reported (21) with modifications. Briefly, 1 µl of reverse-transcribed cDNA was coamplified with a known concentration of gene-specific competitor in a 50-µl reaction volume containing 10 mM dNTPs, 100 ng of sense and antisense primers, and 0.25 units of Taq polymerase (Promega, Madison, WI). The specific primers for murine IL-2, IL-4, IL-7, and GAPDH were used as previously reported (4). IL-9 (sense 5'-CAT CCT TGC CTC TGT TTT G-3', antisense 5'-AGG AGG GGA GGT TTT GTA A-3'), and IL-15 (sense 5'-GAC ACC ACT TTA TAC ACT G-3', antisense 5'-TGG ACA ATG CGT ATA AAG-3') specific primers were generated using published sequences. The gene-specific DNA competitors (with 60 to 80 bp deletions from wt cDNA) were generated from either Con A-stimulated splenic mononuclear leukocytes or rejecting allografts by using a specially designed double sense primers (21). All competitors were cloned in a TA cloning vector (Invitrogen, San Diego, CA), transfected into DH5 cells, purified, and then quantitated in UV spectrophotometer (Beckman, Columbia, MD).
The PCR amplification schema consisted of the following cycle components: denature at 94°C for 1 min, annealing at 55°C for 45 s, and extension at 72°C for 1 min for each cycle in a thermocycler (Perkin-Elmer Cetus, Norwalk, CT) for a total of 40 cycles. A positive and a negative control was included for each PCR amplification. Negative controls were performed by omitting initial cDNA in the PCR reaction mixture. As a positive control, cDNA from Con A-stimulated splenic mononuclear leukocytes was used. In addition, amplification of the universally expressed GAPDH gene served to confirm successful isolation and reverse transcription of total cellular RNA. PCR products were analyzed in ethidium bromide-stained 2% agarose gel and photographed with Polaroid positive/negative films under ultraviolet light. The PCR results on the negative film were scanned using a desktop scanner into a computer, and the density of wt cDNA and the gene-specific competitor bands were analyzed using ImmunoQuan computer software (version 1.1, Hercules, CA). The magnitude of target gene expression is calculated and expressed as pg of target gene cDNA per pg of GAPDH cDNA in each sample.
Cell proliferation assay
Spleens were removed from IL-2-/- and IL-4-/- DKO mice under sterile conditions, and single cell suspensions were prepared in RPMI 1640 medium supplemented with 10% FCS, 1% penicillin, and streptomycin. Cells (2 x 105) were stimulated with anti-CD3 (2 µg/ml) in the presence or absence of various concentrations of cytokines for 3 days. For the last 18 h of culture, the cells were pulsed with 1 µCi [3H]TdR (Amersham, Boston, MA) and then harvested onto glass filters. Incorporation of [3H]TdR was determined by a scintillation counter (Beckman). Results are expressed as mean cpm ± SD of triplicate assays. For comparison, the proliferation of DKO splenic leukocytes was also converted and presented as percentage of that mounted by wt control mice.
Cell-mediated cytotoxicity assay
The standard 4-h chromium release assay was used (22). Target cells were prepared by culturing splenic mononuclear leukocytes (5 x 106 cells/ml) with Con A (5 µg/ml, Sigma) for 48 h, and the lymphoblasts were harvested and labeled with 51Cr (250 to 500 mCi/mg, Amersham) at 37°C for 1 h. The 51Cr-labeled target cells (2 x 104 cells/well) were placed into 96-well round-bottom culture plates (Costar, Cambridge, MA) along with various numbers of effector cells to achieve the effector/target cell ratio of 100/1, 50/1, 25/1, and 12.5/1. Total culture volume was 0.2 ml in each well, and all assays were performed in triplicate. After a 4-h incubation at 37°C, the plates were centrifuged at 700 x g for 10 min, and 0.1 ml supernatant was removed from each well. The radioactivity present in the supernatant was quantitated in a gamma counter (Beckman). Total cellular release was determined by lysing the target cells with 0.1% Triton-100 (Sigma). The supernatant from target cells cultured with medium alone was used to determine the spontaneous release. Specific cytotoxicity was calculated using the formula: (experimental cpm - spontaneous cpm)/(total cpm - spontaneous cpm) x 100.
Statistics
A log-rank test was used for analysis of graft survival, and p < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, all islet
allografts transplanted from DBA/2J (H-2d) into DKO mice
(H-2b) and wt control Ola129 mice (H-2b) were
rejected. The mean survival time (MST) of the islet allografts placed
into DKO mice was 17 days (17 ± 7, n = 8) while
wt recipients rejected the islet allografts with a MST of 13 days
(13 ± 4 days, n = 7). In contrast, syngeneic
islet transplants were not rejected by the DKO mice
(n = 3). Histologic assessment of rejecting
islet allografts in DKO mice revealed a dense and invading mononuclear
leukocytic infiltrate consisting predominantly of CD4+ and
CD8+ cells (data not shown). This pattern of cellular
infiltration was identical to that observed in wt recipients. To
determine whether the rejection process in DKO mice is truly a T
cell-mediated process, DKO mice were treated with anti-CD3 mAb
after islet transplantation (50 µg i.p. daily for 14 days). This
treatment markedly prolonged the survival of islet allografts in DKO
mice (39 ± 4 days, n = 5)
(p < 0.05) (Fig. 1). We then sought to examine
whether rapamycin-sensitive TCGF-signaling pathways play a role in the
rejection of islet allografts by the DKO recipients. Rapamycin is a
potent blocker of growth factor-mediated signal transduction in T cell
proliferation (24). DKO recipient mice were treated with rapamycin (0.2
mg/kg/day i.p. daily for the first 3 days, followed by every other day)
until the advent of hyperglycemia. As shown in Figure 1, this treatment
also markedly prolonged the survival of islet allografts (45 ± 11
days, n = 6) (p < 0.05),
demonstrating the critical role of rapamycin-sensitive TCGF signals in
the execution of islet allograft rejection despite the absence of both
IL-2 and IL-4.
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IL-9 transcripts were also not detected in the islet allografts
harvested early after transplantation (day 4) or when the islet
transplants were completely rejected (day 14 after grafting).
Intragraft cytokine protein staining by immnuoperoxidase method also
demonstrated dense peri-islet labeling for IL-7 and IL-15 (Fig. 3) whereas IL-9 was not detected in
either wt or DKO recipients (data not shown). The rejection of islet
allografts in both the DKO mice and the wt control mice was also
associated with marked intragraft gene expression for CTL attack
molecules, including perforin and granzyme B (Fig. 4).
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). To test this
possibility, allogeneic DBA/2J splenic leukocytes (107)
were inoculated i.p. into DKO mice and wt controls. DKO peritoneal
exudate cells (PEC) were harvested on day 12 post i.p. injection, and
the cytotoxic activity was assessed against 51Cr-labeled
DBA/2J Con A blasts. As shown in Figure 5, specific CTL activity was induced in
both DKO mice and wt mice, although the donor-specific CTL activity in
DKO mice was consistently lower than that in wt mice. PEC harvested
from primed DKO mice did not lyse third party CBA/J target cells.
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, splenic mononuclear leukocytes from
DKO mice did not mount a proliferative response to the stimulation with
anti-CD3. Provision of exogenous IL-2, IL-4, IL-7, or IL-15
supported vigorous proliferation of anti-CD3-activated DKO splenic
mononuclear leukocytes. Interestingly, exogenous IL-9 had no effect on
the proliferation of anti-CD3-stimulated DKO splenic leukocytes
over a wide range of doses examined (50 to 400 U/ml). In comparison
with wt controls, the proliferation of anti-CD3-activated DKO
splenic mononuclear leukocytes was <6% of that mounted by the wt
mice. Provision of 100 U/ml exogenous IL-2, IL-7, or IL-15 restored the
anti-CD3-triggered proliferative response to 60%, 25%, and 52%
of wt mice, respectively. A combination of IL-7 and IL-15 (100 U/ml
each) restored the proliferation of DKO splenic mononuclear leukocytes
to 78% of wt mice, which is equivalent to proliferation occurring with
the addition of both IL-2 and IL-4 in the culture (82%).
The intragraft TCGF gene transcript analysis and in vitro splenic
leukocyte proliferation studies strongly suggest a role for IL-7 and
IL-15 in supporting IL-2- and IL-4-independent islet allograft
rejection. To probe the credibility of this possibility, we treated DKO
recipients with two blocking mAbs (4G3 and 3E12) against the c
chain, a shared signal-transducing component by receptors for IL-2,
IL-4, IL-7, IL-9, and IL-15. The anti-c mAbs used have been
shown to effectively block IL-7-, IL-9-, or IL-15-driven T cell
proliferation in vitro and T cell maturation in vivo (18). As shown in
Figure 7, treatment of DKO mice with the
anti-c mAbs on days 0, 3, and 5 after transplantation (0.5 mg
each/injection) significantly prolonged the survival of islet
allografts (MST 26 ± 4, n = 4) as compared with
control mAb-treated DKO mice (MST 16 ± 4, n = 4)
(p < 0.05), suggesting an active role of IL-7
and IL-15 in supporting the IL-2- and IL-4-independent islet allograft
rejection.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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), and 3) is associated with intragraft expression of
gene transcripts for CTL-attacking molecules (Fig. 4). Furthermore, DKO
mice are capable of generating donor-specific CTL upon in vivo priming
with allogeneic leukocytes (Fig. 5). These findings suggest that the in
vivo allograft rejection response mounted by DKO mice is relatively
intact. However, the in vitro immune activation of DKO splenic
mononuclear leukocytes is severely impaired because the splenic
mononuclear leukocytes from DKO mice failed to proliferate in vitro to
anti-CD3 or polyclonal mitogen stimulation (Fig. 6). DKO splenic
mononuclear leukocytes also fail to proliferate in response to
allogeneic leukocytes (data not shown). The in vitro immune deficiency
of DKO mice is unlikely due to abnormal T cell development since the
development of both T cells and B cells is normal in
IL-2-/- and IL-4-/- DKO mice (30). These
results strongly suggest that TCGFs that are critical for allograft
rejection in DKO mice are not produced in the classical in vitro
systems. Thus, endogenous production of IL-2 and IL-4 is quintessential
for the in vitro activation and proliferation of T cells while
alternative TCGFs present in vivo may not be efficiently produced upon
in vitro stimulation of DKO mononuclear leukocytes.
What are the possible alternative TCGFs that support the IL-2 and IL-4
independent T cell clonal expansion and graft rejection? TCGFs,
especially those triggering rapamycin-sensitive signals, are clearly
important, since treatment of DKO mice with rapamycin (an agent that
blocks growth factor-triggered cell cycle progression through
inhibition of p70s6k and cdk-cyclin E (24)) markedly
delayed the rejection of islet allografts (Fig. 1). We then treated
DKO-recipient mice with noncytolytic mAbs that block the common c, a
shared critical signaling component by receptors for IL-2, IL-4, IL-7,
IL-9, and IL-15, to determine whether the c-transduced signals play
a role in islet allograft rejection. Indeed, the c-transduced
signals are actively involved in mediating allograft rejection despite
the absence of both IL-2 and IL-4, since blocking the common c also
prolonged the survival of islet allografts in DKO mice (Fig. 7).
Intragraft gene transcript analysis, as well as immunohistochemical
staining of TCGFs sharing the common c, showed a robust expression
of IL-7 and IL-15, but not IL-9, in rejecting islet allografts in DKO
mice (Figs. 2 and 3). Furthermore, both IL-7 and IL-15 can effectively
restore the in vitro proliferation of anti-CD3-activated DKO
splenic mononuclear leukocytes (Fig. 6). These studies strongly suggest
a critical role of non-T cell-derived TCGFs, especially IL-7 and IL-15,
in mediating IL-2- and IL-4-independent alloimmune activation and graft
rejection. It should be noted that treatment with anti-c mAbs
only delayed islet allograft rejection in DKO mice. However, we cannot
rule out the possibility that the blocking effect of the mAbs is
overcome by high IL-7 and IL-15 production since the ability of the
anti-c mAbs to block cytokine functions is dependent on both the
concentration of mAbs and cytokine levels. Alternatively, an undefined
c-independent signaling pathway might be involved in the T cell
activation and clonal expansion.
Although IL-9 also utilizes the common c in its receptor complex, we
doubt that IL-9 has a significant role in graft rejection since IL-9
gene transcripts were conspicuously absent in the rejecting islet
allografts in either wt or DKO mice, despite vigorous expression of
gene transcripts of other TCGFs. Furthermore, IL-9, in contrast to IL-2
and other c binding TCGFs, did not stimulate the proliferation of
freshly activated DKO splenic mononuclear leukocytes in vitro, which is
consistent with a previous study showing that IL-9 is unable to support
the proliferation of PMA-activated spleen cells, lymph node cells, and
purified CD4+ T cells (31). Since IL-9 is a very potent
growth factor for transformed T cells and long-term cultured T cell
clones (12), IL-9 may not be a growth factor for freshly activated T
cells.
Clearly, the expression of TCGFs during in vivo and in vitro immune
activation is differentially regulated. Most strikingly, IL-7, a potent
stromal cell-derived TCGF, is not present in monodispersed splenic
mononuclear cells stimulated with mitogen in vitro but vigorously
expressed in splenic tissue and rejecting allografts in vivo (4).
Similarly, IL-15, a TCGF derived from a variety of cell types with the
notable exception of T cells, is not expressed by PHA-activated T cells
(16) and is barely detectable in cultures of Con A-stimulated splenic
leukocytes in vitro. However, its level of gene expression was markedly
increased in the rejecting islet allografts in vivo (Fig. 2). It is
tempting to speculate that the differences in IL-7 and IL-15 expression
(in vivo vs in vitro) may underlie the gross deficiency of DKO mice to
respond to polyclonal mitogens in vitro and yet reject islet grafts in
vivo. Since IL-7 and IL-15 can deliver T cell growth signals that are
resistant to cyclosporine A (32), a powerful drug that mostly inhibits
IL-2 and IL-4 gene transcription, the vigorous expression of IL-7 and
IL-15 may contribute, at least in part, to the chronic graft rejection
in patients while being treated with cyclosporine A. Indeed, we and
others have routinely found IL-7 and IL-15, but not IL-2, gene
transcripts present in all human renal biopsies at the time of
clinically evident rejection (21, 33). Similar to IL-9 gene expression
in rejecting islet allografts in mice, IL-9 gene transcripts were also
not detected in human renal biopsies obtained 4 to 251 days after
transplantation, regardless of the presence or absence of histologic
evidence of rejection (our unpublished observation). Thus, the
expression of IL-7 and IL-15 may also play a critical role in
supporting allograft rejection in humans under conventional
immunosuppression.
In summary, the present study demonstrated for the first time that a
classical allograft rejection process can be mounted in the absence of
IL-2 and IL-4, two potent T cell-derived TCGFs, and that the non-T
cell-derived TCGFs, especially IL-7 and IL-15, are actively involved in
supporting the IL-2- and IL-4-independent allograft rejection. Our
study also suggests that efficient therapeutic intervention of
allograft rejection should target the common receptor components (e.g.,
IL-2 receptor c chain) of TCGFs and/or the common pathways of
TCGF-triggered signal transduction.
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Acknowledgments |
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Footnotes |
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2 These authors contributed equally to this project.
3 Address correspondence and reprint requests to Dr. Terry B. Strom, Department of Medicine, Division of Immunology, Beth Israel Deaconess Medical Center, P.O. Box 15707/Research North-Room 380, Boston, MA 02215. E-mail address:
4 Abbreviations used in this paper: TCGF, T cell growth factor; DKO, double knockout mice; QRT-PCR, quantitative reverse transcriptase-PCR; PEC, peritoneal exudate cells; wt, wild-type; GAPDH, glyceraldehyde phosphate dehydrogenase; MST, mean survival time; wt, wild type.
Received for publication November 24, 1997. Accepted for publication March 19, 1998.
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T. R. Jones, J. Ha, M. A. Williams, A. B. Adams, M. M. Durham, P. A. Rees, S. R. Cowan, T. C. Pearson, and C. P. Larsen The Role of the IL-2 Pathway in Costimulation Blockade-Resistant Rejection of Allografts J. Immunol., February 1, 2002; 168(3): 1123 - 1130. [Abstract] [Full Text] [PDF]
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 S. M. Stepkowski, R. A. Erwin-Cohen, F. Behbod, M.-E. Wang, X. Qu, N. Tejpal, Z. S. Nagy, B. D. Kahan, and R. A. Kirken Selective inhibitor of Janus tyrosine kinase 3, PNU156804, prolongs allograft survival and acts synergistically with cyclosporine but additively with rapamycin Blood, January 15, 2002; 99(2): 680 - 689. [Abstract] [Full Text] [PDF]
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S. Ferrari-Lacraz, X. X. Zheng, Y. S. Kim, Y. Li, W. Maslinski, X. C. Li, and T. B. Strom An Antagonist IL-15/Fc Protein Prevents Costimulation Blockade-Resistant Rejection J. Immunol., September 15, 2001; 167(6): 3478 - 3485. [Abstract] [Full Text] [PDF]
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F. Behbod, R. A. Erwin-Cohen, M.-E. Wang, B. W. Trawick, X. Qu, R. Verani, B. D. Kahan, S. M. Stepkowski, and R. A. Kirken Concomitant Inhibition of Janus Kinase 3 and Calcineurin-Dependent Signaling Pathways Synergistically Prolongs the Survival of Rat Heart Allografts J. Immunol., March 15, 2001; 166(6): 3724 - 3732. [Abstract] [Full Text] [PDF]
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T. A. Fehniger and M. A. Caligiuri Interleukin 15: biology and relevance to human disease Blood, January 1, 2001; 97(1): 14 - 32. [Full Text] [PDF]
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X. G. Smith, E. M. Bolton, H. Ruchatz, X.-q. Wei, F. Y. Liew, and J. A. Bradley Selective Blockade of IL-15 by Soluble IL-15 Receptor {alpha}-Chain Enhances Cardiac Allograft Survival J. Immunol., September 15, 2000; 165(6): 3444 - 3450. [Abstract] [Full Text] [PDF]
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Z. Liu, K. Geboes, S. Colpaert, G. R. D'Haens, P. Rutgeerts, and J. L. Ceuppens IL-15 Is Highly Expressed in Inflammatory Bowel Disease and Regulates Local T Cell-Dependent Cytokine Production J. Immunol., April 1, 2000; 164(7): 3608 - 3615. [Abstract] [Full Text] [PDF]
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X. C. Li, A. Ima, Y. Li, X. X. Zheng, T. R. Malek, and T. B. Strom Blocking the Common {gamma}-Chain of Cytokine Receptors Induces T Cell Apoptosis and Long-Term Islet Allograft Survival J. Immunol., February 1, 2000; 164(3): 1193 - 1199. [Abstract] [Full Text] [PDF]
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X. C. Li, Y. Li, I. Dodge, A. D. Wells, X. X. Zheng, L. A. Turka, and T. B. Strom Induction of Allograft Tolerance in the Absence of Fas-Mediated Apoptosis J. Immunol., September 1, 1999; 163(5): 2500 - 2507. [Abstract] [Full Text] [PDF]
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