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-Chain Enhances Cardiac Allograft Survival1
*
Department of Surgery, University of Cambridge, Cambridge, United Kingdom; and
Department of Immunology and Bacteriology, University of Glasgow, Glasgow, United Kingdom
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-chain, to
investigate the contribution of IL-15 to the rejection of fully
vascularized cardiac allografts in a mouse experimental model.
Administration of soluble fragment of the murine IL-15R -chain
(sIL-15R) to CBA/Ca (H-2k) recipients for 10 days
completely prevented rejection of minor histocompatibility
complex-mismatched B10.BR (H-2k) heart grafts (median
survival time (MST) of >100 days vs MST of 10 days for control
recipients) and led to a state of donor-specific immunologic tolerance.
Treatment of CBA/Ca recipients with sIL-15R alone had only a modest
effect on the survival of fully MHC-mismatched BALB/c
(H-2d) heart grafts. However, administration of sIL-15R
together with a single dose of a nondepleting anti-CD4 mAb (YTS
177.9) delayed mononuclear cell infiltration of the grafts and markedly
prolonged graft survival (MST of 60 days vs MST of 20 days for
treatment with anti-CD4 alone). Prolonged graft survival was
accompanied in vitro by reduced proliferation and IFN-
production by
spleen cells, whereas CTL and alloantibody levels were similar to those
in animals given anti-CD4 mAb alone. These findings
demonstrate that IL-15 plays an important role in the rejection of a
vascularized organ allograft and that antagonists to IL-15 may be of
therapeutic value in preventing allograft
rejection. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and TNF- contribute significantly to the
effector mechanisms responsible for graft destruction (1, 2). The T cell-derived cytokine IL-2 was the first major T cell
growth factor identified, and therapeutic Abs directed against the
-chain of the IL-2R (CD25) have recently been shown, when combined
with conventional immunosuppressive agents, to reduce the incidence of
acute rejection after human organ transplantation (3, 4).
However, allograft rejection still occurs in the presence of IL-2/IL-2R
blockade (3, 4, 5). Moreover, IL-2 gene knockout mice and
IL-2/IL-4 double-knockout mice are still able to reject allografts,
highlighting the redundancy in the cytokine network and suggesting a
potentially important role for other immunoregulatory cytokines, such
as IL-7 and IL-15, in the graft rejection process (6, 7).
IL-15 is a recently identified cytokine that is similar in structure to
IL-2 and shares with it a number of biological activities, including
its ability to stimulate the proliferation and differentiation of
activated T cells (8, 9). However, unlike IL-2, IL-15 mRNA
is expressed in a wide range of different cell types, including
activated macrophages, activated vascular endothelial cells,
fibroblasts, muscle cells, epithelial cells, and T cells (10, 11). Moreover, although IL-15 and IL-2 share the same IL-2Rß
and common -chain receptor subunits, IL-15 uses a unique -chain,
IL-15R, which is expressed on a wide variety of cell types,
including activated T cells, B cells, NK cells, macrophages, and some
types of nonimmune cells (10, 11, 12). The biological effects
of IL-15 are diverse. In addition to acting as a T cell growth factor,
IL-15 stimulates the differentiation of NK cells, induces T cell
chemotaxis, promotes B cell activation and isotype switching, and
increases the production of proinflammatory cytokines by macrophages
(10, 11). It also promotes the growth and activation of
mast cells and influences activity in some types of nonimmune cell
(10, 11).
The role of IL-15 in the allograft rejection response is not clearly
defined, but an important role for this cytokine has been suggested in
other types of immunopathology, such as inflammatory arthritis,
inflammatory bowel disease, sarcoidosis, and multiple sclerosis
(13, 14, 15, 16, 17). Several recent studies have observed an increase
in the expression of intragraft IL-15 mRNA transcripts and
IL-15-expressing cells after transplantation and suggested that
increased IL-15 expression correlates with acute rejection
(18, 19, 20, 21, 22). Therefore, blockade of the IL-15/IL-15R pathway
may be of value in modifying the immune response to an organ allograft.
In this paper we report that administration of a soluble fragment of
the murine IL-15R -chain
(sIL-15R)3 to
neutralize IL-15 prevents rejection of fully vascularized, minor
histocompatibility Ag-mismatched cardiac allografts. Furthermore,
sIL-15R, in combination with a single dose of a nondepleting
anti-CD4 mAb, markedly prolongs the survival of fully allogeneic
heart allografts.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Male CBA/Ca (H-2k), B10.BR (H-2k), AKR/J (H-2k), and BALB/c (H-2d) mice were obtained from Harlan U.K. (Bicester, U.K.). All animals were maintained under conventional conditions at Central Biomedical Services, University of Cambridge (Cambridge, U.K.), and were used when they were 8–12 wk old.
Heart transplantation
Vascularized cervical heterotopic heart transplantation was performed using standard microsurgical techniques as previously described (23). The innominate artery of the donor heart was anastomosed end-to-end to the right common carotid artery of the recipient, and similarly, the donor pulmonary artery was anastomosed to the recipient external jugular vein. Cold ischemic times were <30 min. Graft function was assessed by daily palpation of the heart, and rejection was defined as the complete cessation of myocardial contraction.
Skin grafting
Tail skin grafts from adult donor mice were transplanted to the flanks of heart graft recipients, essentially as described previously (24). Dressings were removed after 7 days, and skin graft rejection was defined as complete destruction of the graft.
Histology
Heart grafts were excised, formalin fixed, embedded in paraffin wax, sectioned, and stained with hematoxylin and eosin.
sIL-15R
A soluble fragment of IL-15R -chain lacking transmembrane and
cytoplasmic domains was generated as described previously
(14). The histidine-tagged recombinant protein was
purified using nickel-agarose and dialyzed into PBS for in vivo use.
The sIL-15R fragment used has been shown previously to inhibit
rIL-15-mediated in vitro proliferation of CTLL and D10 cells, but does
not bind to IL-2 or inhibit IL-2-dependent CTLL proliferation
(14). Heart graft recipients received 60 µg of
sIL-15R i.p. on the day of transplantation and daily for 9 days
thereafter.
This schedule was chosen on the basis that daily i.p. administration of
40 µg of sIL-15R for 10 days profoundly suppressed the development
of murine collagen-induced arthritis (14), although it is
not known whether the amount of sIL-15R given was sufficient to
completely neutralize IL-15 for the treatment duration.
Antibodies
The rat anti-mouse CD4 mAb YTS 177.9 was provided by Dr. Steve Cobbold, Sir William Dunn School of Pathology (Oxford, U.K.) (25). Ig, purified by ammonium sulfate precipitation, was administered to recipient mice as a single dose of 1 mg given i.p. at the time of heart transplantation. The phenotype of recipient splenocytes was determined by flow cytometry, using fluorochrome-conjugated rat anti-mouse mAbs KT3 (CD3), KT15 (CD8; both from PharMingen, Becton Dickinson, Oxford, U.K.) and YTS 177.9 (CD4; Serotec, Oxford, U.K.). Mouse alloantibody levels were determined by flow cytometry after incubating recipient serum samples with donor splenocytes, followed by FITC-labelled rabbit Ab against mouse IgG plus IgM (F0313, Dako, Cambridge, U.K.) or against mouse IgG1, IgG2a, and IgG3 (PharMingen).
CTL activity
The CTL activity of splenocytes was determined as described previously (26). Recipient splenocytes were cocultured with irradiated donor splenocytes (20 Gy) for 5 days to generate CTL, then incubated with [3H]thymidine-labeled donor strain Con A blast target cells for 4 h to determine their cytotoxic activity. Reduced scintillation counts indicated enhanced cytotoxic activity.
Lymphocyte proliferation and cytokine production
Lymphocyte proliferation assays were performed essentially as
described previously (27). Responder splenocytes (2
x 105/well) were cultured with irradiated (20
Gy) stimulator splenocytes (2 x 105/well)
for 72, 96, and 120 h in 96-well plates at 37°C in 5%
CO2. Proliferation was assessed by uptake of
[3H]thymidine for 6 h at the end of the
culture period. Supernatant was harvested from cell culture plates and
was assayed by ELISA for production of IFN- and IL-4 using capture
and detection Abs (PharMingen) according to the manufacturer’s
instructions.
Statistical analysis
Differences between groups were compared by nonparametric analysis using the Mann-Whitney U test. Values of p (two-tailed) < 0.05 were considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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on cardiac allograft survival
The effect of disrupting the IL-15/IL-15R pathway on cardiac
allograft survival was examined by administering sIL-15R to
recipients of either minor (mHC) or MHC Ag-mismatched heart grafts.
CBA/Ca (H-2k) recipients of mHC-disparate B10BR
(H-2k) heart grafts were treated daily with an
i.p. injection of 60 µg of sIL-15R for 10 days from the day of
transplant. This treatment schedule was based on our experience of
using sIL-15R to control murine collagen-induced arthritis
(14). Control recipients rejected their heart grafts
promptly, with a median survival time (MST) of 10 days, whereas
treatment with sIL-15R extended heart graft survival well beyond the
10-day treatment schedule in all recipients, and in 70% of recipients
led to long term (>100 days; p < 0.01) graft survival
(Fig. 1
). Histologic examination of
rejected heart grafts in control recipients showed characteristic
features of acute rejection, with a heavy mononuclear cell infiltrate
and widespread tissue destruction (Fig. 2A). Nonrejecting hearts in
sIL-15R-treated recipients examined at >100 days were still beating
strongly and showed no histologic evidence of graft rejection (Fig. 2B).
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treatment had induced donor-specific
tolerance, three sIL-15R-treated CBA/Ca recipients with long
surviving B10BR heart allografts (>100 days) were grafted with both
donor strain (B10BR, H-2k) and third-party
(AKR/J, H-2k) skin. Third-party AKR/J skin grafts
were rapidly rejected (MST, 14 days) by CBA/Ca recipients, whereas
donor strain B10BR grafts survived for >100 days, confirming the
development of donor-specific immunologic tolerance.
Administration of sIL-15R to CBA/Ca recipients bearing fully
allogeneic BALB/c (H-2d) heart grafts produced
only a modest prolongation of graft survival compared with
MHC-mismatched controls (MST of 11 days vs MST of 7 days, respectively;
Fig. 3a).
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alone was relatively ineffective in this fully
MHC-disparate mouse strain combination, we chose in subsequent
experiments to combine it with an additional immunomodulatory agent in
the form of a nondepleting anti-CD4 mAb. YTS 177.9 is a rat
anti-mouse CD4 mAb of the IgG2a subclass (25) that
after in vivo administration induces rapid and profound modulation of
CD4 from residual CD4 T cells, resulting in transient interruption of
the alloimmune response, but only limited prolongation of cardiac
allograft survival (28). CBA/Ca recipients of BALB/c
hearts received 1 mg of YTS 177.9 given i.p. at the time of heart
transplantation together with a 10-day course of sIL-15R. Phenotypic
analysis of spleen cells from transplanted animals showed that the
anti-CD4 mAb treatment schedule led to a modest reduction in CD4 T
cell numbers, and this reduction was most apparent in recipients given
a combination of sIL-15R and YTS 177.9 (Fig. 4). Cardiac allograft recipients given
anti-CD4 mAb alone rejected their grafts with an MST of 15 days
(Fig. 3
b). In recipients treated with a combination of
sIL-15R and anti-CD4 mAb, cardiac allograft survival was
markedly prolonged (MST of 60 days vs MST of 20 days for controls; Fig. 3b). Histologic examination of heart grafts excised on day
15 from control recipients given anti-CD4 mAb showed a heavy
mononuclear cell infiltrate and widespread tissue destruction (Fig. 5A). In contrast, examination
of hearts excised on day 15 from sIL-15R plus anti-CD4-treated
recipients showed a moderate mononuclear cell infiltrate, but minimal
graft damage (Fig. 5B).
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Spleen cells were obtained from CBA/Ca recipients of BALB/c hearts
at 10 and 15 days after transplantation, and cytotoxic T cell activity
against donor target cells was determined. CTL activity against BALB/c
targets was higher on day 10 than on day 15 after transplantation, but
at neither time point was there any significant difference between
experimental groups (Fig. 6).
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Anti-BALB/c Ab was readily detected by flow cytometry in serum
obtained from anti-CD4-treated CBA/Ca recipients of BALB/c heart
grafts and was tested using the F0313 rabbit anti-mouse Ig
that detects both IgG and IgM. Additional treatment with sIL-15R
had no discernible effect on the Ab titers observed (Fig. 7). Three of five recipients treated with
sIL15R plus anti-CD4 plus showed low titers (<1/27) of the
Th1-type IgG2a alloantibody and no detectable IgG3 or Th2-type IgG1
alloantibody. Control recipients given anti-CD4 mAb alone had
marginally higher titers of circulating IgG alloantibody, with four of
six animals having detectable IgG2a alloantibody with titers of up to
1/81, no detectable IgG3, and IgG1 titers of <1/27 (data not
shown).
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Spleen cells obtained on day 15 from CBA/Ca recipients of BALB/c
heart allografts were assessed for their ability to proliferate in
vitro and to produce IFN- in response to irradiated allogeneic
stimulators. Lymphocytes from recipients treated with a combination of
sIL-15R and anti-CD4 mAb showed a marked reduction in
proliferation to donor-specific (BALB/c) stimulator cells compared with
naive responder cells from normal CBA/Ca mice
(p < 0.05). The level of proliferation
observed was significantly lower (p
< 0.02) than that shown by cells obtained from control recipients
treated with anti-CD4 mAb alone (Fig. 8a). Spleen cells from animals
treated with a combination of sIL-15R and anti-CD4 mAb also
showed lower levels of spontaneous proliferation than cells obtained
from control recipients given anti-CD4 mAb alone
(p < 0.02). Lymphocytes from recipients
treated with sIL-15R plus anti-CD4 mAb gave a lower
proliferative response to third-party (C57BL/10) stimulators compared
with naive control cells, but the residual levels of proliferation
observed were not significantly different from those shown by spleen
cells from control recipients given anti-CD4 mAb alone.
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and
anti-CD4 mAb produced levels of IFN- comparable to those
produced by naive splenocytes from normal CBA/Ca mice and significantly
less IFN- after 96 and 120 h of coculture than splenocytes from
control recipients treated with anti-CD4 mAb alone
(p < 0.05; Fig. 8b). IL-4 was not
detected in any of the coculture supernatants examined in these
experiments. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-helix bundle family of cytokines,
initially identified through its ability to stimulate T cell growth and
differentiation, but with wide ranging effects on both lymphoid and
nonlymphoid cells (8, 9, 29). Many cell types
constitutively express IL-15 mRNA, although production of IL-15 protein
is subject to considerable post-transcriptional regulation (10, 11). Recent studies have shown that expression of IL-15 mRNA is
increased in some types of immune-mediated tissue injury, and there is
considerable interest in the potential contribution of this cytokine to
the pathogenesis of tissue destruction in these situations (13, 15, 16, 17, 18, 19, 20, 21, 22). Following organ transplantation, expression of IL-15
mRNA is readily detectable in the graft, and increased levels of
expression have been shown to correlate with the presence of acute
rejection, leading to speculation that IL-15 may contribute to the
rejection process (18, 19, 20, 21, 22).
The results of the present study provide clear in vivo evidence that
IL-15 plays a role in the rejection of fully vascularized heart
allografts. In the case of multiple mHC-mismatched cardiac allografts,
the contribution of IL-15 to acute rejection appears critical, because
administration of a sIL-15R not only prevented the rejection of
mHC-mismatched cardiac allografts, but also led to the development of
operational donor-specific tolerance, as shown by rejection of
third-party, but not donor strain, skin grafts. It might have been
expected, in view of the considerable functional overlap between
cytokines of the T cell growth factor family, that there would be
sufficient redundancy in the cytokine network to allow rejection of
mHC-mismatched heart grafts in the presence of IL-15 antagonism
(1, 30). IL-15, produced mainly by monocytes, and IL-2,
produced by T cells, have considerable functional overlap, and both
cytokines support T cell proliferation and differentiation, augment B
cell and NK cell activities, and are chemoattractant for T cells. The
extent of this functional overlap is explained in part by sharing of
common receptor subunits (30). Both IL-15 and IL-2 use the
IL-2R ß-chain and common -chain, but each has a distinct
-chain. Interestingly the IL-15R -chain has such a high affinity
for IL-15 that it binds with a Ka of
1011 M, which is 1000-fold higher than that for
IL-2R for IL-2 (12). In view of the functional
similarities between IL-15 and IL-2, it is important to note that the
sIL-15R fragment used in the present study does not bind to IL-2 in
vitro and does not inhibit IL-2-dependent CTLL proliferation
(14). This argues strongly against cross-reactivity of the
sIL-15R with IL-2 as an explanation for our findings and points
instead to the importance of IL-15 in mediating allograft
rejection.
IL-15 has a number of biological functions not shared with IL-2, and these may arise because of the site of synthesis and regulation of IL-15 expression, the wide tissue distribution of the IL-15R, and the existence of another unique IL-15R (IL-15RX) (10, 11). Production of IL-15 by dendritic cells may, for example, strongly influence T cell activation. In addition, IL-15 stimulates the proliferation of mast cells and bone marrow cells and plays a key role in the differentiation and development of NK cells (10, 11). Neither the cell type and anatomic location of IL-15 production nor the nature of the target cells through which IL-15 exerts its effects on cardiac allograft rejection were directly addressed in the present study. Many cell types express IL-15 mRNA, but there is considerable post-transcriptional control of protein production as well as regulation at the level of intracellular trafficking of IL-15 protein (11). Activated monocytes and macrophages are one of the major sources of IL-15 protein and large numbers of macrophages expressing IL-15 can be identified in human cardiac allografts (19). APCs, recipient lymphocytes, monocytes, NK cells, and donor endothelial cells may all express receptors for IL-15 and therefore are potential target cells for IL-15 during an alloimmune response (11). Further studies are now needed to dissect in detail the role of IL-15 in allograft rejection.
The rejection response to MHC-mismatched heart allografts is
considerably more powerful than that to grafts differing only in mHC,
and therefore it is not surprising that administration of
sIL-15R alone induced only a modest prolongation of graft
survival beyond that of control recipients. Therefore, we chose in
subsequent experiments to combine sIL-15R treatment with a single
dose of the nondepleting anti-CD4 mAb YTS 177.9. A combination of
sIL-15R and anti-CD4 mAb prolonged survival of fully
MHC-mismatched heart grafts far more effectively than anti-CD4 mAb
alone, thereby demonstrating the contribution of IL-15 to rejection of
MHC disparate allografts. The choice of a nondepleting anti-CD4 mAb
as an additional immunomodulatory agent for these studies arose because
of our long-standing interest in anti-CD4 mAbs as agents for
preventing allograft rejection. However, it seems reasonable to
hypothesize that combinations of sIL-15R and various other
immunosuppressive agents might also have a synergistic effect on
allograft survival.
Analysis of the effector mechanisms responsible for allograft rejection
reveals that delayed-type hypersensitivity, cytotoxic T cells and
alloantibody-dependent effector mechanisms may all contribute to graft
destruction. In the present study administration of sIL-15R did not
reduce the level of anti-donor CTL in the spleens of
anti-CD4-treated heart graft recipients, nor did it further reduce
the total serum Ig alloantibody levels below those seen in control
animals given anti-CD4 mAb alone, although experimental data
suggested that the anti-CD4-mediated reduction in IgG alloantibody
was enhanced by additional sIL-15R. However, spleen cells from
recipients given sIL-15R showed a reduction in proliferation and
produced less of the proinflammatory cytokine IFN- in response to in
vitro restimulation by donor alloantigen.
The finding that IL-15 contributes to allograft rejection is consistent
with the emerging role of IL-15 in other types of T cell-dependent
immunopathology, such as rheumatoid arthritis (13).
Targeting the IL-15R with an antagonist IL-15 mutant/Fc2a fusion
protein has recently been shown to attenuate the ability of mice to
mount an Ag-specific delayed-type hypersensitivity response
(31). Similarly, injection of sIL-15R delays the
development of collagen-induced arthritis and suppresses the
accompanying collagen-specific T cell response (14). The
recent availability of mice genetically deficient in IL-15 will further
clarify the role of IL-15 in these and other immunopathologies
(32)
T cell growth factors play an essential role in allograft rejection, as
highlighted by the recent demonstration that blockade of the common
-chain, a key signaling component shared by IL-2, IL-4, IL-7, IL-9,
and IL-15 receptors, prevents rejection in a murine islet transplant
model (33). Further studies are now needed to define more
clearly the contributions of individual growth factors in the graft
rejection process, and in the case of IL-15 these will be facilitated
by the availability of sIL-15R. In view of the increasing use of
anti-CD25 mAb in clinical transplantation it will be of interest to
combine sIL-15R with anti-CD25 mAb in experimental studies.
Combinations of sIL-15R and calcineurin blockade will also be of
particular interest in view of the resistance of in vitro IL-15
production to treatment with cyclosporin (34).
In conclusion, the results of this study provide in vivo evidence that IL-15 plays an important role in the rejection of a vascularized organ allograft and suggest that targeting IL-15/IL-15R interaction may, when combined with other chemical or biological immunosuppressive agents, be of therapeutic value in preventing allograft rejection.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Prof. J. Andrew Bradley, Department of Surgery, University of Cambridge Clinical School, Addenbrooke’s Hospital, Cambridge, U.K. CB2 2QQ.
3 Abbreviations used in this paper: sIL-15R, soluble fragment of IL-15R -chain; mHC, minor histocompatibility complex; MST, median survival time.
Received for publication May 3, 2000. Accepted for publication June 30, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-chain of the IL-2 receptor. EMBO J. 14:3654.[Medline]
-chain administration prevents murine collagen-induced arthritis: a role for IL-15 in development of antigen-induced immunopathology. J. Immunol. 160:5654.2a protein blocks delayed-type hypersensitivity. J. Immunol. 160:5742.-chain of cytokine receptors induces T cell apoptosis and long-term islet allograft survival. J. Immunol. 164:1193.-chains on human peripheral blood mononuclear cells and effect of immunosuppressive drugs on receptor expression. J. Immunol. 157:2813.[Abstract]
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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. 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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X.-q. Wei, M. Orchardson, J. A. Gracie, B. P. Leung, B.-m. Gao, H. Guan, W. Niedbala, G. K. Paterson, I. B. McInnes, and F. Y. Liew The Sushi Domain of Soluble IL-15 Receptor {{alpha}} Is Essential for Binding IL-15 and Inhibiting Inflammatory and Allogenic Responses In Vitro and In Vivo J. Immunol., July 1, 2001; 167(1): 277 - 282. [Abstract] [Full Text] [PDF]
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, p <
0.05 vs naive.
