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Divisions of
* Immunology and Rheumatology and
Bone Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305; and
Core Research for Engineering, Science, and Technology and Department of Molecular Immunology, Chiba University Graduate School of Medicine, Chiba, Japan
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Abstract |
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 Top Abstract IntroductionMaterial and MethodsResultsDiscussionReferences |
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281-/- hosts with markedly reduced NK T
cells were used instead of wild-type hosts, then the conditioning
regimen failed to induce tolerance to the heart allografts despite the
development of mixed chimerism. Tolerance could be restored to the
CD1-/- hosts by infusing enriched T cells from the bone
marrow of wild-type mice containing CD1-reactive T cells but not from
CD1-/- host-type mice. Tolerance could not be induced in
either IL-4-/- or IL-10-/- hosts given the
regimen despite the development of chimerism and clonal deletion of
host T cells to donor MHC-Ags in the IL-10-/- hosts. We
conclude that immune tolerance to bone marrow transplants involves
clonal deletion, and tolerance to heart allografts in this model also
involves regulatory CD1-reactive NK T cells. |
Introduction |
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TopAbstractIntroductionMaterial and MethodsResultsDiscussionReferences |
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The above studies may have important implications for clinical transplantation and suggest that acceptance of bone marrow transplants will not necessarily result in the acceptance of other donor tissue transplants due to either tissue-specific transplantation Ags or to differences in the immunogenicity or susceptibility of different tissues to immune rejection. However, there is considerable variability of skin and s.c. myocardial graft acceptance in mixed chimeras depending upon the host-conditioning regimen that is used, the level of donor T cell chimerism achieved, and the time interval between transplantation of the donor bone marrow/hemopoietic progenitor cells and the organ graft (2, 3, 11, 12). In some studies, there is uniform acceptance of these organ grafts (2, 3, 11) and in others the majority of the organ grafts are rejected despite high levels of chimerism (5, 12).
The object of the current study in mice was to elucidate the mechanisms by which mixed chimeras accept or reject s.c. heart grafts using a completely posttransplant-conditioning regimen in which donor bone marrow cells are infused after the transplantation of the heart graft. This posttransplant-conditioning regimen consisting of total lymphoid irradiation (TLI)3 and anti-thymocyte globulin has been previously shown to induce mixed chimerism and tolerance to vascularized heart grafts in completely MHC-mismatched rats (13, 14). A key advantage of the posttransplant regimen is that it can be applied to human cadaver organ transplantation. Because the timing of the availability of cadaver organs cannot be predicted or planned, pretransplant-conditioning regimens cannot be used in the clinical setting. In addition, tolerance induction using the TLI and anti-thymocyte globulin regimen is facilitated by the use of the calcineurin inhibitor, cyclosporine, a frequently used immunosuppressive drug in clinical organ transplantation (14).
We found that the different parts of the host-conditioning regimen, the makeup of the residual host T cell subsets, and host secretion of IL-4 and IL-10 were critical in determining whether tolerance to both the bone marrow and heart grafts was induced. We found a marked increase in the fraction of host T cells that expressed NK cell markers in wild-type recipients, and that the latter T cells, as well as host secretion of IL-4 and IL-10, were required for heart graft acceptance even in mixed chimeras with clonal deletion of host T cells. Thus, acceptance of marrow transplants and associated clonal deletion does not ensure the acceptance of organ grafts, and additional mechanisms of tolerance such as immune regulation are required for organ graft acceptance in this model.
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Material and Methods |
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TopAbstractIntroductionMaterial and MethodsResultsDiscussionReferences |
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Wild-type BALB/c (H-2d), C57BL/6 (H-2b),
and C3H/He(H-2k) mice were purchased from the Department of
Comparative Medicine, Stanford University (Stanford, CA). Male BALB/c
IL-4-/- (BALB/c-IL-4tm2Nnt), BALB/c
IFN-
-/- (BALB/c IFN-tm1Ts), C57BL/6
IL-4-/- (C57BL/6J-IL-4tm1Cgn), and C57BL/6
IL-10-/- (C57BL/6J-IL-10tm1Cgn)
mice were purchased from The Jackson Laboratory (Bar Harbor, ME).
Development of CD1-/- founder mice was described
previously (15) and those in the current study were
maintained on the BALB/c background and kindly provided by Drs. M.
A. Exley and S. P. Balk (Harvard University,
Boston, MA), and have been backcrossed for more than 10 generations.
J281-/- founder mice were backcrossed for
nine generations with C57BL/6 mice (16).
Cardiac transplantation technique and monitoring
Neonatal hearts were transplanted into a pouch in the ear pinna according to the procedure described by Trager et al. (17), on day 0. Heart grafts were monitored daily for visible contractions and survival was based on the time interval until contractions stopped.
Irradiation
TLI was delivered to the abdomen, lymph nodes, thymus, and spleen with shielding of the skull, lungs, limbs, pelvis, and tail as described previously (2).
Rabbit anti-thymocyte serum (ATS)
Rabbit ATS was purchased from Accurate Chemical and Scientific (Westbury, NY). BALB/c recipients were injected i.p. with 0.05 ml of ATS in 0.5 ml of saline on days 0, 2, 4, 8, and 10 in combination with 10 doses of TLI, or on day 0 in combination with 17 doses of TLI.
Antibodies
Anti-Gr-1-biotin and anti-Mac-1-biotin were purchased from
Caltag Laboratories (Burlingame, CA). Anti-H-2Kb-FITC,
anti-H-2Kb-PE, anti-H-2Kd-FITC,
anti-H-2Kd-PE, anti-Thy1.2-PE, anti-B220-PE,
anti-DX5-biotin, anti-NK1.1-PE, anti-TCR
-APC,
anti-CD3-APC, anti-V2, V3,
V4, V5, V6,
V8, V9, V11, &
V12-FITC, and anti-CD16/32 mAb to block
FcR-II/III were purchased from BD PharMingen (San Diego, CA).
Streptavidin-PE was obtained from Southern Biotechnology Associates
(Birmingham, AL). CD1 tetramer staining reagent loaded with
-galactosylceramide was kindly provided by Dr. M. Kronenberg (La
Jolla Institute for Allergy and Immunology, La Jolla, CA).
Flow cytometric analysis and sorting
Single cell suspensions of blood lysed with ammonium chloride
buffer and spleen cells were harvested, stained, and analyzed by flow
cytometry as previously described (18).
TCR+ T cells from the bone marrow were enriched by
immunomagnetic-beads, stained, and sorted as before
(18).
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Results |
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TopAbstractIntroductionMaterial and MethodsResultsDiscussionReferences |
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To achieve long-term cardiac tissue allograft acceptance and mixed
chimerism using BALB/c (H-2d) host and C57BL/6
(H-2b) donor mice, we conditioned hosts with a
nonmyeloblative posttransplantation regimen of fractionated irradiation
of the spleen, lymph nodes, and thymus with marrow shielding (TLI),
depletive anti-T cell Abs, and an infusion of donor bone marrow
cells that had been reported to tolerize MHC-mismatched rats (13, 14). Host mice received neonatal donor heart allografts
transplanted to the ear pinnae on day 0, 5 doses of ATS i.p. starting
on day 0, 10 doses of TLI (240 cGy each) between days 1 and 14, and an
i.v. injection of donor marrow cells (50 x 106) on
day 15. Table I
shows that all hosts
given the complete regimen became mixed chimeras, and 11 of 13 accepted
their heart grafts as judged by continued graft contractions for >100
days. Untreated control hosts rejected all their grafts by 17 days
(Table I).
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). Surprisingly, mixed chimerism developed in the group
given ATS, TLI, and marrow cells, and in the group given TLI and marrow
cells without ATS despite the rejection of seven of eight heart
allografts in the latter group (Table I). Multilineage chimerism was
documented in both groups by immunofluorescent staining of white blood
cells for the donor MHC (H-2Kb) marker vs T cell (Thy-1.2),
B cell (B220), and granulocyte and macrophage (Gr-1 and Mac-1) markers
28 days after the bone marrow cell injection. In the representative
analyses shown in Fig. 1, hosts given the
complete regimen of TLI, ATS, and donor bone marrow cells had 4.2%
donor T cells, 54.6% donor B cells, and 14.2% donor granulocytes and
monocytes among white blood cells. When gated donor T cells
(H-2Kb+Thy1.2+) were analyzed for the presence
of NK T cells, <1% were NK1.1+ (data not shown). Similar
percentages of donor T and B cells (6.9 and 74.2%) and granulocytes
and monocytes (14.9%) were found in hosts given the TLI and marrow
cells without ATS (Fig. 1). Levels of chimerism were stable when
reanalyzed at 100 days (data not shown). Hosts in the group given ATS
and donor marrow cells had <0.1% donor-type cells in all lineages
tested.
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Role of CD1-reactive T cells and cytokines in heart graft acceptance
Recent studies showed that the combined regimen of TLI and ATS
administered to BALB/c or C57BL/6 mice altered the balance of
residual T cell subsets such that the minor (
2%) subset of T
cells expressing NK cell markers,
DX5+TCR+, and
NK1.1+TCR+ T cells, became the
majority of all T cells (19). These unusual T cell subsets
were regulatory and prevented graft-vs-host disease (19).
The role of CD1-reactive DX5+TCR+ and
NK1.1+TCR+ cells in long-term graft
acceptance in the current study was examined by comparing graft
survival in wild-type, CD1-/-, or
J281-/- hosts given the complete
host-conditioning regimen. Previous studies showed peripheral
NK1.1+ T cells are markedly reduced in CD1-/-
and J281-/- mice as compared to wild-type
mice due to either the lack of positive selection by CD1 or the
inability to generate the invariant CD-1 reactive
V14J281 TCR chain, respectively
(20, 21, 22). In addition, our studies of bone marrow
TCR+ T cells showed that about 20% of the latter T
cells are NK T cells in wild-type mice, and about 4% are NK T cells in
CD1-/- mice (21). Less than 1% of bone
marrow T cells that are CD1-reactive as judged by staining with a
CD1-tetramer reagent loaded with -galactosylceramide are present in
CD1-/- mice (data not shown).
Immunofluorescent staining and two-color flow cytometric analysis of
spleen cells for DX5 vs TCR or NK1.1 vs TCR markers was
performed in BALB/c and C57BL/6 wild-type mice before and immediately
after treatment with the combined TLI and ATS regimen without organ and
marrow transplants (Fig. 2A).
Before treatment the DX5+ and NK1.1+ T cells
accounted for between 3.6 and 3.7% of all T cells in wild-type hosts
and no discrete population of cells was observed (enclosed in boxes in
Fig. 2A). At that time point, the mean ± SD percentage
of TCR+ T cells was 34 ± 4% in four wild-type
BALB/c mice and 26 ± 5% in five wild-type C57BL/6 mice. After
TLI and ATS, the mean percentage of T cells in wild-type mice was
reduced to 0.4 ± 0.1 and 0.6 ± 0.5%, respectively. The
percentage of DX5+ and NK1.1+ T cells amongst
all residual T cells rose at least 10-fold to about 54 and 38%,
respectively, but the absolute numbers of DX5+ and
NK1.1+ T cells were slightly reduced as compared to
pretreatment levels (19). The rise in the percentage of
DX5+ or NK1.1+ T cells amongst all T cells was
attenuated after treatment of CD1-/- BALB/c mice
(10%) and of J281-/- C57BL/6 mice
(5%) as compared to that of the wild-type mice (Fig. 2A). The CD1 reactivity of the DX5+ and
NK1.1+ T cells in wild-type BALB/c and C57BL/6 hosts that
received TLI and ATS was confirmed by >90% staining positively with
CD1 tetramers loaded with -galactosylceramide (data not shown).
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B). Since previous studies (15, 23) indicated that the regulatory functions of
NK1.1+ T cells are mediated at least in part by IL-4 or
IFN-, the survival of heart allografts was compared in
IL-4-/-, IFN--/-, and wild-type BALB/c
hosts given the complete conditioning regimen. Fig. 2B shows
that all heart grafts survived >100 days in the
IFN--/- group, but that only about one-third of grafts
survived during the same period in the IL-4-/- hosts
(p < 0.01 IL-4-/- vs
IFN--/-; p < 0.01
IL-4-/- vs wild-type). Untreated IFN--/-
hosts rejected heart grafts within the same time interval as untreated
wild-type hosts (data not shown).
Table II shows that the use of
CD1-/- instead of wild-type BALB/c hosts had an impact on
the development of chimerism, since three of six CD1-/-
hosts had 1% or less donor-type cells amongst white blood cells (mean
23%). All wild-type hosts had at least 51% donor-type cells (mean
59%) (p < 0.001 by Student’s t
test). However, remaining chimeric hosts in the CD1-/-
group (23–50% donor-type cells) still rejected their heart allografts
despite the complete conditioning regimen. Similarly, six of nine hosts
in the IL-4-/- group rejected their heart grafts, and
five of six of the latter were chimeras (Table II). Thus, deficiency in
CD1 and IL-4 genes had a more robust effect on the rejection of
heart as compared to bone marrow allografts.
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+ T cells. To reconstitute these T cells in the
CD1-/- hosts, we injected them with 0.5 x
106 sorted TCR+ T cells from the bone
marrow of wild-type BALB/c mice. Sorted T cells had 
95% purity as
judged by reanalysis. Amongst gated T cells in a wild-type BALB/c bone
marrow sample not used for sorting, there were 4.9% CD1-reactive cells
as judged by staining with the CD1-tetramer reagent, and there were
<0.1% in a CD1-/- marrow sample. Previous studies
showed that NK1.1+ T cells depleted from the periphery can
be replaced within 48 hr from dividing precursors in the marrow
(24). Because the marrow is shielded during TLI,
proliferating cells in the marrow are protected from irradiation. To
reduce the possibility that ATS injected into hosts would kill the
transferred bone marrow T cells, the conditioning regimen was changed
to include only 1 dose of ATS on day 0, and 17 instead of 10 doses of
TLI. The BALB/c marrow T cells were injected after 8 doses of TLI. Fig. 2C shows that wild-type BALB/c mice given the regimen of 1
dose of ATS, and 17 doses of TLI and an injection of donor marrow cells
all accepted donor C57BL/6 heart grafts for >100 days. These long-term
hosts developed immune tolerance, since four hosts given third-party
C3H/He heart grafts rejected them within 8–22 days.
CD1-/- BALB/c hosts all rejected the donor C57BL/6 grafts
by day 69 (p < 0.001), but
CD1-/- hosts given the sorted wild-type marrow
TCR+ T cells all accepted their grafts for at least
100 days (Fig. 2C). A control group of CD1-/-
hosts given sorted marrow TCR+ T cells from
CD1-/- BALB/c mice rejected all grafts by day 45. Thus, T
cells from wild-type, but not CD1-/- BALB/c, mice
prevented the rejection of heart grafts in CD1-/-
hosts.
The TCR chain of most peripheral CD1-reactive NK1.1+ T
cells is derived from an invariant rearrangement of V14
and J281 gene segments (25, 26). To
determine whether CD1-reactive cells that regulate heart allograft
rejection express the invariant TCR chain, the donor and host mouse
strains were reversed so that wild-type and
J281-/- C57BL/6 host mice could be
compared for their ability to reject BALB/c heart grafts. The C57BL/6
hosts were conditioned with five doses of ATS, 10 treatments of TLI,
and an infusion of 50 x 106 BALB/c marrow cells as
before. Fig. 2D shows that the C57BL/6 wild-type hosts
accepted all BALB/c heart grafts for at least 100 days, and Table II
shows that all hosts were mixed chimeras. In contrast, four of seven
J281-/- hosts rejected their grafts within
50 days (p < 0.0001) (Fig. 2D). All
of the latter hosts were mixed chimeras with between 70 and 78%
donor-type cells amongst white blood cells (Table II). The more
complete loss of tolerance in the CD1-/- as compared to
the J281-/- hosts may be due to the
presence of CD1-reactive T cells in the latter mice that do not express
the V14-J281 invariant TCR chain
(27). We also compared the ability of
IL-4-/- and IL-10-/- C57BL/6 hosts with
that of wild-type C57BL/6 hosts given the complete conditioning regimen
to accept BALB/c heart grafts. The IL-10-/- hosts
rejected all heart grafts by day 65, and four of six heart grafts were
rejected by day 55 by the IL-4-/- hosts (Fig. 2D). The graft survival in the IL-10-/- and
IL-4-/- hosts was significantly reduced
(p < 0.0001 and p < 0.01,
respectively) as compared to wild-type mice. All of the gene-deficient
hosts were mixed chimeras (Table II).
Rejection of second heart grafts in IL-10-/- chimeras with clonal deletion
The development of immune tolerance by host T cells to donor MHC
Ags in mixed chimeras has been shown to be due to clonal deletion
(28, 29). It was possible that the process of tolerance
and clonal deletion in mixed chimeras that rejected heart grafts
required several weeks, and that rejection occurred before clonal
deletion to donor MHC Ags was complete. This hypothesis was tested by
studying IL-10-/- chimeric hosts that rejected heart
grafts. Six of these hosts received a second donor (BALB/c) heart graft
at day 42 (after all first heart grafts had been rejected). All of
these hosts had at least 68% donor-type cells amongst white blood
cells at day 63 (Table II).
All second heart grafts were rejected within 10 to 28 days (Table III). Chimerism was tested 21 days after
the second heart transplantation, and remained in the range of
74–80% donor-type cells (Table III). Chimeras that rejected second
heart grafts were tested for clonal deletion of host T cells by
staining the spleen cells for the host-type MHC marker
(H-2Kb) vs CD3 and a panel of V receptors.
Gated host T cells (H-2Kb+CD3+) were analyzed
for the percentage of V2, 3, 4, 5, 6, 8, 9, 11, and 12
cells. Because the percentage of the nondeleted V8 T
cells amongst all T cells can vary from group to group, analysis of
deleted versus nondeleted V subsets was measured as a
ratio of Vn:V8 T cells. Table IV shows that in the control untreated
BALB/c spleen, V3, V5,
V11, and V12 T cells are deleted (ratio
<0.10) as compared to C57BL/6 splenic T cells as judged by the reduced
ratios of these V receptors to that of the nondeleted
V8 receptor. The ratios of the V2,
V4, V6, and V9 receptors
were similar in the two strains. The gated host-type (C57BL/6) T cells
in the IL-10-/- chimeras showed significant reductions in
the ratios for the V3, V5,
V11, and V12 receptors
(p < 0.05) as compared to untreated wild-type
C57BL/6 mice. Ratios for V2, V4,
V6, and V9 were not significantly
different (p > 0.1). Similar reductions of the
ratios of V3, V5, V11, and
V12 were found in the C57BL/6 wild-type chimeras that
had accepted the heart grafts (Table IV). No significant reductions
were measured for V2, V4,
V6 T cells (p > 0.05). There
was a significant reduction (p < 0.05) in the
ratio of V9 cells in the latter mice as compared to
C57BL/6 wild-type mice and the IL-10-/- chimeras, but the
ratios differed by <2-fold; in contrast, the ratios of deleted
V3, 5, and 11 T cells were reduced by at least 5-fold as
compared to wild-type mice. Thus, second heart grafts were rejected by
the IL-10-/- chimeras despite clonal deletion.
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Discussion |
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TopAbstractIntroductionMaterial and MethodsResultsDiscussionReferences |
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We analyzed the role of residual host NK1.1+ and/or
DX5+ T cells in the development of tolerance to the heart
grafts. NK1.1+ T and DX5+ T cells are markedly
increased in hosts given TLI, but do not increase significantly after
sublethal total body irradiation (19). More than 90% of
these C57BL/6 and BALB/c host T cells were reactive to CD1 and
expressed the NK T cell invariant TCR chain as judged by positive
staining with a CD1 tetramer loaded with the -galactosylceramide
ligand (data not shown). NK1.1+ T cells have been shown to
facilitate tolerance to tissue allografts after costimulatory blockade
(23), prevent graft-vs-host disease (18, 19),
and facilitate tolerance to heterologous proteins in the anterior
chamber autoimmune eye disease model (30). The critical
role of the host NK1.1+ and DX5+ T cells in the
current study was shown by the loss of tolerance to heart grafts in the
CD1-/-- or J281-/--deficient
hosts as compared to wild-type hosts, and the ability to reconstitute
long-term heart graft acceptance by the transfer of wild-type host bone
marrow T cells containing CD1--reactive T cells, but not
by the transfer of CD1-/- marrow T cells. Although the
C57BL/6 donor marrow cells contained about the same level of
CD1-tetramer+ T cells as the BALB/c marrow cells (data not
shown), the CD1-reactive T cells contained in the donor marrow
(injected after TLI) did not allow for graft acceptance, and donor-type
NK T cells could not be detected in the spleen at day 28 after
transplantation. Injection of host marrow T cells was done during
rather than after TLI. Long-term heart graft acceptance was markedly
reduced in the IL-4-/- and IL-10-/-, but
not in the IFN--/-, hosts. The results suggest that
secretion of both IL-4-/- and IL-10-/- by
CD1-reactive NK T cells and/or conventional T cells in the hosts
facilitates tolerance induction to the heart grafts. We did not
demonstrate that the IL-4 and IL-10 were secreted by the CD1-reactive
NK T cells in the current study, but our previous studies showed that
the regulatory function of enriched NK T cells was lost when obtained
from IL-4-/- mice (18). Thus, the latter
cells are the likely source of the cytokines required for tolerance.
However, the NK T cells may polarize other host or donor T cells toward
a Th2-immune response. Thus, tolerance may require IL-4 and/or IL-10
secretion by both NK and non-NK T cells. Determination of the
contribution of T cell subsets to cytokine secretion is the subject of
a separate study. Despite the failure of heart graft acceptance,
IL-10-/- hosts developed uniform mixed chimerism
associated with clonal deletion of C57BL/6 host T cells. Yet, second
BALB/c heart grafts were rejected within 28 days, despite the high
levels of chimerism measured at 21 days.
The clonal deletion pattern of the host V T cell subsets
indicates that the C57BL/6 (H-2b) host cells have lost
reactivity to donor (H-2d) MHC Ags. Previous studies of
mixed chimeras have shown that negative selection of host T cells is
due to the presence of donor-derived dendritic cells in the host thymus
(28). However, the ability of the chimeric hosts to
reject the heart, but not bone marrow, grafts indicated that
tissue-specific minor, non-MHC, transplantation Ags are likely
expressed by the donor heart cells but are not expressed by the donor
bone marrow cells or their progeny. Presumably neither host nor
donor-derived dendritic cells in the thymus express these
heart-specific minor Ags which are the likely targets of rejection in
some chimeric hosts. Reactivity to the latter Ags and associated
rejection appears to be prevented by the regulatory cells and the
secretion of IL-4 and IL-10.
In conclusion, clonal deletion of host T cells to donor MHC Ags was insufficient to achieve tolerance to the heart grafts. Other tolerance mechanisms were involved that included the contribution of regulatory CD1-reactive T cells with NK cell markers that secrete high levels of IL-4 and IL-10. We previously called these regulatory T cells from TLI-treated mice "natural suppressor" cells (31). The results impact on clinical organ transplantation and suggest that acceptance of bone marrow transplants from an organ donor and associated clonal deletion will not result in uniform organ graft acceptance unless additional mechanisms of immune tolerance are in place.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Samuel Strober, Division of Immunology and Rheumatology, Stanford University School of Medicine, Center for Clinical Science Research Building, MC:5166, 300 Pasteur Drive, Stanford, CA 94305-5166. E-mail address: sstrober{at}stanford.edu
3 Abbreviations used in this paper: TLI, total lymphoid irradiation; ATS, anti-thymocyte serum.
Received for publication May 20, 2002. Accepted for publication September 5, 2002.
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References |
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TopAbstractIntroductionMaterial and MethodsResultsDiscussionReferences |
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14 NK T cells in IL-12-mediated rejection of tumors. Science 278:1623. or DX5+TCR+ T cells in mice conditioned with fractionated lymphoid irradiation protects against graft versus host disease. J. Immunol. 167:2087.14 NK T cells in IL-12-mediated rejection of tumors. Science 278:1623.
14+ TCR chain in NK1.1+ T cell populations. Int. Immunol. 7:1157.
mouse bone marrow chimeras. Transplantation 65:1216.[Medline]
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