вход по аккаунту



код для вставкиСкачать
Publication of the International Union Against Cancer
Publication de l’Union Internationale Contre le Cancer
Int. J. Cancer: 70, 330–334 (1997)
r 1997 Wiley-Liss, Inc.
Jacques ROBERT1,2*, Chantal GUIET1, Nicholas COHEN2 and Louis DU PASQUIER1
1Basel Institute for Immunology, CH-4005 Basel, Switzerland
2University of Rochester Medical Center, Rochester, NY 14642, USA
Major-histocompatibility-complex homozygous partially inbred adults of the ff strain of Xenopus reject transplants of
tumor cells of ff strain origin; ff tadpoles do not. Thymectomy, performed 5 days after fertilization, abrogated the
adult tumor-rejection response suggesting that in this system
tumor rejection is immunologically mediated by T cells.
Thymectomy later in larval life did not alter tumor rejection,
but it did reduce T-cell numbers. Tolerance to minorhistocompatibility(H) antigens segregating within the ff family, which was induced by grafting adult skin to metamorphosing larvae, did not affect the tumor-rejection capacity of the
tolerant adult hosts. This suggests that the ff-2 tumor expresses (a) tumor-specific antigen(s). Immunization of larvae
with tumor cells did not induce tolerance to skin grafts
transplanted during adult life. Indeed, such grafts were rejected in accelerated fashion, suggesting that memory cells
generated in the larvae persist through metamorphosis. Int. J.
Cancer, 70: 330–334, 1997.
r 1997 Wiley-Liss, Inc.
The concept that a tumor expresses antigens that can be
recognized by the cognate immune system is supported principally
by data from syngeneic murine model systems and from studies in
humans (reviewed by Boon et al., 1994; Klein, 1991). The first
clear-cut demonstration of tumor immunogenicity showed that
immunization of recipient syngeneic mice or rats with irradiated
cells from a chemically induced sarcoma of host strain origin
protected the recipient against further challenge with live tumors
(reviewed by Boon et al., 1994). The capacity to elicit protective
immunity has been extended to other types of chemically or virally
induced tumors (review by Klein, 1991) and, in a few studies, to
spontaneous tumors (Srivastava and Old, 1988). The immune
response against tumors is mainly T-cell-mediated, as shown by the
impairment of immune protection after depletion of cytotoxic killer
T cells and by the possibility of deriving autologous cytotoxic
T-cell lines from tumor tissues that can specifically kill tumor-cell
targets. Although some tumor antigens have been identified (Boon
et al., 1994), the molecular nature of those antigens that elicit a
cognate immune response is still largely unknown.
By and large, experimental models for studying tumor immunity
have been restricted to murine species. Recently, however, thymic
tumors have been observed in individuals from a cloned Xenopus
‘‘strain’’ known as LG-15 (Kobel and Du Pasquier, 1975), and in
Xenopus from a major-histocompatibility-complex(MHC) homozygous partially inbred strain known as ff (Du Pasquier and Chardonnens, 1975). Stable lymphoid cell lines derived from these tumors
have been well-characterized and display a dual T/B-cell phenotype comparable to that seen in rare mammalian lymphocytic
leukemias (Du Pasquier and Robert, 1992; Robert et al., 1994).
These cell lines provide a unique opportunity to study tumor
immunity in an ectothermic vertebrate. Cell lines derived either
from LG-15 or ff tumors (e.g., 15/0 and ff-2 respectively) will grow
after transplantation in larval recipients provided that the tumor and
host are MHC-identical (Du Pasquier and Robert, 1992; Robert et
al., 1994). Although LG-15 tumors will also grow in adult LG-15
recipients, tumors originating from ff-strain animals are rejected by
adult members of that partially inbred strain.
Tumor rejection can be abrogated by sub-lethal irradiation of the
frog host (Robert et al., 1995). Rejection capacity developed
gradually during the weeks following metamorphosis in parallel
with (i) second histogenesis observed in the thymus, (ii) surface
expression of MHC-class-II molecule by peripheral T-cells, and
(iii) recovery of T-cell-effector function such as mixed leukocyte
responses (MLR) (Robert et al., 1995). These observations are
consistent with the possibility that tumor rejection is immunologically mediated. The precipitation of surface proteins expressed
only by ff-2 cells with an ff adult anti-serum generated against ff-2
cells (Robert et al., 1995) indicates that ff-2 cells express unique
determinants. However, given that the ff strain is not fully inbred, it
is not easy to distinguish whether tumor rejection is evoked by
tumor-specific antigens or by minor-histocompatibility(H) antigens
that are still segregating within the ff family (Robert et al., 1995).
The present study was designed to obtain basic information
concerning the effector cells that mediate tumor rejection and the
nature of antigens involved in immune responses elicited by ff-2
tumor cells in mature ff adults. Our first approach involved
transplanting tumors to ff adults whose T-cell function (e.g.,
allograft rejection, MLR, cell-mediated lympholysis) had been
ablated by early thymectomy (Horton and Manning, 1972). This
procedure profoundly impaired tumor rejection by ff adult hosts,
indicating that T cells are required to protect adults against the
development of transplanted tumors. A second approach was based
on the fact that perimetamorphic, but not adult, Xenopus invariably
become tolerant of MHC-compatible minor-H-locus-disparate skin
allografts (Du Pasquier and Chardonnens, 1975). Tolerance of ff
recipients to minor-H-antigens segregating in the partially inbred ff
family was induced by grafting adult ff skin to ff larvae during the
metamorphic period. Since this allotolerant state failed to impair
the ability to reject ff-2 tumors, the T-cell anti-tumor response
appears to be directed against tumor-specific antigens. Both results
are consistent with the idea that T-cell-mediated tumor immunity is
a fundamental function of the immune system of vertebrates.
Furthermore, this Xenopus system provides a new non-mammalian
model of cancer immunology in which the ontogeny of tumor
immunity can be studied.
The Xenopus ff partially inbred strain is MHC-homozygous (ff
haplotype) and can retain fully viable ff-strain skin allografts for
more than 40 days at 20°C. LG15 (MHC haplotype a/c) isogeneic
clones have been described by Kobel and Du Pasquier (1975).
Developmental stages were determined according to the normal
tables of Nieuwkoop and Faber (1967).
Flow cytometry
Samples of 105 cells were stained with hybridoma supernatants,
followed by fluorescein-labeled goat anti-mouse Ig, before being
analyzed by flow cytometry on a FACScan. The technique and the
monoclonal antibodies (MAbs) used (TB17, anti-MHC class I;
AM20, anti-MHC class II; AM22, anti-CD8; XT-1, anti-pan T cell)
*Correspondence to: Department of Microbiology & Immunology, Box
672, University of Rochester Medical Center, 601 Elmwood Avenue,
Rochester, New York 14642, USA. Phone: (716) 275-5359. Fax: (716)
473-9573. E-mail:
Received 29 July 1996; revised 23 October 1996.
are describe elswhere (Robert et al., 1995). The anti-CD5 MAb,
2B1, is described in Jürgens et al. (1995).
Thymectomy was performed by microcautery (Horton and
Manning, 1972) between 5 and 7 days of age (stage 47) or at the
pro-metamorphic stage 58. The absence of the thymus was
confirmed by external observation of larvae and by autopsy of
adults. The immunological efficacy of thymectomy was determined
by evaluating rejection of MHC-disparate skin grafts and by
flow-cytometric analysis of peripheral-blood lymphocytes with
anti-T-cell-specific antibodies; splenic lymphocytes were also
analyzed flow-cytometrically at the time of autopsy.
Skin grafting
Skin from LG15 or ff donors was grafted to ff adults according to
published methods (Du Pasquier and Bernard, 1980). Briefly,
pieces of ventral skin (5 mm2) were inserted under the dorsal skin
of recipient animals, and 48 hr later the overlying host skin was
removed. Rejection was considered complete when all pigment
cells in the donor graft were destroyed.
Tumor-cell culture
The cell lines ff-2 and 15/0 were derived from spontaneous
thymic lymphoid tumors (Robert et al., 1994). Culture media and
culture conditions described elsewhere (Du Pasquier and Robert,
1992) were used in the present study, except that the tumor cells
were grown in Iscove DMEM basal medium (instead of L-15)
supplemented with 0.25% Xenopus serum.
Tumor-cell transplantation
Adult ff frogs were challenged with 5 3 105 ff-2 tumor cells by
s.c. injection in the dorsal lymph sac. At 20°C, solid tumors usually
develop within one month close to the site of injection (Robert et
al., 1995). To control for the viability and tumorigenicity of the ff-2
tumor cells at the time of injection, ff tadpoles were anesthetized in
0.01% tricaine methansulfonate (MS-222) and injected i.p. with
5 3 104 tumor cells aliquoted from the same population of cells that
were injected into post-metamorphic animals. Peritoneal fluid
samples were collected from these tadpoles after 2 to 3 weeks and
tumor cells in the ascites fluid were counted.
Larvae were immunized by an i.p. injection of 2 3 104 irradiated
(50 Gy cobalt source) and washed (23 in amphibian PBS) tumor
cells, and boosted one week later with 2 3 104 irradiated cells.
All experiments were performed in accordance with Swiss and
US regulations governing experimental animal welfare.
Effect of early larval thymectomy on adult tumor immunity
ff-strain larvae were thymectomized 5 to 7 days after fertilization, before colonization of the organ by precursor lymphocytes.
Pre-metamorphic tadpoles were examined under a dissecting
microscope and any larvae that had discernible thymic tissue were
discarded from the study. Seven months after metamorphosis,
thymectomized and control animals were examined for the presence of peripheral-blood T cells (Table I) and for their ability to
reject MHC-disparate skin grafts. At this age, normal ff animals are
resistant to tumor challenge (Robert et al., 1995).
Skin allografts on 12 larvally thymectomized post-metamorphic
ff frogs exhibited no signs of rejection for more than 2 months after
transplantation, and peripheral blood from these animals had
virtually no lymphocytes displaying T-cell markers (CD8, CD5).
When these animals were killed later in the protocol, their spleens
also lacked CD81 and CD51 T lymphocytes (Table I) as well as
XT-11 lymphocytes (a pan-T-cell marker; data not shown). The
CD5 homologue recognized by the 2B1 MAb is expressed by
Xenopus by thymocytes and peripheral T cells, but not by sIgM1 B
cells (Jürgens et al., 1995). The fraction of CD51 splenocytes that
did not stain with anti-CD8 MAb presumably consisted of helper T
cells (anti-Xenopus CD4 MAbs are not yet available). MHCrestricted cytotoxic and helper-T-cell responses have both been
characterized in adult Xenopus (review in Flajnik et al., 1987).
When these 12 effectively thymectomized ff animals and 15
intact sibling controls were 10 months old, they were each injected
s.c. with 5 3 105 ff-2 tumor cells. One month later, tumor
development was recorded at the site of injection in 7 of 12
thymectomized animals. In contrast, no tumors were detectable in
any of the 15 controls (Table II). All controls and the 5 tumor-free
thymectomized frogs were observed for another 6 months during
which time no tumors developed.
Since a second period of lymphocyte histogenesis occurs in the
thymus just after metamorphosis, we questioned whether this event
was important for generation of an anti-tumor response. Thus, we
thymectomized ff tadpoles at the pro-metamorphic stage 57–58.
None of these 20 late larvally thymectomized individuals developed a tumor during the 2-month period following their inoculation
with 5 3 105 ff-2 cells tumor cells at 8 months of age (Table II). In
all but one instance, a second injection of 5 3 105 ff-2 cells,
followed 2 months later by a third challenge of 1 3 106 ff-2 cells,
was similarly ineffective in producing tumors (one frog developed
a tumor 2 months after the last challenge).
To control for the viability and tumorigenicity of the ff-2 tumor
cells at the time of injection, ff tadpoles were injected ip with 5 3
104 tumor cells aliquoted from the same population of cells that
were injected into the post-metamorphic animals. Within one
month after injection, all tadpoles (n 5 5 for each injection)
developed ascites.
Although late larval thymectomy was without a significant effect
on tumor development or rejection of MHC- or minor-H-antigendisparate skin grafts, it did clearly effect a significant reduction in
Number AM22 (CD-8 like)
of frogs
Peripheral-blood lymphocytes
ff adults (8 months old)
Intact control
Early thymectomy1
Late thymectomy1
Splenic lymphocytes
ff adults (1 year-old)
Intact control
Early thymectomy1
Late thymectomy1
3.9 6 0.78
0.36 6 0.14
0.39 6 0.15
36.6 6 6.96
1.1 6 1.47
25.4 6 4.90
2B1 (CD5-like)
AM20 (class II)
10A9 (IgM)
9.8 6 3.63
0.16 6 0.09
0.22 6 0.17
18.5 6 2.42
4.05 6 2.54
4.0 6 2.58
(not done)
62.3 6 12.95 93.2 6 1.80
21.7 6 4.16
0.35 6 0.92 59.6 6 22.25 35.6 6 16.05
27.75 6 17.27 82.0 6 17.27 48.64 6 12.69
1Early thymectomy was performed 5 to 7 days after fertilization, late thymectomy at pro-metamorphic
stages 58–59.–2Two individuals displayed metastases and were not included, since ff-2 tumor cells strongly
express surface CD8 and CD5 molecules.
ff adults 8 months old
Tumor incidence after 6 months2
Intact controls
Early thymectomy3
Late thymectomy3
0/15 (0%)
7/12 (58.3%)
1/20 (5.0%)2
1With 5 3 105 ff-2 tumor cells.–26 months after a third tumor
challenge.–3Early thymectomy was performed 5 to 7 days after
fertilization, late thymectomy at pro-metamorphic stage 58.
Treatment of ff hosts
ff donor
LG15 adult skin grafts given
during metamorphosis
Tolerance induced by ff adult
skin grafts during metamorphosis4
Immunized with irradiated ff-2
cells before metamorphosis
(st 54–55)
Immunized with irradiated ff-2
cells during metamorphosis
(st 58–59)
incidence 6
months after
2nd tumor
LG15 donor challenge3
Rejection of test grafts
at 8 months of age2
no rejection
1Interval, 1 month, with 1 3 106 ff-2 tumor cells in ff recipient after
tolerance induction or immunization at larval and metamorphic stages.–
2See Table IV for detailed results of graft rejection. Skin-graft rejection
in less than 25 days.–3The viability and tumorigenicity of challenged
tumor cells was controlled by injecting sensitive younger postmetamorphic ff froglets; all (5/5) developed tumors at the site of
injection within one month.–4The extent of tolerance has been optimized by giving 2 groups of 20 ff animals skin grafts from adult ff
donors of different progeny and a third group of 20 individuals both
types of donor skin.
the number of T lymphocytes in the peripheral blood and spleen, as
determined by flow cytometry (Table I).
Effect of tolerance induction
Sharing of minor-H antigens between ff skin and ff-2 tumor cells
was suggested by the accelerated rejection of ff skin grafts by adults
that had been immunized with irradiated ff-2 tumor cells (Robert et
al., 1995). To determine whether such minor-H antigens are the
only determinants eliciting a tumor-rejection response by the adult,
tolerance of adult ff skin grafts was induced in ff animals by
grafting them with ff skin at metamorphosis. To optimize the
diversity of minor-H antigens to which animals had become
tolerant, 2 groups of 20 ff animals received grafts from adult ff
donors derived from 2 different matings, and a third group was
grafted with both types of donor skin. Tolerance was demonstrated
not only by the long-term survival of these grafts but also by the
inability of the hosts to reject a skin graft from a third-party ff donor
when they were adults. This tolerance was specific, since the hosts
were capable of acutely rejecting MHC-disparate grafts from an
LG15 donor (Table IV).
None of the 60 ff adults (8 months old) that were tolerant of ff
skin developed a tumor within 6 months after receiving 2 injections
of ff-2 tumor cells separated by one month (Table III). Since all
(5/5) younger non-tolerant control ff animals that had been injected
with an aliquot of the same ff-2 cells developed tumors within a
month after inoculation, the preparation was tumorigenic. Furthermore, tumor cells injected in the 5 ff animals that were tolerant of 2
sets of adult ff skin grafts (Table IV), failed to produce tumors or to
induce rejection of the tolerated ff skins within a 2-month period.
Individual mean survival
times of skin grafts1
Treatment of adult ff hosts
Untreated control
Thymectomized at
5–7 days old
Thymectomized at
stage 58
Adult LG15 skin
grafts at pro-metamorphic stage 58
Tolerance induced
by adult ff skin
grafts at pro-metamorphic stages
Immunized with
irradiated ff-2
tumor cells before
(stage 54)
Immunized with
irradiated ff-2
tumor cells at prometamorphic
stage 58–59
from LG15(a/c) donors
from ff donors
(MHC 1 minor-Hlocus-disparate)
18, 22, 24
(21.3 6 3.06)
.60, .60, .60
18, 18, 20
(18.7 6 1.15)
53, 53, 53, 55
(53.7 6 1.15)
20, 20, 20, 25
(21.25 6 2.50)
49, 53, 57, .60
(53 6 4.0)
18, 20, 24, 25
(21.8 6 2.86)
.80, .80, .80,
.80, (.80)
19, 20, 22, 25
(21.5 6 2.65)
22, 25, 25, 29
(25.25 6 2.87)
18, 20, 25
(19 6 1.41)
22, 25, 25
(24.25 6 1.5)
49, 49, 52
(50 6 1.73)
at 22°C; mean 6 SD in parentheses; ND, not done.
In another experiment, we attempted to induce tolerance to ff-2
tumor cells by priming pre-metamorphic stage-52 hosts or at
peri-metamorphic stage-58-59 hosts with irradiated ff-2 cells. In
neither instance did this priming affect the adults’ ability to reject
subsequently transplanted ff-2 tumor cells. That is, none of the
adult ff animals primed in larval life and challenged twice with ff-2
tumor cells had developed a tumor by 6 months after the second
challenge. Furthermore, priming of ff recipients with irradiated ff-2
cells at either larval stage did not impair their capacity to reject ff
skin grafts. Indeed, rejection of such skin grafts was sub-acute (25
days). This timing contrasts sharply with the much more chronic
rejection of ff skin by adult ff animals that had not been primed with
tumor cells during larval life. In other words, it appears that
injecting ff larvae with ff tumor cells elicits a second-set rejection of
skin grafts, whereas grafting larvae with skin induces long-lasting
Nature of adult anti-tumor effector cells
Data revealing the development of the ability of ff adults to reject
ff-2 tumors during metamorphosis and the abrogation of this
response by sub-lethal irradiation have suggested that tumor
rejection was immunologically mediated (Robert et al., 1995). In
the present study, thymectomy of very young tadpoles before initial
colonization of the thymus by embryonic stem cells (Horton and
Manning, 1972) provided a useful way to investigate the in vivo
requirement for T cells in the rejection of ff-2 tumor cells by ff
adults. Indeed, thymectomy markedly impaired host resistance to
tumor development after ff-2-tumor-cell transplantation. Thymectomy of larval Xenopus abrogates T-cell functions in adult life, e.g.,
the IgY-antibody response, allograft rejection, and MLR and PHA
responsiveness (review in Flajnik et al., 1987). Other immune
functions such as IgM-antibody response against T-dependent or
T-independent antigens, remain unimpaired (Flajnik et al., 1987).
At the phenotypic level, T-cell populations expressing surface
pan-T-cell, CD8 or CD5 markers are virtually absent from cells in
the peripheral blood and spleens of thymectomized animals
(Jürgens et al., 1995; and Table I). The impairment of tumor
rejection in ff adults thymectomized during the first week of life
strongly suggests, therefore, that as in mammals, the immune
response elicited against tumor cells is T-cell-mediated.
Some thymectomized recipients of tumor cells did not develop
tumors. Whether this reflects activity of residual T cells and/or
natural-killer(NK) cells is unknown. On the other hand, the early
education of T cells in the thymus in the absence of MHC-class-I
expression (review in Flajnik et al., 1987; Flajnik and Du Pasquier,
1990) could be insufficient to allow for full protection in tadpoles;
additional maturation of anti-tumor effectors must occur during
metamorphosis. The thymus environment, however, does not
appear to be required for this metamorphic maturation, since
thymectomy performed at the beginning of metamorphosis failed
to impair tumor resistance during adult life. This suggests that the
second wave of stem-cell immigration in the thymus (Turpen and
Smith, 1989) following the loss of about 90% of larval thymocytes
(review in Flajnik et al., 1987) is not the major source of mature
anti-tumor effectors. It has been shown in mice and humans that the
generation of a potent cytotoxic response against tumors or virus
depends on efficient antigen presentation by a macrophage sub-set
(Suto and Srivastava, 1995) or by dendritic cells (Celluzzi et al.,
1996), as well as on cytokine release. On the assumption of similar
involvement in Xenopus, it may be speculated that some of these
elements are still differentiating during metamorphosis. It is
known, for example, that cells with characteristics of mammalian
Langerhans cells first appear in Xenopus skin after metamorphosis
(Flajnik and Du Pasquier, 1990). Such cells, or new macrophage
populations that differentiate during metamorphosis, may promote
a better immune response by more efficiently presenting antigen
and/or by producing cytokines. Alternatively, other types of
effectors, such as NK cells or gamma/delta T cells, may develop
during metamorphosis and comprise a parallel anti-tumor defense
system. There is some indirect evidence of NK-cell activity in
Xenopus (Horton et al., 1996) but there is no information whatsoever about gamma/delta T cells in this species.
Nature of antigens
Since the ff family is only partially inbred (i.e., adults reject skin
grafts chronically), rejection of ff-2 tumor cells could result from an
immune response directed against minor-H antigens that are
segregating in the family. Indeed, the accelerated rejection of skin
grafts by ff adults that had been immunized with ff-2 tumor cells
implies sharing of minor-H antigens between ff skin and ff-2 tumor
cells (Robert et al., 1995). However, the fact that tumor development was never observed in any of the numerous ff adults
transplanted with ff-2 tumor suggests rather rapid and efficient
rejection, which is uncharacteristic of that elicited by minor-H
antigens (Robert et al., 1994, 1995). In addition, a tumor-specific
product has been detected by immunoprecipitation of tumor cells
with ff adult anti-serum generated against ff-2 cells (Robert et al.,
1995), indicating that ff-2 tumor cells do express unique determinants.
To further characterize the tumor antigens recognized by adults,
we took advantage of the fact that an antigenically specific and
long-lasting tolerance can be induced to minor-H antigens (Du
Pasquier and Chardonnens, 1975) and sometimes to MHC antigens
by skin grafts transplanted to larvae at metamorphic stages.
Establishment of this tolerance is thymus-dependent (Barlow and
Cohen, 1983). The induction of tolerance in ff animals toward ff
minor-H-antigens did not affect the capacity of adults to reject ff
tumors, suggesting that ff-2 tumor cells express additional antigens
(i.e., tumor antigens) capable of eliciting an immune response.
Immunization at pre- or pro-metamorphic stages with irradiated
ff-2 cells did not impair tumor rejection by adults. Furthermore, it
did not induce tolerance to minor antigens shared between ff skin
and ff-2 tumor cells. On the contrary, ff animals that had been
immunized with ff-2 tumor cells at pre- or pro-metamorphic stages
acutely rejected ff skin grafts transplanted during adult life,
suggesting that memory persisted through metamorphosis. The
generation and persistence of tumor-specific memory through
metamorphosis by immunization at larval stages was already
suggested by the significant protection to tumor transplantation (a
fraction of transplanted hosts did not develop tumors) obtained just
after the end of metamorphosis, when very young frogs are usually
sensitive to development of transplanted tumor (Robert et al.,
1995). The amount and/or the preparation of immunogen (presence
or absence of adjuvant) injected or the route by which it was
introduced could have been inadequate to evoke tolerance, as has
been recently demonstrated in tolerance induction of mouse
neonates (Ridge et al., 1996). Nevertheless, memory detected after
metamorphosis implies that larval lymphocytes, most likely T
lymphocytes, can recognize tumor determinants; additional factors,
however, must mature during metamorphosis to provide effective
tumor immunity.
In summary, current data support the proposition that Xenopus,
like mice and rats, are capable of mounting a T-cell-mediated
tumor-rejection response directed against tumor-associated antigens. Further analysis of each of these facets of tumor immunity are
in progress.
We wish to thank Dr. E. Lord and Dr. C. Steinberg for helpful
suggestions and critical reading of the manuscript. The Basel
Institute for Immunology was founded and is supported by F.
Hoffman La Roche, Basel, Switzerland. Research at the University
of Rochester was supported by USPHS HD-07901.
BARLOW, E.H. and COHEN, N., The thymus dependency of transplantation
allotolerance in the metamorphosing frog Xenopus laevis. Transplantation,
35, 612–619 (1983).
VAN PEL, A., Tumor antigens recognized by T lymphocytes. Ann. Rev.
Immunol., 12, 337–365 (1994).
L.D., Peptide-pulsed dendritic cells induce antigen-specific CTL-mediated
protective tumor immunity. J. exp. Med., 183, 283–287 (1996).
DU PASQUIER, L. and BERNARD, C.C., Active suppression of the allogeneic
histocompatibility reactions during the metamorphosis of the clawed toad
Xenopus. Differentiation, 16, 1–7 (1980).
DU PASQUIER, L. and CHARDONNENS, X., Genetic aspects of the tolerance to
allografts induced at metamorphosis in the toad Xenopus laevis. Immunogenetics, 2, 431–440 (1975).
DU PASQUIER, L. and ROBERT, J., In vitro growth of thymic tumor cell lines
from Xenopus. Devel. Immunol., 2, 295–307 (1992).
FLAJNIK, M.F. and DU PASQUIER, L., The major histocompatibility complex
of frogs. Immunol. Rev., 113, 47–63 (1990).
FLAJNIK, M.F., HSU, E., KAUFMAN, J. and DU PASQUIER, L., Changes in the
immune system during metamorphosis of Xenopus. Immunol. Today, 8,
58–63 (1987).
HORTON, J.D., HORTON, T.L. and RITCHIE, P., Immune system of Xenopus:
T-cell biology. In: R.C. Tinsley and H.R. Kobel (eds.), The biology of
Xenopus. Symposium of the Zoological Society of London, pp. 279–299,
Oxford University Press, Oxford (1996).
HORTON, J. and MANNING, M.J., Response to skin allografts in Xenopus
laevis following thymectomy at early stages of lymphoid-organ maturation.
Transplantation, 14, 141–154 (1972).
J.D. and COOPER, M.D., Identification of a candidate CD5 homologue in the
amphibian Xenopus laevis. J. Immunol., 155, 4218–4223 (1995).
KLEIN, G., Immunovirology of transforming viruses. Curr. Opin. Immunol.,
3, 665–673 (1991).
KOBEL, H.R. and DU PASQUIER, L., Production of large clones of histocompatible, fully identical clawed toads (Xenopus). Immunogenetics, 2, 7–91
NIEUWKOOP, P.D. and FABER, J., Normal table of Xenopus laevis (Daudin).
North Holland, Amsterdam (1967).
RIDGE, J.P., EPHRAIM, J.F. and MATZINGER, P., Neonatal tolerance revisited:
turning on newborn T cells with dendritic cells. Science, 271, 1723–1726
ROBERT, J., GUIET, C. and DU PASQUIER, L., Lymphoid tumors of Xenopus
laevis with different capacities for growth in larvae and adults. Dev.
Immunol., 3, 297–307 (1994).
ROBERT, J., GUIET, C. and DU PASQUIER, L., Ontogeny of the allo-immune
response against transplanted tumor in Xenopus laevis. Differentiation, 59,
135–144 (1995).
SRIVASTAVA, P.K. and OLD, L.J., Individually distinct transplantation
antigens of chemically induced mouse tumors. Immunol. Today, 9, 78–83
SUTO, R. and SRIVASTAVA, P.K., A mechanism for the specific immunogenicity of heat-shock-protein-chaperoned peptides. Science, 269, 1585–1588
TURPEN, J.B. and SMITH, P.B., Precursor immigration and thymocyte
succession during larval development and metamorphosis in Xenopus. J.
Immunol., 142, 41–47 (1989).
Без категории
Размер файла
58 Кб
Пожаловаться на содержимое документа