| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
CUTTING EDGE |
Laboratory of Immunology, Division of Hematologic Products, Center for Biologics Evaluation Research and Review, U.S. Food and Drug Administration, Bethesda, MD
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
|---|
During pregnancy, the fetus represents a true allograft because of the expression of paternal Ags, yet this allograft is not normally rejected by the maternal immune system. Although the reasons for this are still not understood, this unique situation nevertheless provides a physiologic system to evaluate peripheral tolerance in which the maternal immune system is challenged with relatively rare Ags not previously encountered in the thymus. Our experiments were initiated to address the fate of fetal-reactive peripheral T cells in the maternal immune system during pregnancy. Because of the low precursor frequency of specific T cells for any one Ag, we have used transgenic mice expressing a TCR specific for H-Y, which provides an easily followable T cell population specific for an Ag expressed on some fetuses. In this study, we demonstrate that T cells specific for fetal Ags decrease in an Ag-specific manner during pregnancy, consistent with peripheral clonal deletion in the maternal immune system. Furthermore, the remaining clonotypic T cells become unresponsive to antigenic stimulation, demonstrating that multiple mechanisms of tolerance induction are active after encounter with physiologic levels of Ag.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
|---|
H-Y TCRtg mice bearing TCRs specific for
H-Y/Db were bred to mice in which the recombinase
activating gene-2
(RAG-2)3
had been eliminated by homologous recombination (RAG-/-) as
previously described (14). Timed pregnant RAG-/- H-2b or
H-2d TCRtg mice were generated by mating females for
18 h with C57BL/6 or BALB/c males (National Cancer Institute,
Frederick, MD), respectively. The day that the pair was separated was
counted as day 1 of gestation. In some experiments, RAG+/-
H-2d or RAG+/- H-2b TCR were used. Pregnant
females were sacrificed at day 7, 14, or 18 of gestation or allowed to
give birth and then sacrificed 5 or 21 days postpartum.
Breeding pairs of C57BL/6J (B6), B6Smn, C3H-gld (B6gld), and C3H/HeJ-gld (C3Hgld) were purchased from The Jackson Laboratory (Bar Harbor, ME) and bred in our facility. To isolate trophoblasts, timed pregnant mice were generated by mating B6gld females with either (B6gld x C3Hgld)F1 (gld/gld) or (B6 x C3Hgld)F1 (wt/gld) males for 12 h. The day that the pairs were separated was considered day 1 of gestation.
Flow cytometry and reagents
Spleen and pooled lymph nodes (mesenteric, axillary, and inguinal) were harvested from each animal and single-cell suspensions prepared and counted. Cells (1 x 106) were stained with anti-CD4, anti-CD8, anti-Thy1.2, and anti-IgM (PharMingen, San Diego, CA) or anti-clonotypic TCR (T370 (15), generous gift of Dr. Elizabeth Shores, Center for Biologics Evaluation Research and Review, Bethesda, MD) and analyzed on a FACScan cytometer (Becton Dickinson, Mountain View, CA) after gating on viable lymphocytes. Cell recovery of T cell subsets was determined by multiplying the total cell recovery from that tissue by the percentage of that subset present in the tissue as determined by flow cytometry.
Isolation of trophoblasts
Isolation of trophoblasts was performed as previously described (16). Briefly, placenta from 18-day pregnant mice were harvested aseptically, digested with 0.5% dispase (Boehringer Mannheim, Indianapolis, IN) and 0.1% DNase I (Sigma Chemicals, St. Louis, MO) in PBS for 1 h at 37°C, then resuspended into 64% Percoll solution (density, 1.08 g/ml). This mixture was then overlayed with Percoll solutions of decreasing densities (1.06, 1.05, 1.04, 1.03, and 1.01 g/ml) and centrifuged at 600 x g for 30 min at room temperature. In these experiments, the interface from the top layer, the lowest interface, and the pellet were discarded and the remaining layers 2 through 5 were pooled for use as effectors in the DNA fragmentation assay. Cells obtained from these layers consisted of large cells and had previously been characterized as predominantly of a trophoblastic phenotype (16). No difference in trophoblast recoveries was observed between the wild-type (wt/gld) or Fas ligand (Fas-l)-deficient (gld/gld) strains of mice.
DNA fragmentation assay
Determination of cell death was made using the DNA fragmentation test that has previously been described (17). Briefly, 1 x 106/ml target cell lines (L1210, a DBA/2 lymphocytic leukemia that does not express Fas; L1210 Fas, that has been transfected with the Fas gene; d11S, a mouse T cell hybridoma that does not express Fas; (18) or 2B4.11, a mouse T cell hybridoma that does expresses Fas (19)) were labeled with 5 µCi/ml [3H]thymidine for 3 h at 37°C. Labeled targets were cultured in triplicate at 5 x 104 cells/well with titrated numbers of effector cells (either trophoblasts or control cell lines) in 96-well U-bottom plates for 4 h at 37°C. The results are expressed as percentage of cell death and is calculated by: [(C - E)/C] x 100 = % cell death, where C = cpm of cells cultured in the control (i.e., medium alone) and E = cpm of cells cultured in experimental conditions.
T cell proliferation assays
1 x 105 lymph node cells were cultured in 96-well flat-bottom plates with titrated numbers of T-depleted irradiated (3000 rad) spleen cells from either male or female B6 mice or with 25% anti-TCR culture supernatant obtained from H57. Cultures were maintained for 4 days at 37°C in a 5% CO2 atmosphere in complete tissue culture medium, which contained RPMI 1640 supplemented with 10% FBS, 2 mM L-glutamine, 100 U/ml penicillin, 20 mM HEPES, 100 µM nonessential amino acids, 1 mM sodium pyruvate, and 25 µM 2-ME. All cultures were supplemented with 20 u/ml of human rIL-2. [3H]Thymidine (1 µCi/well) was added during the last 16 h of culture before harvest. At the end of this time, the cells were harvested onto fiberglass filters using a Tomtec 96-well cell harvester (Tomtec, Orange, CT) and counted on an LKB Betaplate counter (Wallac, Gaithersburg, MD).
|
Results and Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
|---|
H-Y TCRtg). H-2b H-Y TCRtg RAG-/- pregnant females
that had been mated to C57BL/6 males were evaluated at 7, 14, or 18
days of gestation, 5 or 21 days postpartum. Despite the presence of
H-Y-specific T cells in these mice, pregnancies were normal with the
expected frequency of male offspring (data not shown). Lymphoid tissues
from the mothers were harvested, and cells were counted and analyzed by
flow cytometry for expression of the clonotypic TCR (recognized by the
Ab T370). Interestingly, clonotypic T cells initially decreased but
then increased in the spleen by day 14 of gestation before decreasing
during late gestation (Fig. 1
A). By day 18 of
gestation, the number of clonotypic T cells in pregnant females had
decreased by 42% (9.8 ± 2.1 x 106 vs 16.8
± 2.9 x 106), and by 5 days postpartum, these
females had only 34% of the number of T cells observed in nonpregnant
transgenic females (5.8 ± 0.6 x 106). Similar
to the spleen, the number of clonotypic T cells in the lymph nodes
initially began to drop at 7 days of gestation, then expanded by
gestational day 14 before decreasing (Fig. 1B). The
number of clonotypic T cells was 25% lower (3.0 ± 0.7 x
106 vs 4.2 ± 1.1 x 106) at day 18
of pregnancy, and by 5 days postpartum, only 50% of the clonotypic T
cells observed in nonpregnant controls were detected (2.0 ±
0.5 x 106). The apparent decrease in the number of T
cells could not be explained by TCR or coreceptor down-regulation in
response to antigenic stimulation, as the number of Thy1-expressing and
CD8-expressing T cells decreased equivalently to the number of
clonotypic T cells (Fig. 1, A and B). To
determine when the number of fetal-reactive T cells was restored to
normal levels, we evaluated lymphoid tissues from parous females up to
3 wk postpartum. Even after 21 days, the number of clonotypic T cells
was still only 50% of the nulliparous controls (Fig. 1 A
and B). There is a slight increase in the number of
Thy+ T cells detectable at 21 days postpartum. Possibly,
this increase may reflect freshly exported T cells from the thymus.
However, the long term decrease observed in T cells is consistent with
the occurrence of clonal deletion.
|
H-Y TCRtg RAG-/- mothers that were
either H-2b or H-2d were compared.
H-2d TCR transgenic mice serve as a control for Ag
specificity because they do not express the Db molecule
that would present the H-Y peptide. In marked contrast to
H-2b pregnant females, which showed a decrease in
clonotypic T cells, H-Y-specific splenic T cells increased more than
twofold in H-2d pregnant females compared with nonpregnant
females (Fig. 1
C). This increase appears to be a
nonspecific effect of pregnancy, since similar increases in T cells
during pregnancy were observed in cytochrome-c-specific TCR
transgenic mice (data not shown). When compared 5 days postpartum, the
number of H-Y-specific T cells in the parous H-2d females
remained higher than in nulliparous controls, whereas there were even
fewer clonotypic T cells in the H-2b parous females. This
decrease could not be accounted for by relocalization of H-Y-specific T
cells to the placenta. Analysis of placental tissues from
H-2b pregnants did not reveal increased numbers of T cells
compared with placental tissues from H-2d pregnants (data
not shown). In addition, the fate of H-Y-specific T cells in day 14
pregnant RAG+/- females was examined, since these mice also possess
nonclonotypic T cells that serve as an internal control to assess the
specificity of changes observed in the clonotypic population (Fig. 1D). While significant decreases are observed in the
CD8+ clonotypic T cells of both the spleen (9.2 ±
2.4 x 106 vs 4.6 ± 0.6 x 106)
and lymph nodes (7.9 ± 1.2 x 106 vs 4.0 ±
0.6 x 106) compared with nonpregnant controls, no
decrease was observed in either the CD4+ or
CD8+ nonclonotypic population. Together, these findings
demonstrate that fetal-reactive T cell are specifically deleted during
pregnancy.
To address the origin of the cells mediating deletion, we examined the
fate of maternal T cells from day 14 H-2d, H-Y TCRtg
RAG+/- females that had been mated with either C57BL/6
(H-2b) or BALB/c (H-2d) males. When we assessed
the number of clonotypic T cell in H-2d females bred to
H-2b males, we detected a 60% decrease in the lymph node
and a 48% decrease in the spleen (Fig. 2A). However, this
decrease was not observed in H-2d females that had been
bred to H-2d males. Since the only source of APCs
expressing Db is the H-2bxd fetus, these
results demonstrate that deletion of H-Y-specific T cells can result
from an encounter with fetally derived cells. However, maternal
presentation of shed fetal Ag is also a possibility that cannot be
excluded as a mechanism of tolerance induction in the H-2b
females.
|
B) was not.
However, 2B4.11 was not killed by trophoblasts isolated from placentas
that are homozygous for the gld mutation and therefore
express nonfunctional Fas-l. To eliminate the possibility that other
differences between the cell lines were responsible for the
susceptibility to trophoblast-induced killing, purified trophoblasts
were tested for the ability to induce cell death in two mouse cell
lines that varied only in expression of Fas (18). In Figure 2C, L1210Fas is very efficiently killed by trophoblasts from
mice that have normal Fas-l expression, whereas L1210 is not.
Furthermore, L1210Fas is not killed by trophoblasts isolated from
placenta homozygous for the gld mutation. Together, these
findings are consistent with the proposal of clonal deletion as a
mechanism of tolerance induction during pregnancy and, moreover,
support a role for Fas-mediated death signals in this process.
Experiments were performed to assess whether the remaining T cells in
pregnant TCRtg mice were responsive to Ag. Culture of T cells isolated
from either nonpregnant or day 18 pregnant H-2b H-Y
TCRtg RAG-/- mice with female APCs did not result in proliferation
(data not shown), whereas T cells from nonpregnant TCRtg females
responded in a dose-dependent manner to male APC (Fig. 3A). However, there was a
substantial decrease in responsiveness by T cells from day 18 pregnant
TCRtg mice, despite equal numbers of clonotype-expressing cells present
in the cultures. Notably, cells from pregnant females were consistently
more responsive to Ab-mediated TCR stimulation (Fig. 3B), demonstrating that these cells were quite
capable of responding to stimuli. These experiments reveal that those T
cells that have not been deleted have nonetheless been tolerized and
are Ag nonresponsive. This does not appear to be a case of
"classical" anergy, because the T cells are unresponsive to
antigenic stimulation even in the presence of IL-2. T cell
responsiveness to TCR stimulation via Ab cross-linking may occur
because high avidity interactions can overcome nonresponsiveness.
However, nonresponsiveness did not correlate with either TCR or
coreceptor down-regulation (Figs. 1, A and B, and
3C). as has been reported in other model systems of
peripheral tolerance (3, 8) including pregnancy (28).
|
The mechanisms by which peripheral tolerance is maintained have been
shown to include clonal deletion (2, 3, 4), clonal unresponsiveness or
anergy (5, 6, 7), and down-regulation of TCR or coreceptors (3, 8, 9),
although the factors that determine which mechanism is invoked are as
yet unclear. Recently, Tafuri et al. found that T cells from
Kb -specific TCR transgenic mice mated to
Kb-expressing males down-regulated CD8 coreceptors during
pregnancy, resulting in reversible functional unresponsiveness to the
paternal Ags (28). Our results demonstrate that transient coreceptor
down-regulation is not the only mechanism by which maternal T cells are
tolerized to fetal Ags and that mechanisms with more long term effects
are active as well. Differences in the avidity of the TCR for the
MHC/peptide complex, the expression and presentation of the target Ag,
the nature of the APC, or the microenvironment in which the T cell
encounters Ag may ultimately dictate the mechanism of tolerance that is
invoked. One intriguing possibility to explain the existence of
multiple tolerance mechanisms in our system is that presentation of
fetal Ags by APCs of either fetal or maternal origin may evoke
different mechanisms. Experiments are currently being performed to
address this issue. Furthermore, although it has been suggested that
chronic exposure to Ag results in down-regulation of TCR and/or CD8
(11, 12, 13), we did not observe down-regulation of either TCR or
coreceptors on fetal-specific T cells during pregnancy, despite the
fact that coreceptor down-regulation has been observed in other models
of peripheral tolerance using the H-Y TCRtg mice (3, 13). This
finding would argue that coreceptor down-regulation may not be simply
the result of chronic stimulation but, potentially, Ag concentration
and route of exposure as well.
In conclusion, this work demonstrates that clonal deletion can occur at physiologic Ag concentrations and can serve as a mechanism of peripheral tolerance. Moreover, maternal T cell recognition of fetal Ags can lead to Ag-specific tolerance. Thus, not only does the maternal immune system respond to the fetus, but more importantly, it is actively tolerized by it. Interestingly, these results reveal that there are multiple mechanisms of peripheral tolerance induction during pregnancy and that those cells that are not clonally deleted become unresponsive to antigenic challenge. The fact that multiple mechanisms of tolerance are involved in response to this "natural" antigenic challenge may be indicative of the critical importance that mature T cells be tolerant of pregnancy-related and other developmentally regulated Ags to prevent autoimmune attack and allow the survival of the species.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Melanie S. Vacchio, Division of Hematologic Products, FDA/CBER, 1401 Rockville Pike, Suite 200N HFM 538, Rockville, MD 20852.
3 Abbreviations used in this paper: RAG-2, recombinase activating gene-2; Fas-l, Fas-ligand.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
|---|
ß T-cell receptor determine the CD4/CD8 phenotype of T cells. Nature 335:229.[Medline]
This article has been cited by other articles:
|
|
 |
|
  L. M. Moldenhauer, K. R. Diener, D. M. Thring, M. P. Brown, J. D. Hayball, and S. A. Robertson Cross-Presentation of Male Seminal Fluid Antigens Elicits T Cell Activation to Initiate the Female Immune Response to Pregnancy J. Immunol., June 15, 2009; 182(12): 8080 - 8093. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Robertson, L. R. Guerin, J. J. Bromfield, K. M. Branson, A. C. Ahlstrom, and A. S. Care Seminal Fluid Drives Expansion of the CD4+CD25+ T Regulatory Cell Pool and Induces Tolerance to Paternal Alloantigens in Mice Biol Reprod, May 1, 2009; 80(5): 1036 - 1045. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Osorio, D. L. Bonilla, A. G. Peniche, P. C. Melby, and B. L. Travi Pregnancy enhances the innate immune response in experimental cutaneous leishmaniasis through hormone-modulated nitric oxide production J. Leukoc. Biol., June 1, 2008; 83(6): 1413 - 1422. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Guleria and M. H. Sayegh Maternal Acceptance of the Fetus: True Human Tolerance J. Immunol., March 15, 2007; 178(6): 3345 - 3351. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Seavey and T. R. Mosmann Paternal Antigen-Bearing Cells Transferred during Insemination Do Not Stimulate Anti-Paternal CD8+ T Cells: Role of Estradiol in Locally Inhibiting CD8+ T Cell Responses J. Immunol., December 1, 2006; 177(11): 7567 - 7578. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. L. Straszewski-Chavez, V. M. Abrahams, and G. Mor The Role of Apoptosis in the Regulation of Trophoblast Survival and Differentiation during Pregnancy Endocr. Rev., December 1, 2005; 26(7): 877 - 897. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. Vacchio and R. J. Hodes Fetal Expression of Fas Ligand Is Necessary and Sufficient for Induction of CD8 T Cell Tolerance to the Fetal Antigen H-Y during Pregnancy J. Immunol., April 15, 2005; 174(8): 4657 - 4661. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Frangsmyr, V. Baranov, O. Nagaeva, U. Stendahl, L. Kjellberg, and L. Mincheva-Nilsson Cytoplasmic microvesicular form of Fas ligand in human early placenta: switching the tissue immune privilege hypothesis from cellular to vesicular level Mol. Hum. Reprod., January 1, 2005; 11(1): 35 - 41. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Li, M. L. Baroja, A. Majumdar, K. Chadwick, A. Rouleau, L. Gallacher, I. Ferber, J. Lebkowski, T. Martin, J. Madrenas, et al. Human Embryonic Stem Cells Possess Immune-Privileged Properties Stem Cells, July 1, 2004; 22(4): 448 - 456. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D.-I. Ham, S. J. Kim, J. Chen, B. P. Vistica, R. N. Fariss, R. S. Lee, E. F. Wawrousek, H. Takase, C.-R. Yu, C. E. Egwuagu, et al. Central Immunotolerance in Transgenic Mice Expressing a Foreign Antigen under Control of the Rhodopsin Promoter Invest. Ophthalmol. Vis. Sci., March 1, 2004; 45(3): 857 - 862. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. M. Abrahams, S. L. Straszewski-Chavez, S. Guller, and G. Mor First trimester trophoblast cells secrete Fas ligand which induces immune cell apoptosis Mol. Hum. Reprod., January 1, 2004; 10(1): 55 - 63. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Ando and T. F. Davies Postpartum Autoimmune Thyroid Disease: The Potential Role of Fetal Microchimerism J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 2965 - 2971. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. D. Dixit, H. Yang, V. Udhayakumar, and R. Sridaran Gonadotropin-Releasing Hormone Alters the T Helper Cytokine Balance in the Pregnant Rat Biol Reprod, June 1, 2003; 68(6): 2215 - 2221. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Zhang, M. S. Vacchio, B. P. Vistica, S. Lesage, C. E. Egwuagu, C.-R. Yu, M. P. Gelderman, M. C. Kennedy, E. F. Wawrousek, and I. Gery T Cell Tolerance to a Neo-Self Antigen Expressed by Thymic Epithelial Cells: The Soluble Form Is More Effective Than the Membrane-Bound Form J. Immunol., April 15, 2003; 170(8): 3954 - 3962. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. Vacchio and R. J. Hodes CD28 Costimulation Is Required for In Vivo Induction of Peripheral Tolerance in CD8 T Cells J. Exp. Med., January 6, 2003; 197(1): 19 - 26. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Luppi, C. Haluszczak, D. Betters, C. A. H. Richard, M. Trucco, and J. A. DeLoia Monocytes are progressively activated in the circulation of pregnant women J. Leukoc. Biol., November 1, 2002; 72(5): 874 - 884. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. G. Olivares, R. Munoz, G. Tejerizo, M. J. Montes, F. Gomez-Molina, and A. C. Abadia-Molina Decidual Lymphocytes of Human Spontaneous Abortions Induce Apoptosis but Not Necrosis in JEG-3 Extravillous Trophoblast Cells Biol Reprod, October 1, 2002; 67(4): 1211 - 1217. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ando, M. Imaizumi, P. N. Graves, P. Unger, and T. F. Davies Intrathyroidal Fetal Microchimerism in Graves' Disease J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3315 - 3320. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Ait-Azzouzene, S. Caucheteux, F. Tchang, J. Wantyghem, R. Moutier, A. Langkopf, M.-C. Gendron, and C. Kanellopoulos-Langevin Transgenic Major Histocompatibility Complex Class I Antigen Expressed in Mouse Trophoblast Affects Maternal Immature B Cells Biol Reprod, August 1, 2001; 65(2): 337 - 344. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Yamasaki, T. Sasho, H. Moriya, M. Kanno, M. Harada, N. Kamada, E. Shimizu, T. Nakayama, and M. Taniguchi Extrathymic Development of V{{alpha}}11 T Cells in Placenta During Pregnancy and Their Possible Physiological Role J. Immunol., June 15, 2001; 166(12): 7244 - 7249. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Dang and K. D. Heyborne Cutting Edge: Regulation of Uterine NKT Cells by a Fetal Class I Molecule Other Than CD1 J. Immunol., March 15, 2001; 166(6): 3641 - 3644. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. D. Dixit and N. Parvizi Pregnancy Stimulates Secretion of Adrenocorticotropin and Nitric Oxide from Peripheral Bovine Lymphocytes Biol Reprod, January 1, 2001; 64(1): 242 - 248. [Abstract] [Full Text]
|
|
|
|
 |
|
 D. Finkenzeller, B. Fischer, J. McLaughlin, H. Schrewe, B. Ledermann, and W. Zimmermann Trophoblast Cell-Specific Carcinoembryonic Antigen Cell Adhesion Molecule 9 Is Not Required for Placental Development or a Positive Outcome of Allotypic Pregnancies Mol. Cell. Biol., October 1, 2000; 20(19): 7140 - 7145. [Abstract] [Full Text]
|
|
|
|
|
|
N. Hanna, I. Hanna, M. Hleb, E. Wagner, J. Dougherty, D. Balkundi, J. Padbury, and S. Sharma Gestational Age-Dependent Expression of IL-10 and Its Receptor in Human Placental Tissues and Isolated Cytotrophoblasts J. Immunol., June 1, 2000; 164(11): 5721 - 5728. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Mincheva-Nilsson, O. Nagaeva, K.-G. Sundqvist, M.-L. Hammarstrom, S. Hammarstrom, and V. Baranov {gamma}{delta}T cells of human early pregnancy decidua: evidence for cytotoxic potency Int. Immunol., May 1, 2000; 12(5): 585 - 596. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.A. Habiba, S.C. Bell, and F. Al-Azzawi The effect of hormone replacement therapy on the number and the proliferation index of endometrial leukocytes Hum. Reprod., December 1, 1999; 14(12): 3088 - 3094. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Baker, A. I. Bamford, and D. F. Antczak Modulation of Allospecific CTL Responses During Pregnancy in Equids: An Immunological Barrier to Interspecies Matings? J. Immunol., April 15, 1999; 162(8): 4496 - 4501. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Arck, J. Dietl, and D. Clark From the Decidual Cell Internet: Trophoblast-Recognizing T Cells Biol Reprod, February 1, 1999; 60(2): 227 - 233. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
