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TRANSPLANTATION
From the Department of Dermatology, University of Texas
Southwestern Medical Center, Dallas; the Department of Immunology,
Juntendo University School of Medicine, Tokyo, Japan; and Core Research
for Evolutional Science and Technology (CREST), Japan Science
and Technology Corporation, Tokyo, Japan.
Allogeneic immune responses, which are initiated by dendritic cells
(DCs) of both donor and host origins, remain a major obstacle in organ
transplantation. Presentation of intact major histocompatibility complex (MHC) molecules by allogeneic DCs and allogeneic peptides by
syngeneic DCs leads to complex allogeneic immune responses. This study
reports a novel strategy designed to suppress both pathways. A stable
DC line XS106 (A/J mouse origin) was transfected with CD95L cDNA and
fused with splenic DCs purified from allogeneic BALB/c mice. The
resulting "killer" DC-DC hybrids: (1) expressed CD95L and
MHC class I and class II molecules of both A/J and BALB/c origins,
while maintaining otherwise characteristic surface phenotypes of mature
DCs; (2) inhibited MHC class I- and class II-restricted mixed leukocyte reactions between the parental strains by triggering apoptosis of alloreactive T cells; and (3) abolished delayed-type hypersensitivity responses of A/J (and BALB/c) mice to
BALB/c-associated (and A/J-associated) alloantigens when injected
intravenously into A/J (and BALB/c) mice. The onset of
graft-versus-host disease in (BALB/c × A/J) F1 hosts
receiving A/J-derived hematopoietic cell transplantation was suppressed
significantly (P < .001) by killer DC-DC hybrid
treatment. These results form both technical and conceptual frameworks
for clinical applications of CD95L-transduced killer hybrids created
between donor DCs and recipient DCs in the prevention of allogeneic
immune responses following organ transplantation.
(Blood. 2001;98:3465-3472) Transplantation of hematopoietic organs (eg, bone
marrow) into immunocompetent hosts induces the activation of
alloreactive T cells of both recipient and donor origins, thus causing
the host Many therapies have been developed to prevent the onset of allogeneic
immune responses after organ transplantation. For example, GVHD, a
major complication after allogeneic bone marrow
transplantation, has been prevented and treated clinically by
conventional immunosuppressive agents and, in selected cases, by ex
vivo removal of T cells from the donor inoculum before in vivo
infusion.7,8 GVHD in experimental animals has been
successfully treated by more innovative immunomodulatory strategies
that are designed to: (1) trigger clonal anergy of effector T cells by
blocking costimulatory molecules9-13; (2) control the
expansion and differentiation of effector T cells by administration of
recombinant cytokines or cytokine inhibitors7,14-17; or
(3) interfere with effector T-cell trafficking by blocking adhesion
molecules.18-20 Our ultimate goal is to develop a new strategy that is designed to selectively kill alloreactive T cells.
Recently, we have created "killer" DCs by introducing the
CD95L cDNA into a fully mature DC line (XS106) derived from A/J mice.21 The resulting CD95L-transduced killer DC clone,
when pulsed with ovalbumin (OVA), induced rapid apoptosis of
OVA-reactive T cells and prevented the induction of delayed-type
hypersensitivity (DTH) responses to OVA in syngeneic A/J mice.
Likewise, contact hypersensitivity responses to dinitrofluorobenzene
(DNFB) were suppressed almost completely by administration of
DNFB-pulsed killer DCs. On the other hand, when administered into
allogeneic BALB/c hosts, killer DCs inhibited only partially the host
immune responses to A/J-associated MHC molecules. We have interpreted these results to suggest that killer DCs may deliver apoptotic signals
only to the host T cells that recognize allo-MHC molecules via direct
presentation. Thus, we have hypothesized that complex alloimmune
responses may be suppressed more efficiently if one can create
CD95L-transduced killer hybrids by fusing donor DCs and host DCs
(Figure 1A).
Animals and cell lines
Generation of killer DC-DC hybrids
Reverse transcriptase-polymerase chain reaction and fluorescence-activated cell sorter analyses To examine CD95L mRNA expression, we isolated total RNA from the parental XS106 line and its derivatives and hybrids and subjected it to reverse transcriptase-polymerase chain reaction (RT-PCR) using the primers 5'-GCAGAAGGAACTGGCAGAAC-3' and 5'-TGAATACTGCCCCCAGGTAG-3'. Primers for -actin were purchased
from Clontech (Palo Alto, CA). PCR products were harvested within the
linear range of amplification (30 cycles for CD95L and 25 cycles for
-actin) and analyzed as described previously.21 Surface
expression of MHC molecules was examined with haplotype-specific
monoclonal antibodies (mAbs) against MHC class I (H-2Kd or
H-2Kk) and MHC class II (I-Ad or
I-Ak) (BD Pharmingen, San Diego, CA). All other mAbs,
including anti-CD95L (Kay-10), were also purchased from BD Pharmingen.
Other conditions for fluorescence-activated cell sorter (FACS) analyses
are described elsewhere.21,24
3H-thymidine release assay Apoptosis of the Jurkat target and alloreactive T-cell targets was examined by the standard 3H-thymidine release assay.21 To generate alloreactive T cells, we immunized A/J (or BALB/c) mice by subcutaneous (SC) injection of BALB/c (or A/J) spleen cells (1 × 107 cells/animal), harvested the spleen 7 days later, and restimulated the spleen cells for 48 hours with -irradiated (20 Gy) BALB/c (or A/J) spleen cells. Actively
proliferating cells were labeled with 3H-thymidine for the
last 16 hours and used as targets. In some experiments, anti-CD95L mAb
Kay-10 or isotype-matched control immunoglobulin (Ig) G2b (10 µg/mL)
was added to the apoptosis assay.
Allo-mixed leukocyte reaction assays In 2-way mixed leukocyte reaction (MLR), unfractionated spleen cells freshly isolated from A/J mice and BALB/c mice (1 × 105 cells/well) were cultured together for 5 days, and proliferative responses were measured by 3H-thymidine uptake in the last 16 hours. In one-way MLR, CD4+ or CD8+ T cells were purified from A/J (or BALB/c) mice using magnetic beads and cocultured (1 × 105 cells/well) with-irradiated (15 Gy) splenic DCs isolated from BALB/c (or A/J) mice
(1 × 104 cells/well). CD95L-transduced or control DC-DC
hybrids were added to the MLR (3 × 104 cells/well) after
-irradiation.
Allo-DTH assay Mice were immunized on the dorsal flank by SC inoculation of spleen cells (1 × 107 cells/animal) isolated from allogeneic mice on day 0 and challenged on day 7 at the right hind footpad by injecting the same antigens (1 × 107 cells/animal). Footpad thickness was then measured on days 8 and 9 with a calipers-type engineer's micrometer by a third experimenter masked to the sample identity. The extent of swelling was calculated as the thickness of the right footpad (receiving spleen cells) minus the baseline thickness of the left footpad (receiving phosphate-buffered saline [PBS] alone). CD95L-transduced or control DC-DC hybrids were injected intravenously (IV) (1 × 106 cells/injection/animal) on days 6, 4, 0, 3, and 6. In some experiments, these animals were rechallenged with the same spleen cells
on days 14 and 60.
Acute GVHD model Spleen cells and lymph node cells isolated from A/J mice were combined at a ratio of 12.5:1 and cultured (5 × 106 cells/mL) for 16 hours with-irradiated spleen cells
(5 × 105 cells/mL) isolated from (BALB/c × A/J) F1
mice. The resulting ex vivo-activated leukocyte preparations were used
as effector cells without further purification. (BALB/c × A/J) F1
recipients received whole-body -irradiation of 5 Gy and IV
administration of graded numbers of effector cells (from
3 × 106 to 1 × 108 cells/recipient) on
day 0. In the treatment panel, killer DC-DC hybrids were added to the
above 16-hour ex vivo preactivation cultures (7.5 × 105
cells/mL) and injected IV (1 × 106
cells/injection/animal) into the recipients on days 0, 3, 5, and 7. The
control panel received IV infusion of the effector cells activated in
the absence of killer DC-DC hybrids and 4 IV injections of PBS alone.
Animals in the treatment and control panels were housed in a randomly
mixed manner. A third experimenter recorded survival and body weight
every day (11 mice/panel). Three additional animals in each panel were
killed on day 7 to examine histologic changes and cytotoxic
T-lymphocyte (CTL) activities. For CTL assays, spleen cells
individually prepared from 3 mice per panel were cultured for 5 days in
complete RPMI in the absence of added cytokine with -irradiated (20 Gy) F1 spleen cells. These ex vivo-activated cells were then examined
for cytotoxicity against fibroblast lines established from A/J mice
(NS46 line) and BALB/c mice (NS47 line) in a standard 16-hour
51Cr release assay.25
Statistical analyses Animal experiments were conducted with 5 to 11 mice per panel, and in vitro experiments were performed with triplicate samples. Experimental results were analyzed for statistical significance by using a 2-tailed Student t test. The survival data were plotted by the Kaplan-Meier method and analyzed for statistical significance using the generalized Wilcoxon test and the log-rank test.
Generation of killer DC-DC hybrids We created killer DC-DC hybrids by using an A/J mouse-derived, mature DC line XS106.21,22 Considering the MHC haplotype of A/J mice (H-2Kk/H-2Dd/H-2Ld/I-Ak/I-Ek), we chose BALB/c mice (H-2Kd/H-2Dd/H-2Ld/I-Ad/I-Ed) as a fusion partner. When XS106 DCs were fused with splenic DCs purified from BALB/c mice, only small fractions (less than 5%) of the resulting cells expressed both A/J and BALB/c haplotypes, indicating relatively low frequencies for heterotypic DC-DC fusion (data not shown). To overcome this technical problem, we used a double-selection protocol (Figure 1B). Briefly, we first selected a HAT-sensitive XS106 mutant clone (XS106-7), introduced the CD95L and neomycin resistance genes into this DC clone, and established a stably transfected DC clone (XS106-7-CD95L) by limiting dilution. The XS106-7-CD95L DC clone was, indeed, HAT sensitive and G418 resistant, whereas the parental XS106 line was HAT resistant/G418 sensitive and the XS106-7 clone was HAT sensitive/G418 sensitive (Figure 1C). Subsequently, we fused the XS106-7-CD95L clone with splenic DCs freshly purified from BALB/c mice and selected hybrid clones in the presence of HAT and G418. In theory, only heterotypic hybrids should grow in this medium because nonfused XS106-7-CD95L cells and nonfused spleen DCs will be killed by HAT and by G418, respectively. In fact, many HAT-resistant/G418-resistant hybrid lines (in bulk) and clones (after limiting dilution) were readily generated by our protocol (Figure 1C).Neither the parental XS106 line nor the HAT-sensitive XS106-7 clone
expressed CD95L mRNA at detectable levels (Figure
2A). CD95L mRNA expression was detected
in killer DCs (XS106-7-CD95L) and killer DC-DC hybrids, but not in
control DC-DC hybrids transfected with vector alone. Likewise, surface
CD95L expression was detected only on killer DCs and killer DC-DC
hybrids (Figure 2B). All tested killer DC-DC hybrid lines and clones
expressed both MHC class I and class II molecules derived from A/J mice
(H-2Kk/I-Ak) and from BALB/c mice
(H-2Kd/I-Ad), indicating high efficiency of our
double-selection protocol (Figure 2C). Moreover, killer DC-DC hybrids
expressed CD40, CD80, CD86, and CD54 at relatively high levels, thus
maintaining the mature DC phenotype observed in the parental XS106 line
(Figure 2D). Interestingly, killer DC-DC hybrids expressed CD11c, which was detected on splenic DCs but not on the parental XS106 line. Surface
markers for T cells (eg, CD3), monocytes/macrophages (CD14), or B cells
(B220) were absent from killer DC-DC hybrids. Control DC-DC hybrids
were phenotypically indistinguishable from the killer DC-DC hybrids
except for the lack of surface CD95L (data not shown). Consistent with
the observation that killer DC-DC hybrids continued to proliferate in
culture without undergoing suicidal death (Figure 1C), CD95 (a receptor
of CD95L) was not detectable on their surfaces (Figure 2D).
In vitro function of killer DC-DC hybrids We next tested the potential of killer DC-DC hybrids to kill Jurkat targets that are known to express CD95 constitutively. Killer DC-DC hybrids, but not control DC-DC hybrids, induced apoptosis of this target (Figure 2E), and their cytotoxicity was blocked with neutralizing mAb against CD95L (Figure 2F), validating the functional activity of CD95L molecules on killer DC-DC hybrids. The observed cytotoxicity was modest, requiring relatively high effector-to-target (E/T) ratios of 0.3:1 to achieve 20% to 40% specific lysis in an 18-hour assay. Control DC-DC hybrids expressing MHC class I and class II molecules of both BALB/c and A/J origins induced marked proliferation of A/J-derived spleen cells as well as BALB/c-derived spleen cells (Figure 3A). By contrast, killer DC-DC hybrids failed to activate either A/J or BALB/c spleen cells, and anti-CD95L mAb restored their allostimulatory capacity. Thus, transduced expression of CD95L is fully responsible for the inability of killer DC-DC hybrids to activate alloreactive T cells.
We next determined whether killer DC-DC hybrids would inhibit the
activation of alloreactive T cells in the 2-way MLR. Unfractionated spleen cells (containing T cells and DCs) from A/J mice and from BALB/c
mice were cultured together in the absence of Killer DC-DC hybrids killed BALB/c-reactive T-cell targets (derived from A/J mice) with extremely high efficiency, with 30% to 45% lysis achieved at E/T ratios of 0.04:1 to 0.2:1 in 6 hours (Figure 3E, left panel). A/J-reactive T-cell targets (derived from BALB/c mice) were lysed even more efficiently (Figure 3E, right panel). By contrast, control DC-DC hybrids failed to kill either target even at higher E/T ratios. These results document the potent ability of killer DC-DC hybrids to trigger apoptosis of alloreactive T cells. The CD95L-transduced XS106 cells expressing A/J-derived MHC molecules
(killer DCs) suppressed the 2-way MLR between the A/J and BALB/c spleen
cells only modestly (Figure 4A). In
one-way MLR, killer DCs inhibited almost completely (more than 95%)
BALB/c T-cell responses to A/J DCs (Figure 4B) and only partially
inhibited (50% to 60%) A/J T-cell responses to BALB/c DCs (Figure
4C). In all the MLR experiments, killer DC-DC hybrids were
significantly more potent than killer DCs, producing complete
inhibition in 2 opposing directions, signifying the advantage of the
new technology.
In vivo impact of killer DC-DC hybrids Allospecific DTH responses provide a relatively handy, fully quantitative, and reproducible assay system to study allospecific immune responses.27,28 BALB/c mice immunized with A/J spleen cells showed marked DTH responses upon challenge (Figure 5A). This BALB/c A/J response was
inhibited almost completely by repeated injections of killer DC-DC
hybrids before and after sensitization. In all 4 independent
experiments, killer DC-DC hybrids induced 70% to 100% inhibition,
whereas control DC-DC hybrids injected in the same protocol never
caused significant inhibition. To test allospecificity, we immunized
BALB/c mice with spleen cells isolated from C57BL/6 mice
(H-2Kb/H-2Db/H-2Lb/I-Ab/I-Eb).
As shown in Figure 5B, killer DC-DC hybrids (A/J × BALB/c) failed
to affect allo-DTH responses to C57BL/6 spleen cells, formally excluding the possibility that suppressive effects induced by killer
DC-DC hybrids might simply reflect nonspecific cytotoxicity of in
vivo-administered CD95L molecules.
We next examined the time course and bidirectionality. Killer DC-DC
hybrids suppressed DTH responses of BALB/c mice to A/J spleen cells
after initial challenge on day 7 (left panels in Figure 5C) and even
after the second challenge on day 14 (middle panels in Figure 5C).
Significant inhibition became undetectable after the third challenge on
day 60 (right panels in Figure 5C). The footpad-swelling responses
detected in the PBS-sensitized control group at the second and third
challenges (top panel in Figure 5C) most likely reflect successful
sensitization by the injected A/J spleen cells at the first challenge.
As observed in MLR experiments, killer DC-DC hybrids also suppressed
allo-DTH responses of A/J mice to BALB/c spleen cells, documenting
their unique property to inhibit bidirectional alloresponses (left
panels in Figure 5D). Unresponsiveness in this direction (A/J As an initial step toward clinical application, we assessed the
preclinical efficacy of killer DC-DC using a standard GVHD model. In
this model, spleen cells and lymph node cells isolated from A/J mice
were infused into sublethally irradiated (BALB/c × A/J) F1 mice,
leading to the activation of donor T cells (H-2a) that
recognized MHC molecules of the H-2d haplotype on the F1
hosts (H-2d/a).13 To optimize the frequency of
H-2d-reactive T cells, we first cultured the donor cell
preparations for 16 hours with
The present study introduces an entirely new immunosuppressive strategy that is designed to selectively eliminate alloreactive effector T cells. Killer DC-DC hybrids expressed functionally active CD95L and MHC class I and class II molecules of both parental strains, induced rapid apoptosis of alloreactive T cells, and inhibited bidirectional activation of alloreactive CD4+ and CD8+ T cells between the parental strains. Upon in vivo administration, killer DC-DC hybrids inhibited allo-DTH responses, delayed the onset of acute GVHD, and suppressed significantly the generation of allospecific CTL activities. Is the killer DC-DC hybrid technology potentially applicable to the
prevention of acute GVHD in human patients? Short-term DC lines can be
readily generated by culturing CD34+ progenitors or
CD14+ monocytes from human peripheral blood in the presence
of selected cytokines,29,30 and transfection efficiency
for DCs has been improved dramatically by the use of viral
vectors.31 Thus, we believe it is technically feasible to
generate killer hybrids between the donor DCs and recipient DCs. In the
present study, donor hematopoietic cells were activated ex vivo with
recipient antigen-presenting cells in the presence of killer DC-DC
hybrids. Guinan et al12 recently used a similar protocol to
prevent acute GVHD in leukemia patients receiving bone marrow
transplantation from MHC-mismatched donors. Before infusion, the donor
bone marrow cells were cultured with With regard to safety, we considered liver toxicity as a potential risk because massive apoptosis of hepatocytes has been induced experimentally by systemic administration of agonistic anti-CD95 mAb.32 None of the more than 300 animals that had been treated with killer DC-DC hybrids, except for those in the GVHD experiments, died during the experimental periods. Consistent with our previous observations after killer DC treatments,21 we detected no significant changes in the liver histology or serum levels of aspartate aminotransferase or alanine aminotransferase after administrations of killer DC-DC hybrids (data not shown). Thus, the risk of acute liver cytotoxicity appears to be limited, perhaps reflecting the relatively low CD95L expression detected on killer DC-DC hybrids. In this regard, killer DC-DC hybrids killed alloreactive T-cell targets much more efficiently than the Jurkat target, and they failed to suppress allo-DTH responses to irrelevant MHC antigens (ie, C57BL/6 spleen cells). We interpret these observations to suggest that killer DC-DC hybrids require signal 1 (ligation of the MHC-peptide complex with relevant T-cell receptor complex on the targets) and perhaps signal 2 (coupling of the costimulatory molecules with corresponding ligands on the targets) to exert their maximal cytotoxicity. If so, the resulting target specificity may serve as a safety mechanism to minimize uncontrolled tissue damage caused simply as a consequence of exogenous CD95L administration. We previously reported the potential of CD95L-transduced XS106 cells (ie, killer DCs) to prevent DTH responses to foreign protein antigens and contact hypersensitivity responses to reactive haptens in an antigen-specific manner.21 More recently, Min et al33 extended these observations by introducing the CD95L gene into bone marrow-derived murine DCs of BALB/c origin and testing the impact on allogeneic graft rejection. These investigators were able to induce hyporesponsiveness to BALB/c-associated alloantigens and prolong the survival of BALB/c-derived cardiac grafts in C57BL/6 mice by injecting CD95L-transfected DCs repeatedly. Zhang et al34,35 also reported that T-cell-mediated immune responses to foreign antigens as well as alloantigens (assessed by MLR) were suppressed by using CD95L-transfected macrophages. On the other hand, our attempt to prolong the survival of A/J-derived skin grafts by repeated injections of killer DC-DC hybrids into BALB/c recipients has not been successful thus far. Considering that the same protocol abrogated the bidirectional allo-DTH responses almost completely, one may argue that threshold numbers of alloreactive T cells required for skin graft rejection are much smaller than those required for DTH responses. Alternatively, these observations may imply the inability of killer DC-DC hybrids to eliminate effector T cells that recognize unique, tissue-specific minor antigens. CD95L is thought to contribute to immune privilege in the eye, testis,
and some cancers by inducing CD95-mediated apoptosis of infiltrating
cells.36,37 Genetically engineered CD95L expression in the
allografts has been shown to induce graft immunoprotection in some
reports.38-40 On the other hand, CD95L expression on graft tissues was frequently found to induce inflammation (mostly neutrophil infiltration) and allograft rejection, perhaps reflecting the chemotactic potential of soluble CD95L and/or caspase-mediated processing and secretion of interleukin (IL)-1 As described in "Introduction" and illustrated in Figure 1A,
transplantation immunology is highly complex, being mediated by diverse
T-cell subsets that recognize donor- or host-derived alloantigen, in an
MHC class I- or class II-restricted manner, and by a direct or
indirect presentation mechanism. Vector-transfected control DC-DC
hybrids expressed MHC class I and class II molecules of both parental
strains and induced robust activation of alloreactive CD4+
and CD8+ T cells isolated from either strain. Although our
primary objective was to study the outcome of transduced expression of
CD95L, the DC-DC hybrid technology per se may be applicable to the
development of other strategies to prevent allogeneic immune responses.
Conventional DCs have been converted into tolerogenic
antigen-presenting cells by exposure to ultraviolet B
irradiation,45 pretreatment with IL-10,46 or
transfection with viral IL-10, transforming growth factor (TGF)-
We thank Dr Michael Bennett for his intellectual input to the GVHD experiments, Julie Loftus and Dale Edelbaum for their technical assistance, and Pat Adcock for her secretarial assistance.
Submitted April 24, 2001; accepted August 7, 2001.
Supported by National Institutes of Health grants (RO1-AI46755, RO1- AR35068, RO1-AR43777, RO1-AI43232) and by Centre de Recherches et d' Investigations Épidermiques et Sensorielles (CE.R.IES.) Award (A.T.).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Hiroyuki Matsue, Department of Dermatology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-6069; e-mail: hiroyuki.matsue{at}utsouthwestern.edu.
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H. Einsele Killer aAPCs as tools for immunosuppression Blood, April 1, 2008; 111(7): 3305 - 3305. [Full Text] [PDF]
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C. Schutz, M. Fleck, A. Mackensen, A. Zoso, D. Halbritter, J. P. Schneck, and M. Oelke Killer artificial antigen-presenting cells: a novel strategy to delete specific T cells Blood, April 1, 2008; 111(7): 3546 - 3552. [Abstract] [Full Text] [PDF]
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Q. Wang, Y. Liu, J. Wang, G. Ding, W. Zhang, G. Chen, M. Zhang, S. Zheng, and X. Cao Induction of Allospecific Tolerance by Immature Dendritic Cells Genetically Modified to Express Soluble TNF Receptor J. Immunol., August 15, 2006; 177(4): 2175 - 2185. [Abstract] [Full Text] [PDF]
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S. Hoves, S. W. Krause, D. Halbritter, H.-G. Zhang, J. D. Mountz, J. Scholmerich, and M. Fleck Mature But Not Immature Fas Ligand (CD95L)-Transduced Human Monocyte-Derived Dendritic Cells Are Protected from Fas-Mediated Apoptosis and Can Be Used as Killer APC J. Immunol., June 1, 2003; 170(11): 5406 - 5413. [Abstract] [Full Text] [PDF]
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T. Wolfe, C. Asseman, A. Hughes, H. Matsue, A. Takashima, and M. G. von Herrath Reduction of Antiviral CD8 Lymphocytes In Vivo with Dendritic Cells Expressing Fas Ligand--Increased Survival of Viral (Lymphocytic Choriomeningitis Virus) Central Nervous System Infection J. Immunol., November 1, 2002; 169(9): 4867 - 4872. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
and MALA-2.
Transplantation.
1991;52:842-845