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Production1
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Research Service, Department of Veteran Affairs Medical Center, and Division of Rheumatology and Clinical Immunology, University of Maryland School of Medicine, Baltimore, MD 21201;
Rheumatology Division, Veterans Affairs Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH 45267; and
Specialized Center of Research in Systemic Lupus Erythematosus, Hospital for Special Surgery-Cornell University Medical Center, New York, NY 10021
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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production, resulting in chronic GVHD.
Lastly, up-regulation of Fas/FasL in acute GVHD mice could be blocked
by anti-IFN- mAb in vivo. Thus, in this in vivo model of
alloantigen immune responsiveness, Fas/FasL up-regulation is critically
dependent on Ag-specific (donor) CD8+ T cell activation and
IFN- production. Donor CD4+ T cell activation in the
absence of CD8+ T cell activation results in an
autoantibody-mediated response, no significant Fas/FasL up-regulation,
impaired elimination of autoreactive B cells, and persistent humoral
autoimmunity. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A useful model for studying in vivo Ag-driven responses is the
P
F1 model of graft-vs-host disease (GVHD). In
this model, disease takes one of two forms: 1) acute GVHD,
characterized by a severe reduction in host lymphocytes and a profound
immunodeficiency; or 2) chronic GVHD, characterized by
lymphoproliferation, autoantibody production, and a lupus-like disease.
Acute GVHD results from the activation of both donor CD4+
and CD8+ T cell subsets in response to host alloantigen. A
strong cell-mediated immune response ensues, resulting in the
elimination of host lymphocytes in large part by donor anti-host
CTL (9, 10, 11). In contrast, chronic GVHD results from the selective
activation of alloreactive donor CD4+ T cells that provide
cognate help to host B cells leading to activation and autoantibody
production. In the absence of activated donor CD8+ T cells,
anti-host CTL do not develop in chronic GVHD, and persistent
autoantibody production by autoreactive B cells results in a lupus-like
immune complex glomerulonephritis (12). Importantly, in both forms of
GVHD, alloreactive donor T cells appear to undergo normal activation,
expansion, cytokine production, and maturation into effector T cells.
Thus, disease in this model results not from abnormal donor T cell
function but, rather, from the activation of T cells specific for host
alloantigens. Despite the pathologic outcomes observed, the model
provides an opportunity to study normal in vivo Ag-driven CMI or
Ab-mediated immune response.
The present study was undertaken to determine whether differences in
disease outcome in acute and chronic GVHD are associated with
differences in Fas/FasL expression and, if so, whether differential
cytokine production is important in mediating such an effect. In
particular, we asked 1) whether the persistence of autoreactive B cells
and humoral autoimmunity in chronic GVHD is associated with a reduced
Fas/FasL up-regulation; 2) whether the elimination of autoreactive B
cells in acute GVHD is mediated by Fas-dependent anti-host CTL
activity; and lastly 3) whether cytokines such as IFN- contribute to
Fas/FasL up-regulation. Our results indicate that in acute GVHD,
Fas/FasL play a major role in the elimination of autoreactive B cells
and that the up-regulation of these molecules is critically dependent
on IFN- production. In contrast, Fas/FasL up-regulation and IFN-
production are significantly reduced in lupus-like chronic GVHD,
leading to impaired elimination of autoreactive B cells and persistent
autoantibody production.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6J (B6), DBA/2J (DBA), and (C57BL/6 x DBA/2) (BDF1) male mice, 6 to 8 wk of age, were purchased from The Jackson Laboratories (Bar Harbor, ME).
Definition and induction of GVHD
Single cell suspensions were prepared in HBSS from the spleens
of normal DBA or B6 parental donors. Cell suspensions were filtered
through sterile nylon mesh, washed, and diluted to a concentration of
108 viable (trypan blue excluding) cells/ml. Acute GVHD was
induced with 50 x 106 undepleted B6 spleen cells, and
chronic GVHD was induced with either 90 x 106 DBA
undepleted splenocytes or 50 x 106 CD8+ T
cell-depleted B6 splenocytes. These donor cell inocula have been
previously demonstrated to result in acute or chronic GVHD,
respectively (10). Cell suspensions were injected i.v. into the tail
vein of normal, unirradiated BDF1 recipients.
Control mice consisted of uninjected age- and sex-matched
F1 mice. The presence of acute GVHD was defined
as a >50% reduction in host spleen cells and significant engraftment
(>1 x 106) of donor CD4+ and
CD8+ T cells at 14 days after parental cell transfer. The
presence of chronic GVHD was defined as a >120% increase in host
spleen cells and significant engraftment of only donor CD4+
T cells. The effects of IFN- were blocked in vivo by the
administration of neutralizing doses of anti-IFN- mAb, XMG-6
(13), given at 1 mg/mouse iv on days 0 and 7 after parental cell
transfer. Control mAb (GL113) was administered at the same dose and
schedule. Additional controls consisted of untreated acute GVHD mice
and uninjected normal F1 mice.
Depletion of T cell subsets
Spleen cells were depleted of CD4+ or CD8+ T cells by treatment with anti-CD4, RL172 (14), or anti-CD8, 83-12-5 (15), mAb and complement as previously described (16). Flow cytometric analysis confirmed that this procedure resulted in <1% contaminating CD4+ or CD8+ T cells.
Detection of anti-host CTL activity ex vivo
Effector CTL activity was tested using freshly harvested splenocytes without an in vitro sensitization period. F1 splenocytes were tested for their ability to lyse either 1) 2-day LPS-stimulated blasts from DBA (H-2d) mice, or 2) Fas-positive or Fas-negative L1210 cells (H-2d, MHC class I positive, class II negative) (17) in a 4-h 51Cr release assay as described previously (10). Effectors were tested in triplicate at four E:T cell ratios. The percent lysis was calculated according to the formula: [(cpm sample - cpm spontaneous)/(cpm maximum - cpm spontaneous)] x 100%. For studies using LPS-stimulated blasts, counts per minute spontaneous was replaced with counts per minute of splenocytes in normal F1 mice in the calculation of the cytotoxicity of experimental groups. Results are shown as the mean percent lysis ± SEM at a given E:T cell ratio for each treatment group.
RT-PCR
The coupled RT-PCR was used as previously described (18).
RNase-free plastic and water were used throughout the assay. Tissues
were homogenized in RNA-STAT-60 (Tel-Test, Friendswood, TX) at 50 mg of
tissue/ml or 1 ml/107 cells. RNA samples were reverse
transcribed with reverse transcriptase (M-MLV-RT, Life Technologies,
Grand Island, NY); FasL- or IFN--specific primers were used for
amplification as previously described (18). For each gene product, the
optimum number of cycles (that number of cycles that would achieve a
detectable concentration that was well below saturating conditions) was
determined experimentally. To verify that equal amounts of RNA were
added in each RT-PCR reaction within an experiment, primers for the
housekeeping gene, hypoxanthine phosphoribosyl transferase (HPRT), were
used in each experiment. Gene expression was quantitated by
densitometry for individual mice, normalized to each individual HPRT
value, and group means were calculated.
Flow cytometric analysis and engraftment studies
Spleen cells were prepared as previously described (10).
Following incubation with anti-murine Fc receptor mAb, 2.4G2
(19), for 10 min, cells were stained with saturating concentrations of
FITC-conjugated, biotin-conjugated, or PE-conjugated mAb against CD4,
CD8, B220, H-2Kb, Fas (CD95), and FasL purchased from
Becton Dickinson (Mountain View, CA) or PharMingen (San Diego, CA).
Two- and three-color flow cytometric analyses were performed using a
FACScan flow cytometer (Becton Dickinson). Lymphocytes were gated by
forward and side scatter, and fluorescence data were collected for
10,000 cells. Studies of donor T cells were performed on 5,000 gated
cells that were CD4+ or CD8+ and did not stain
positively for MHC class I of the uninjected parent. Monocyte
populations were excluded on the basis of forward and side scatter.
Statistical analysis
Results for group means were compared by Student’s t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To determine the level of FasL gene expression in acute and
chronic GVHD mice, splenic mRNA was isolated and amplified by RT-PCR as
described in Materials and Methods. On day 10 after GVHD
induction (Fig. 1
), mice with acute GVHD
had significantly higher mean FasL expression compared with normal or
chronic GVHD mice (p < 0.05). Mean
densitometric ratios of FasL/HPRT expression were approximately
eightfold higher in splenocytes obtained from mice with acute GVHD
(mean = 0.249 ± 0.06) compared with those from mice with
chronic GVHD (mean = 0.029 ± 0.01; p = 0.02)
or those from normal F1 mice (mean = 0.029;
p = 0.04). Mean values for chronic GVHD did not differ
significantly from normal F1 values. Similar
results were observed on day 14 after parental cell transfer and have
been confirmed in a total of three independent experiments at both time
points. Kinetic studies revealed that increased FasL mRNA expression
was detected as early as day 5 after parental cell transfer in acute,
but not chronic, GVHD (data not shown).
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B6 and DBA mice express different alleles of FasL (20). To verify that the mAb used for these studies could detect FasL on DBA T cells, splenocytes were activated with anti-CD3 mAb, and FasL expression was monitored by flow cytometry. An approximately twofold increase in FasL surface expression compared with that for freshly isolated splenocytes was observed for CD4+ and CD8+ T cells from both B6 and DBA splenocytes (data not shown), indicating that both B6 and DBA splenocytes are capable of up-regulating FasL following activation in vitro and that the mAb used was capable of detecting FasL on both parental donors.
To determine whether the increased FasL mRNA seen in acute GVHD mice
was associated with an increase in FasL surface protein expression,
flow cytometric staining of FasL was performed on splenocytes from
acute or chronic GVHD mice at 10 and 14 days after parental cell
transfer. As shown in Figure 2 and Table I, acute GVHD mice exhibited consistent
and statistically significant increases in FasL expression on both
donor CD4+ and CD8+ T cells compared with
chronic GVHD mice, naive uninjected donor cells, or control uninjected
host (F1) T cells. Interestingly, acute GVHD mice
also exhibited increased FasL expression on host CD4+ and
CD8+ T cells compared with host T cells from either chronic
GVHD or control mice (Fig. 3 and Table I). In contrast, FasL expression on both donor and host T cells from
chronic GVHD was not consistently increased over that in the controls,
although in one experiment using a brighter staining anti-FasL mAb,
a small but statistically significant increase in FasL expression was
observed compared with the control value (Table I, Expt. 3).
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If Fas/FasL play a role in mediating the elimination of host
splenocytes in acute GVHD, it might be expected that the increase in
donor T cell FasL expression seen in acute GVHD would be accompanied by
increased expression of Fas in host lymphocytes. Compared with either
chronic GVHD mice or control F1 mice, acute GVHD
mice exhibited consistent and statistically significant increases in
Fas expression on both donor and host lymphocytes, with the largest
degree of up-regulation seen on host B cells and host CD8+
T cells (Figs. 4 and
5 and Table I
). Fas expression on
lymphocytes from chronic GVHD mice was in some instances greater than
that in control mice, however; the chronic GVHD mcf values were
consistently lower than those observed in acute GVHD mice (Table I).
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A major difference between acute and chronic GVHD is the potent
anti-host CTL activity in acute GVHD (21). Since FasL expression on
T cells is up-regulated in acute, but not chronic, GVHD, it is possible
that FasL contributes to anti-host CTL activity and the elimination
of host lymphocytes. To examine this possibility, spleen cells from
acute GVHD mice were tested for their ability to lyse Fas-positive and
Fas-negative H-2d targets. As shown in Figure 6, anti-host-CTL killed both
Fas-positive and Fas-negative targets: however, the killing of
Fas-positive targets was much greater than that of Fas-negative
targets. These findings suggest that both a Fas-dependent and a
Fas-independent pathway mediate anti-host CTL activity in acute
GVHD. In a second experiment (Fig. 7),
anti-host CTL activity was assessed in the presence and the absence
of concanamycin A (CMA), a perforin pathway inhibitor (22). Treatment
with CMA reduced anti-host CTL activity on Fas-positive host
targets by approximately 50% and reduced killing of Fas-negative
targets to background levels, confirming that CTL use both perforin and
Fas pathways in acute GVHD.
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Up-regulation of FasL on both CD4+ and
CD8+ donor T cells in acute GVHD mice suggests that both T
cell subsets contribute to anti-host CTL activity. Previous studies
of anti-host CTL activity have demonstrated lysis of MHC class
I-positive, class II-negative host targets, consistent with the
presence of CD8+ CTL (21). To determine whether donor
CD4+ CTL also contribute to the killing of host lymphocytes
in acute GVHD, anti-host CTL activity was determined using acute
GVHD splenocytes depleted of either CD4+ or
CD8+ T cells and tested on LPS-stimulated blasts (Fas
positive, MHC class I and class II positive), L1210+ cells
(Fas positive, MHC class I positive), or L1210- cells (Fas
negative, MHC class I positive; Fig. 8).
If MHC class II-restricted CD4+ CTL are present, CD8
depletion should not abolish all killing on host LPS-stimulated blasts.
Alternatively, if CD4+ CTL are present that kill through a
Fas-dependent mechanism, CD8 depletion should eliminate all killing on
Fas-negative targets but not on Fas-positive targets. As shown in
Figure 8, the substantial killing of LPS-stimulated blasts and
L1210-positive and -negative targets seen for undepleted acute GVHD
splenocytes was entirely eliminated by CD8 depletion. Furthermore,
depletion of CD4+ T cells resulted in enhanced killing of
all targets, consistent with the increased concentration of effector
(CD8+) CTL. While these results do not totally exclude the
presence of CD4+ CTL in vivo, they do not support a major
role for such cells in the elimination of host lymphocytes in acute
GVHD mice.
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production
It has been previously shown that DBA CD8+ T cells
have impaired generation of anti-host CTL in vivo and a reduced
allogeneic precursor CTL frequency in vitro compared with H-2-identical
B10.D2 mice (21, 23). Although increased production of IL-4 and IL-10
is seen in both acute and chronic GVHD mice, only acute GVHD mice
exhibit activation of donor CD8+ T cells and increased
IFN- production (23). To test whether these observations could be
linked to Fas/FasL expression, we compared Fas/FasL expression in
F1 mice receiving total
(B6F1) or CD8-depleted B6 donor cells (B6 CD8
deplF1). Chronic GVHD is typically observed in
this latter PF1 combination (21). As shown in
Figure 9, B6 CD8
deplF1 mice exhibit a loss of anti-host
CTL activity on either P815 targets (Fas dull, MHC class I positive) or
on LPS-stimulated blasts (Fas positive, MHC class I and II positive).
It should be noted that the level of Fas expression on LPS-stimulated
blasts is similar to that seen on host B cells in acute GVHD (an
approximately fourfold increase in mcf compared with that in freshly
isolated splenocytes). This loss of functional CTL activity was
associated with a marked reduction in FasL and IFN- mRNA expression
(Fig. 10). Flow cytometric staining of
B6 CD8 deplF1 splenocytes (Fig. 11) confirmed very low expression of
FasL on donor CD4+ T cells and of Fas on host B cells
(compared with undepleted B6 F1 mice),
reminiscent of that observed in DBAF1 chronic
GVHD mice (Fig. 2). To determine whether IFN- was necessary for
Fas/FasL up-regulation, a neutralizing anti-IFN- mAb was
administered in vivo to acute GVHD mice beginning at the time of cell
transfer and at weekly intervals thereafter. As shown in Figure 12, in vivo inhibition of IFN-
significantly reduced expression of FasL on donor CD4+ and
CD8+ T cells and expression of Fas on host B cells compared
with those in untreated acute GVHD mice.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production (by both donor CD4+
and CD8+ T cells) and the development of donor
anti-host CTL (23, 25), which rapidly eliminate
F1 lymphocytes such that by 2 wk after parental
cell transfer, acute GVHD mice exhibit lymphopenia and a profound
immunodeficiency. Because host B cells are eliminated, autoimmunity in
acute GVHD is transient. In contrast, the activation of donor
CD4+ T cells, but not CD8+ T cells, in chronic
GVHD is associated with no detectable IFN- production and no
detectable donor anti-host CTL activity. As a result, autoreactive
B cells are not eliminated, and lymphoproliferation with autoantibody
production continues, resulting in the eventual development of a
lupus-like immune complex glomerulonephritis after several months (12).
We have previously shown that acute GVHD was attenuated when FasL
mutant C3H/gld mice were used as donors (26), suggesting an
important role for FasL in the elimination of host cells. The present
study directly demonstrates that Fas/FasL up-regulation occurs in
acute, but not chronic, GVHD, requires activation of donor
CD8+ T cells, and can be blocked almost entirely by
anti-IFN- mAb treatment in vivo. These results strongly argue
that IFN- plays a major role in the in vivo up-regulation of
Fas/FasL in an alloantigen-driven response. Our inability to achieve
complete inhibition of Fas/FasL up-regulation with anti-IFN- mAb
suggests either failure to neutralize all IFN- in vivo or that other
cytokines contribute to up-regulation of Fas/FasL in vivo.
Based on the correspondence between Fas/FasL expression ex vivo and
functional analysis in vitro, our results also suggest that the
up-regulation of Fas/FasL plays a quantitatively significant role in
anti-host CTL activity. However, donor CTL also kill host cells via
the perforin pathway, as demonstrated by the reduction in cytotoxicity
of CD8+ T cells exposed to a perforin pathway-blocking
agent, concanamycin. These results are similar to those obtained in
another model of GVHD using irradiated recipients and bone marrow
transplantation. In this model, anti-host CTL were significantly
attenuated with either Fas- or perforin-deficient donors (27, 28).
Although CD4+ CTL clones generated in vitro have been shown
to kill exclusively by the Fas pathway (29), and we observed FasL
up-regulation on both donor CD4+ and CD8+ T
cells in the PF1 model, all the anti-host
CTL activity (both Fas dependent and Fas independent) could be
accounted for by donor CD8+ CTL. This result is surprising
considering that IFN--producing CD4+ T cells are present
in acute GVHD (23), and this functional subset expresses FasL.
Donor CD8+ T cells contribute to acute GVHD development not
only through their role as CTL effectors, but also through their
ability to promote IFN- production (23). Our results indicate that
IFN- production, in turn, promotes the elimination of host cells by
making donor CTLs better killers through the up-regulation of FasL and
making host cells better targets through the up-regulation of Fas. Few
studies have examined cytokine regulation of FasL expression in vivo.
In a recent study using cloned T cells, it was reported that
IFN--inducing factor (IL-18) and IL-12 enhanced the FasL-mediated
cytotoxicity of Th1 cells, whereas IFN-, TNF-
, and IFN- had no
effect (30). However, IFN- has previously been shown to increase Fas
expression on naive or umbilical cord lymphocytes, and the Fas-encoding
gene has an IFN--responsive element in its promoter (31, 32). The
reciprocal, although weaker, up-regulation of Fas on donor T cells and
of FasL on host T cells is consistent with a host anti-donor CTL
response described by others (33), which, because of its lesser
magnitude, is unable to prevent the stronger donor anti-host
response.
Our results have important implications for the in vivo regulation of
cell-mediated and antibody-mediated immune responses. In the
PF1 model, both donor and host immune
responses are normal before cell transfer, and no radiation of the
recipient is involved. Disease in this model results not from abnormal
functioning of the immune response but, rather, from the targeting of a
normal immune response to host alloantigens. Thus, acute and chronic
GVHD can be viewed as a paradigm for Ag-driven in vivo cell-mediated or
Ab-mediated immune response, respectively. The data in the present
study suggest that Fas/FasL up-regulation may be a feature of cell
mediated Ag-driven responses, particularly when IFN- is produced,
but not of Ab-mediated responses.
Lastly, our results have implications for the development of humoral
autoimmunity. Escape of autoreactive B cells with subsequent
autoantibody production is felt to be a possible mechanism involved in
the development of humoral autoimmune diseases such as lupus (5, 34).
Fas and FasL are important in the elimination of autoreactive B cells,
as mice deficient in either of these molecules (e.g., lpr or
gld, respectively) exhibit humoral autoimmunity. It has been
postulated that autoreactive B cells are normally kept in check by
Fas/FasL-mediated killing, particularly by CD4+ T cells (5, 6, 29), and that up-regulation of Fas on B cells is essential for their
elimination (35, 36). However, our results indicate that activation of
autoreactive B cells in the absence of IFN- may prevent their
elimination through the down-regulation of Fas/FasL. Not only are
CTL-killing mechanisms impaired through reduced FasL expression, but B
cells are less susceptible to elimination due to reduced Fas expression
(37). We have previously shown that the administration of the
IFN--promoting cytokine, IL-12, to chronic GVHD mice can result in
the elimination of autoreactive B cells by converting disease to acute
GVHD (38). However, this effect was IFN- independent. We are
currently testing the feasibility of inducing Fas/FasL up-regulation
and autoreactive B cell elimination by IFN- administration to mice
undergoing chronic lupus-like GVHD.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Charles S. Via, Division of Rheumatology and Clinical Immunology, MSTF 8-34, 10 S. Pine St., University of Maryland School of Medicine, Baltimore, MD 21201. E-mail address:
3 Abbreviations used in this paper: FasL, Fas ligand; PF1, parent-into-F1; GVHD, graft-vs-host disease; B6, C57BL/6; DBA, DBA/2J; HPRT, hypoxanthine phosphoribosyl transferase; mcf, mean channel fluorescence; CMA, concanamycin A.
Received for publication January 26, 1998. Accepted for publication May 21, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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inducing factor, a novel cytokine, enhances Fas ligand mediated cytotoxicity in murine T helper 1 cells. Cell. Immunol. 173:230.[Medline]
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 D. Arnold, C. Wasem, P. Juillard, P. Graber, I. Cima, C. Frutschi, S. Herren, S. Jakob, S. Alouani, C. Mueller, et al. IL-18-independent cytotoxic T lymphocyte activation and IFN-{gamma} production during experimental acute graft-versus-host disease Int. Immunol., May 1, 2002; 14(5): 503 - 511. [Abstract] [Full Text] [PDF]
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T. J. Lang, P. Nguyen, R. Peach, W. C. Gause, and C. S. Via In Vivo CD86 Blockade Inhibits CD4+ T Cell Activation, Whereas CD80 Blockade Potentiates CD8+ T Cell Activation and CTL Effector Function J. Immunol., April 15, 2002; 168(8): 3786 - 3792. [Abstract] [Full Text] [PDF]
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C. S. Via, A. Shustov, V. Rus, T. Lang, P. Nguyen, and F. D. Finkelman In Vivo Neutralization of TNF-{alpha} Promotes Humoral Autoimmunity by Preventing the Induction of CTL J. Immunol., December 15, 2001; 167(12): 6821 - 6826. [Abstract] [Full Text] [PDF]
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C. Wasem, C. Frutschi, D. Arnold, C. Vallan, T. Lin, D. R. Green, C. Mueller, and T. Brunner Accumulation and Activation-Induced Release of Preformed Fas (CD95) Ligand During the Pathogenesis of Experimental Graft-Versus-Host Disease J. Immunol., September 1, 2001; 167(5): 2936 - 2941. [Abstract] [Full Text] [PDF]
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H. Itoi, Y. Fujimori, H. Tsutsui, K. Matsui, S. Futatsugi, H. Okamura, H. Hara, T. Hada, E. Kakishita, and K. Nakanishi Fas ligand-induced caspase-1-dependent accumulation of interleukin-18 in mice with acute graft-versus-host disease Blood, July 1, 2001; 98(1): 235 - 237. [Abstract] [Full Text] [PDF]
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H. Tang, K. Chen, Y. Wei, G. C. Sharp, L. McKee, and H. Braley-Mullen Apoptosis of thyrocytes and effector cells during induction and resolution of granulomatous experimental autoimmune thyroiditis Int. Immunol., December 1, 2000; 12(12): 1629 - 1639. [Abstract] [Full Text] [PDF]
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J. R. Tschetter, E. Mozes, and G. M. Shearer Progression from Acute to Chronic Disease in a Murine Parent-into-F1 Model of Graft-Versus-Host Disease J. Immunol., November 15, 2000; 165(10): 5987 - 5994. [Abstract] [Full Text] [PDF]
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S. Thornton, G. P. Boivin, K. N. Kim, F. D. Finkelman, and R. Hirsch Heterogeneous Effects of IL-2 on Collagen-Induced Arthritis J. Immunol., August 1, 2000; 165(3): 1557 - 1563. [Abstract] [Full Text] [PDF]
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I. Okamoto, K. Kohno, T. Tanimoto, K. Iwaki, T. Ishihara, S. Akamatsu, H. Ikegami, and M. Kurimoto IL-18 Prevents the Development of Chronic Graft-Versus-Host Disease in Mice J. Immunol., June 1, 2000; 164(11): 6067 - 6074. [Abstract] [Full Text] [PDF]
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O. T. M. Chan and M. J. Shlomchik Cutting Edge: B Cells Promote CD8+ T Cell Activation in MRL-Faslpr Mice Independently of MHC Class I Antigen Presentation J. Immunol., February 15, 2000; 164(4): 1658 - 1662. [Abstract] [Full Text] [PDF]
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J.-K. Lee, T. J. Sayers, A. D. Brooks, T. C. Back, H. A. Young, K. L. Komschlies, J. M. Wigginton, and R. H. Wiltrout IFN-{gamma}-Dependent Delay of In Vivo Tumor Progression by Fas Overexpression on Murine Renal Cancer Cells J. Immunol., January 1, 2000; 164(1): 231 - 239. [Abstract] [Full Text] [PDF]
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S. Brochu, B. Rioux-Masse, J. Roy, D.-C. Roy, and C. Perreault Massive Activation-Induced Cell Death of Alloreactive T Cells With Apoptosis of Bystander Postthymic T Cells Prevents Immune Reconstitution in Mice With Graft-Versus-Host Disease Blood, July 15, 1999; 94(2): 390 - 400. [Abstract] [Full Text] [PDF]
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L. Pan, T. Teshima, G. R. Hill, D. Bungard, Y. S. Brinson, V. S. Reddy, K. R. Cooke, and J. L.M. Ferrara Granulocyte Colony-Stimulating Factor-Mobilized Allogeneic Stem Cell Transplantation Maintains Graft-Versus-Leukemia Effects Through a Perforin-Dependent Pathway While Preventing Graft-Versus-Host Disease Blood, June 15, 1999; 93(12): 4071 - 4078. [Abstract] [Full Text] [PDF]
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 L. L. Perry, K. Feilzer, S. Hughes, and H. D. Caldwell Clearance of Chlamydia trachomatis from the Murine Genital Mucosa Does Not Require Perforin-Mediated Cytolysis or Fas-Mediated Apoptosis Infect. Immun., March 1, 1999; 67(3): 1379 - 1385. [Abstract] [Full Text] [PDF]
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