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Promotes Humoral Autoimmunity by Preventing the Induction of CTL1
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Research Service, Department of Veterans Affairs Medical Center and Division of Rheumatology and Clinical Immunology, University of Maryland School of Medicine, Baltimore, MD 21201; and
Immunology Division, Veterans Affairs Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH 45267.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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in humans with rheumatoid arthritis or
Crohn’s disease has been associated with the development of humoral
autoimmunity. To determine the effect of TNF- neutralization on
cell-mediated and humoral-mediated responses, we administered
anti-TNF- mAb to mice undergoing acute graft-vs-host disease
(GVHD) using the parent-into-F1 model. In vivo
neutralization of TNF- blocked the lymphocytopenic features
characteristic of acute GVHD and induced a lupus-like chronic GVHD
phenotype (lymphoproliferation and autoantibody production). These
effects resulted from complete inhibition of detectable antihost CTL
activity and required the presence of anti-TNF- mAb for the
first 4 days after parental cell transfer, indicating that TNF-
plays a critical role in the induction of CTL. Moreover, an in vivo
blockade of TNF- preferentially inhibited the production of IFN-
and blocked IFN--dependent up-regulation of Fas; however, cytokines
such as IL-10, IL-6, or IL-4 were not inhibited. These results suggest
that a therapeutic TNF- blockade may promote humoral autoimmunity by
selectively inhibiting the induction of a CTL response that would
normally suppress autoreactive B cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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is a
pleiotropic cytokine that plays a major role in inflammatory responses
(1). Recently, agents that neutralize TNF- have been
found to be beneficial in patients with rheumatoid arthritis and
Crohn’s disease (2, 3). A surprising side effect of such
treatment in some patients is the development of humoral autoimmunity
characterized by production of antinuclear and anti-dsDNA Ab
production (4, 5, 6, 7, 8, 9). Less commonly, treated individuals have
developed clinical features of systemic lupus erythematosus
(SLE)3
(4). Although these observations are consistent
with previous reports of a link between SLE and reduced TNF-
production (10), the mechanism responsible for development
of humoral autoimmunity in patients treated with TNF antagonists is not
established.
Suggestions that the inability to suppress or eliminate B cell
hyperactivity because of an ineffective CTL response may contribute to
SLE pathogenesis (11) and observations that membrane
TNF- expression by CTL can contribute to target cell lysis
(12) raise the possibility that TNF- antagonists may
promote humoral autoimmunity by inhibiting CTL responses. To test this
hypothesis, we examined TNF- regulation of graft-vs-host disease
(GVHD) in the parent-into-F1 murine model. This
system, in which homozygous parental T cells are inoculated into
unirradiated heterozygous mice, can lead to the development of either a
cell-mediated (acute GVHD) or an Ab-mediated (chronic GVHD) antihost
response, depending upon the parental mouse strain used. For example,
inoculation of (C57BL/6 x DBA/2)F1 mice
with C57BL/6 parental T cells induces acute GVHD while inoculation of
the same F1 hosts with DBA/2 parental T cells
induces chronic lupus-like GVHD (13). Both acute and
chronic GVHD are characterized initially by B cell hyperactivity and
autoantibody production. In acute GVHD, however, donor cells develop
within 7 days into antihost CTL that eliminate most host B cells,
including autoreactive B cells, during the subsequent 5–7 days
(14). In chronic GVHD, in contrast, antihost CTL fail to
develop and continued autoantibody production results in a lupus-like
immune complex glomerulonephritis. Previous studies demonstrating that
selective in vivo inhibition of CD8+ T cell-CTL
development prevents acute GVHD and leads to the development of chronic
lupus-like GVHD support the view that CD8+ CTL
control autoreactive B cell hyperactivity and that the absence of such
CTL plays a permissive role in humoral autoimmunity development
(15). We now demonstrate that TNF- is required to
suppress humoral autoimmunity in GVHD and does so by inducing CTL
development rather than by contributing to CTL effector function.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6J (B6) and C57BL/6 x DBA/2 (BDF1) male mice, 6–8-wk of age, were purchased from The Jackson Laboratory (Bar Harbor, ME).
Induction of GVHD
Single-cell suspensions were prepared in HBSS from the spleens
of normal 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 by injecting 50 x
106 B6 splenocytes i.v. into the tail veins of
normal unirradiated BDF1 recipients
(16). Chronic GVHD was induced using 50 x 106
CD8-depleted B6 splenocytes (18). Unless otherwise stated, mice
received 2 mg of the rat IgG1 anti-TNF- mAb, MP6-XT22
(17), or control rat IgG1 mAb (GL113) i.v. beginning at
the time of parental cell transfer (day 0) and repeated every 3–4 days
thereafter for a total of four doses. Positive and negative controls
were, respectively, BDF1 mice injected with B6
spleen cells in the absence of mAbs and uninjected age- and sex-matched
BDF1 mice.
Detection of antihost CTL activity ex vivo
Effector CTL activity of freshly harvested splenocytes was tested in a 4-h 51Cr release assay, as described in Ref. 18 , without an in vitro sensitization period. Splenocytes from control and GVHD mice were tested for their ability to lyse Fas-dull P815 cell line (H-2d, MHC class I positive, class II negative) targets. Using serial dilutions, effectors were tested in triplicate at four E:T ratios, beginning at 100:1 (1.5 x 106 effectors and 0.015 x 106 targets/well). The percentage of lysis was calculated according to the formula: (cpm sample - cpm spontaneous)/(cpm maximum - cpm spontaneous) x 100%. Results are shown as the mean percent lysis ± SEM at a given E:T ratio for each treatment group.
Cincinnati cytokine capture assay (CCCA)
A recently described assay, the CCCA (19) was used
to quantitate in vivo production of IFN-, TNF-, IL-2, IL-4, and
IL-6 in mice undergoing GVHD. The CCCA increases the sensitivity of
detection of each of the cytokines measured by a factor of 100-1000.
Briefly, mice are injected i.v. with 10 µg of a biotin-labeled
neutralizing mAb to IL-2, IL-4, IL-6, TNF-, or IFN-, which binds
some, but not all, of the respective cytokine shortly after it is
secreted. The biotin-mAb–cytokine complexes formed have a much longer
in vivo half-life than uncomplexed cytokines and accumulate in serum.
Mice are bled 1 day after biotin-mAb injection and concentrations of
biotin-mAb–cytokine complexes are measured by ELISA using microtiter
plate wells coated with mAbs to an epitope on the appropriate cytokine
that is not blocked by the injected biotin-labeled mAb to the same
cytokine. Biotin-labeled mAb–cytokine complexes in serum samples or
standards (prepared by mixing recombinant cytokines, purchased from BD
PharMingen (San Diego, CA), with the appropriate
biotin-anti-cytokine mAbs at a 1:100 weight ratio) are detected
with streptavidin-HRP (Jackson ImmunoResearch Laboratories, West Grove,
PA), followed by a substrate solution (SuperSignal ELISA Femto Maximum
Sensitivity Substrate; Pierce, Rockford, IL) that generates a
luminescent compound when cleaved by HRP. Plates are read immediately
after addition of substrate with a Fluoroskan Ascent FL luminometer
(Labsystems, Helsinki, Finland).
The CCCA does not interfere with ongoing immune responses because only
a relatively small percentage of secreted cytokine is bound by the
injected biotin-mAb and because biotin-mAb–cytokine complexes contain
only 1 molecule of IgG mAb and thus do not fix, complement, or bind to
FcR more avidly than endogenous serum IgG. The following pairs of
anti-cytokine mAbs were used, all of which were obtained from Dr.
D. Sehy at BD PharMingen: for IL-2, inject biotin-JES6-5H4, then coat
wells with JES6-1A12; for IL-4, inject biotin-BVD4-1D11, then coat
wells with BVD6-24G2.3; for IL-6, inject biotin-MP5-32C11, then coat
wells with MP5-20F3; for IFN-, inject biotin-AN-18, then coat wells
with R46A2; and for TNF-, inject biotin-TN3, then coat plates with
the IgG fraction of rabbit anti-TNF- polyclonal antiserum.
References for all of the mAbs used for this assay are given in the BD
PharMingen catalog; detailed protocols for each cytokine are available
on The Journal of Immunology Web site and will be published
(F. Finkelman, S. Morris, T. Orekltova, and D. Sehy, manuscript
in preparation).
RT-PCR
Cytokines were also measured by semi-quantitative RT-PCR as
previously described (20). Briefly, RNase-free plastic and
water were used throughout the assay and tissues were homogenized in
RNA-STAT-60 (Tel-Test, Friendswood, TX) at 50 mg tissue/ml or 1
ml/107 cells. RNA samples were reverse
transcribed with reverse transcriptase (Life Technologies, Grand
Island, NY); Fas ligand (FasL) or IFN- specific primers were used
for amplification as described in Ref. 20 . 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 within an experiment, primers for the
housekeeping gene hypoxanthine
phosphoribosyltransferase were used in each experiment.
Gene expression was quantitated by densitometry for individual mice,
normalized to each individual hypoxanthine
phosphoribosyltransferase value, and group means calculated.
Flow cytometry analysis and engraftment studies
Spleen cells were prepared as described in Ref. 16 .
Following incubation with the anti-murine FcRII/RIII mAb, 2.4G2,
(21) for 10 min, cells were stained with saturating
concentrations of FITC-, biotin-, or PE-conjugated mAb against CD4,
CD8, B220, Fas, or H-2Kd purchased from BD
Biosciences (Mountain View, CA.) or BD PharMingen. Two-color flow
cytometry was performed using a FACScan (BD Biosciences), lymphocytes
were gated by forward and side scatter, and fluorescence data were
collected on 10,000 cells. Donor T cells were defined as
CD4+ or CD8+ and stained
negatively for MHC class I expressed by the recipient, but not the
donor, cells. Host B cells were identified as B220-positive host
I-A-positive cells. Monocyte populations were excluded on the basis of
forward and side scatter.
Serological studies
Mice were bled at the times indicated and sera were tested by ELISA for the presence of IgG antibodies to ssDNA as described in Ref. 16 . Briefly, microtiter plates were coated with heat-denatured salmon sperm DNA, blocked with 2% BSA-PBS and incubated with 2-fold serial dilutions of experimental mouse sera beginning at a dilution of 1/40. The plates were then incubated with alkaline phosphatase-labeled anti-mouse IgG (Southern Biotechnology Associates, Birmingham, AL) and OD quantitated at 405 nm. For each experiment, pooled MRL/lpr sera were tested in parallel and a standard curve constructed for conversion of experimental sera OD values to units. An arbitrary value of 1000 U was assigned to MRL/lpr sera at a dilution of 1/2000.
Statistical Analysis
Data were examined for normality and equal variance (Kolmogorov-Smirnov test). If satisfactory, groups were compared by two-tailed Student’s t test, if not they were compared by the Mann-Whitney rank sum test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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in vivo inhibits the development of acute
GVHD and enhances anti-DNA Ab production in a dose-dependent
fashion
To determine the role of TNF- in the development of acute GVHD,
BDF1 mice were inoculated with B6 spleen cells
and received either no additional treatment or 0.125–2 mg of
anti-TNF- mAb twice a week, beginning on the day of parental
cell transfer (Table I
). Treatment with
the highest dose of anti-TNF- mAb (2 mg) not only blocked the
reduction in total splenocytes and host B cells typically seen in acute
GVHD, but also resulted in lymphoproliferation, as evidenced by an
40–50% increase in both total spleen cells and host B cells
compared with normal untreated F1 mice
(p < 0.005 for both). Treatment with 0.125 mg
of anti-TNF- mAb did not significantly alter GVHD-associated
splenic lymphopenia or B cell elimination. Intermediate doses
(0.5 mg) of anti-TNF- mAb resulted in a trend toward less severe
acute GVHD; however differences were not statistically significant when
compared with untreated or low-dose mAb-treated acute GVHD mice.
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mAb was associated with a
significant increase in serum anti-ssDNA Ab levels compared with
either untreated acute GVHD mice (2.5-fold) or with normal
F1 mice (8-fold; p < 0.05 for
both; Table I
). Mice treated for 10 days with high-dose
anti-TNF- mAb still exhibited increased spleen cell numbers and
anti-DNA Ab titer 1 month later (data not shown). Taken together,
these data indicate that stringent neutralization of TNF- induces
features of chronic GVHD in mice that would otherwise develop acute
GVHD and suggest that less complete TNF- neutralization can block
features of acute GVHD without inducing lupus-like GVHD.
Neutralization of TNF- in vivo blocks antihost CTL activity in
acute GVHD
Lymphopenia in acute GVHD is mediated, in large part, by
elimination of host cells by host-specific donor CTLs (16, 22). Because selective inhibition of donor antihost CTL activity
can permit the development of chronic GVHD (14, 23), the
above results were consistent with the possibility that neutralization
of TNF- promotes chronic GVHD by inhibiting donor antihost CTL
development. To test this idea, mice received 2 mg of anti-TNF-
or control mAb twice a week and antihost CTL responses were assessed at
the time of maximal CTL activity, 10 days after parental cell transfer
(14). As shown in Fig. 1, in
vivo anti-TNF- mAb treatment completely inhibited antihost CTL
activity, as compared with mice that received parental cells but either
no mAb or control mAb. In contrast to its ability to inhibit the
induction of CTL activity when administered in vivo before the
development of acute GVHD, anti-TNF- mAb did not block the
antihost CTL effector function as evidenced by an inability to: 1)
block anti-DBA cytolytic activity when added to IL-2-stimulated
cultures of spleen cells from day 10 acute GVHD mice (data not shown)
or 2) block antihost CTL effector function when added during the 4-h
assay phase (data not shown).
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is critical in the inductive phase of antihost CTL
generation
Although TNF- has been shown to contribute to CTL effector
function (12), the foregoing data suggest that TNF- is
required in vivo to generate CTLs. Moreover, we have observed that a
single dose of anti-TNF- mAb given the same day as parental cell
transfer can block the lymphocytopenic features of acute GVHD and
promote autoantibody production almost as effectively as twice weekly
mAb administration. Specifically, host B cell numbers in acute GVHD
mice that received a single dose of anti-TNF- mAb did not differ
significantly from host B cell numbers in acute GVHD mice that received
multiple doses of anti-TNF-mAb (data not shown). These results
suggest that TNF- is important early in CTL development. To test
this idea, additional experiments were performed in which the
administration of anti-TNF- mAb was variably delayed after
parental cell transfer to determine the critical time period for
TNF- in the generation of donor antihost CTL. Using depletion of
host B cells as a measure of in vivo antihost CTL generation and acute
GVHD, a single dose of anti-TNF- mAb was able to significantly
inhibit acute GVHD if administered at either day 0, 2, or 4 after
parental cell transfer, but failed to block acute GVHD if administered
7 or more days after parental cell transfer (Fig. 2). Because mature donor antihost CTLs
are first detected in this system 10 days after donor cell transfer and
eliminate host lymphocytes from days 10 to14 (14), these
data indicate that in vivo TNF- blockade prevents acute GVHD by
inhibiting CTL induction but not CTL effector function.
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Increased serum levels of TNF- have been reported in acute GVHD
mice as early as day 10 after parental cell transfer but were not seen
at day 8 (24). Although the foregoing data strongly argue
that TNF- is present in the first few days of acute GVHD, we have
been unable to detect increased serum TNF- at days 3, 5, or 7 by
standard ELISA (data not shown). Recent modifications of the CCCA
significantly increase the sensitivity of this assay (19).
Using this approach, we have determined that as early as day 6, both
acute and chronic GVHD mice exhibit significant increases in several
major cytokines. In particular, acute GVHD mice exhibit significantly
elevated serum TNF- levels which are 
3-fold greater than control
mice and 2-fold greater than chronic GVHD mice (Table II). Moreover, striking elevations in
serum IFN- levels are seen in acute GVHD which are several logs
greater than those of either chronic GVHD mice or control
F1 mice. It should be noted that serum IFN-
levels in chronic GVHD mice, while significantly less than those of
acute GVHD mice, are nevertheless significantly greater than control
mice. By day 9 after parental cell transfer, an 5-fold elevation in
serum IL-2 levels is seen for both acute and chronic GVHD mice compared
with control F1 mice (p
< 0.01, acute GVHD or chronic GVHD vs normal; p = NS,
acute vs chronic). Additionally, chronic GVHD mice exhibited an
approximate 4-fold elevation in serum IL-4 compared with control
F1 mice (p < 0.01);
however, acute GVHD mice exhibited even greater elevations in serum
IL-4 levels compared with either control F1 mice
(9-fold, p < 0.01) or chronic GVHD mice (2-fold,
p < 0.01). These data indicate that although
significant increases in cytokine production are present in both forms
of GVHD, acute GVHD mice make greater amounts of TNF-, IL-4, and
most notably IFN- compared with chronic GVHD mice.
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in acute GVHD selectively blocks
production of IFN-
Activation of donor CD4+ T cells is a common
feature of both acute and chronic GVHD and initially results in the
production of IL-2, IL-4, and IL-10 (14). In acute GVHD,
activation of donor CD4+ T cells leads to donor
CD8+ T cell activation which results in IFN-
production and the development of an antihost CTL response
(14). In contrast, donor CD8+ T cell
activation and marked IFN- production are not features of chronic
GVHD. Because early administration of anti-TNF- mAb inhibits CTL
development (Fig. 2) and IFN- contributes to CTL development in this
model (14, 18), it was possible that anti-TNF- mAb
blocked CTL development, in part, by inhibiting an IFN- response. To
determine whether a TNF- blockade alters cytokine production in
acute GVHD, splenic mRNA was assessed for cytokine gene expression by
semi-quantitative RT-PCR. As shown in Fig. 3A, in vivo treatment with
anti-TNF- mAb resulted in an 3-fold inhibition of IFN-
mRNA expression as compared with untreated or control mAb-treated
BDF1 mice that had been inoculated with B6 spleen
cells. In contrast, anti-TNF- mAb treatment did not
significantly inhibit IL-4 or IL-10 mRNA expression. These results were
confirmed at the level of serum cytokine protein. As shown above in
Table II, acute GVHD mice exhibit very high serum levels of IFN- at
day 6 after parental cell transfer. Anti-TNF- treatment completely
inhibits the acute GVHD-associated rise in serum IFN- but does not
significantly alter the serum levels of a B cell stimulatory cytokine
such as IL-6 (Fig. 3B).
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blockade impairs IFN--mediated Fas
up-regulation in acute GVHD
We have previously shown that elimination of host B cells in acute
GVHD by donor CTL involves both a Fas/FasL pathway and a perforin
pathway (18). Moreover, significant Fas up-regulation on
host B cells is characteristic of acute GVHD, but not chronic GVHD, and
is largely IFN- dependent (18). To determine whether
the striking reduction in serum IFN- in anti-TNF--treated acute
GVHD mice results in functional consequences, IFN--dependent Fas
expression on host B cells was examined by flow cytometry at 10 days
after parental cell transfer. As shown in Fig. 4, A and B, the
characteristic up-regulation of Fas on host B cells in acute GVHD is
mostly, but not completely, down-regulated in mice receiving
anti-TNF- mAb. These results are consistent with previous work
demonstrating a comparable degree of Fas down-regulation in chronic
GVHD mice or in anti-IFN- mAb-treated acute GVHD mice
(18).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production and the development of humoral
autoimmunity. For example, lupus-prone New Zealand Black/White (NZB/W)
mice express an allelic form of the TNF- gene that is
associated with decreased TNF- production (25).
Treatment of NZB/W mice with anti-TNF- mAb exacerbates renal
disease and mortality (25), while administration of
rTNF- at the proper time can retard disease development (26, 27). Furthermore, deletion of the type I TNFR gene
from C57BL/6.lpr mice accelerates the development of
lymphadenopathy and autoimmunity (28), whereas breeding a
defective TNF gene onto New Zealand Black mice enhances the
otherwise mild autoimmune response in these mice and results in severe
renal diseases similar to NZB/W mice (29). In humans,
defective TNF- responses have been widely reported in association
with SLE (10, 30, 31, 32) and have been linked to the
development of lupus nephritis (10), although not all
workers have observed this relationship (33). Lastly, the
development of the anti-nuclear Ab, anti-dsDNA Ab and,
occasionally, clinical SLE in patients treated with TNF antagonists
(4, 7, 34) supports the idea that in some individuals,
reduced TNF activity is associated with humoral autoimmunity.
The present study demonstrates that TNF- is critical for the
induction of CTL in vivo and suggests a mechanism by which reduced
TNF- activity may contribute to the development of humoral
autoimmunity in both mouse and human. In the
parent
F1 GVHD model, both acute and chronic
GVHD are initiated by the activation of donor
CD4+ T cells that produce IL-2 and mature into
effector T helper cells that activate B cells to proliferate and
secrete Ig. As a result, polyclonal B cell activation and autoantibody
production can be observed 7–10 days after parental cell transfer in
both forms of GVHD (14). Activation of donor
CD8+ T cells, which mature into antihost CTL,
eliminates autoantibody-secreting host B cells and serves to
differentiate acute GVHD from chronic GVHD. Actions that selectively
impair CD8+ T cell differentiation into antihost
CTL, such as in vivo treatment with anti-IL-2 mAb
(15), depletion of donor CD8+ T
cells before parental cell transfer (16), or deletion of
the perforin gene from donor CD8+ T cells
(11), convert acute GVHD to chronic lupus-like GVHD. Thus,
CTL likely prevent lupus-like humoral autoimmunity in
parentF1 GVHD by eliminating autoreactive host
B cells. Our results indicate that neutralization of TNF- during the
first few days after parental cell transfer selectively inhibits
CD8+ T cell maturation into CTL effectors, in
association with suppression of IFN- production and decreased
Fas/FasL up-regulation. Because anti-TNF- mAb treatment does not
inhibit all cytokine production or B cell hyperactivity, mice then
develop chronic lupus-like GVHD.
Although TNF- is well known to be involved in the CTL effector
function, a role for TNF- in CTL generation has only recently been
suggested. T cells from TNFR I-deficient mice exhibit reduced in vitro
production of IFN- and IL-2 in response to alloantigen
(35) and anti-TNF- Ab has been described to
decrease CTL generation, reduce splenomegaly and gastrointestinal
pathology, decrease weight loss, and improve survival in an irradiated
recipient model of bone marrow transplantation and GVHD and in a
parentF1 model of GVHD (36, 37, 38, 39).
In addition, impaired CTL function and reduced Th1 cytokine production
were observed in GVHD when donor cells were obtained from TNFR
p55-deficient mice (35). However, previous studies did not
investigate the connection between anti-TNF- treatment and the
development of autoimmunity.
Our finding that TNF- is critical for CTL induction and subsequent
control of autoreactive B cells ties together previous unlinked
clinical and experimental observations that: 1) TNF- suppresses
humoral autoimmunity (26, 27); 2) TNF- can induce
IFN- production (40, 41); 3) IFN- enhances CTL
function by up-regulating Fas and FasL expression (18);
and 4) CTL suppress humoral autoimmunity by killing autoreactive B
cells (11, 16). Our studies do not eliminate the
possibility that TNF- may also contribute to CTL activation by
up-regulating perforin expression, either through an IFN--dependent
or independent mechanism.
Lastly, our results establish a mechanism by which treatment of
autoimmune disease patients with TNF- antagonists could induce or
exacerbate disorders of humoral autoimmunity, such as SLE. Although our
results by no means argue against the clinical use of TNF-
antagonists which have been remarkably effective therapies for many
patients with rheumatoid arthritis or Crohn’s disease, they underscore
the need to carefully monitor treated patients and to identify factors
that might predispose patients to develop autoimmune pathology when
treated with TNF- antagonists. In addition, the possibility that
TNF- may be a general requirement for CTL development should promote
caution in using TNF antagonists in patients with conditions in which
CTL appear to limit severity, such as viral infections. Conversely, TNF
antagonists may be of benefit in conditions in which CTL are
detrimental, such as acute allograft rejection.
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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, University of Maryland School of Medicine, Medical School Teaching Facility 8-34, 10 South Pine Street, Baltimore, MD 21201. E-mail address: cvia{at}umaryland.edu
3 Abbreviations used in this paper: SLE, systemic lupus erythematosus; GVHD, graft-vs-host disease; CCCA, Cincinnati cytokine capture assay; FasL, Fas ligand.
Received for publication August 17, 2001. Accepted for publication October 11, 2001.
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 C. Perez-Garcia, J. Maymo, M. P. Lisbona Perez, M. Almirall Bernabe, and J. Carbonell Abello Drug-induced systemic lupus erythematosus in ankylosing spondylitis associated with infliximab Rheumatology, January 1, 2006; 45(1): 114 - 116. [Full Text] [PDF]
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C Mukhtyar and R Luqmani Current state of tumour necrosis factor {alpha} blockade in Wegener's granulomatosis Ann Rheum Dis, November 1, 2005; 64(suppl_4): iv31 - iv36. [Abstract] [Full Text] [PDF]
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C Eriksson, S Engstrand, K-G Sundqvist, and S Rantapaa-Dahlqvist Autoantibody formation in patients with rheumatoid arthritis treated with anti-TNF{alpha} Ann Rheum Dis, March 1, 2005; 64(3): 403 - 407. [Abstract] [Full Text] [PDF]
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R. Puliaev, P. Nguyen, F. D. Finkelman, and C. S. Via Differential Requirement for IFN-{gamma} in CTL Maturation in Acute Murine Graft-versus-Host Disease J. Immunol., July 15, 2004; 173(2): 910 - 919. [Abstract] [Full Text] [PDF]
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G F Ferraccioli and E Gremese Autoantibodies and thrombophilia in RA: TNF{alpha} and TNF{alpha} blockers Ann Rheum Dis, June 1, 2004; 63(6): 613 - 615. [Full Text]
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 M. I. Kafrouni, G. R. Brown, and D. L. Thiele The role of TNF-TNFR2 interactions in generation of CTL responses and clearance of hepatic adenovirus infection J. Leukoc. Biol., October 1, 2003; 74(4): 564 - 571. [Abstract] [Full Text] [PDF]
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R A Mageed and D A Isenberg Tumour necrosis factor alpha in systemic lupus erythematosus and anti-DNA autoantibody production Lupus, December 1, 2002; 11(12): 850 - 855. [Abstract] [PDF]
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