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*
Mucosal Immunity Section, Laboratory of Clinical Investigation, and
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, but not of IL-4, IL-5, or IL-10. Furthermore, TNF-
production from PBMCs and CD4+ T cells isolated from
patients with WG was elevated, when compared with healthy donors. In
further studies, we investigated the ability of WG patients’ monocytes
to produce IL-12 and showed that both inactive and active patients
produced increased amounts of IL-12. Finally, the in vitro IFN-
production by WG PBMC is inhibited in a dose-dependent manner by
exogenous IL-10. These data suggest that T cells from WG patients
overproduce IFN- and TNF-, probably due to dysregulated IL-12
secretion, and that IL-10 may therefore have therapeutic implications
for this disease. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In recent years, studies of the pathogenesis of various autoimmune and infectious diseases have shown that the inflammatory lesions occurring in some of these diseases are driven by T cells that display either a Th1- or Th2-type pattern of cytokine secretion. For example, in infection due to Mycobacterium tuberculosis or in Crohn’s disease (an inflammatory bowel disease of unknown etiology), the granulomatous lesions are dominated by T cells exhibiting a Th1-type pattern (9, 10, 11, 12). In contrast, in the inflammatory lesions seen in schistosomiasis and extrinsic asthma, the associated infiltrates are dominated by T cells exhibiting a Th2-type pattern (13, 14, 15, 16). This paradigm also holds for various animal models of infection and autoimmunity; in several of these models, treatment directed toward the blocking of the Th1-type or Th2-type T cell response leads to amelioration of disease (17). Thus, the cytokine pattern present in a given autoimmune disease is of more than theoretical interest.
In previous studies, it has been shown that the granulomatous lesions of giant cell arteritis contain cells that display a Th1-type cytokine pattern (18), and it is reasonable to ask whether WG falls into the same or a different category. In the present studies, we address the latter question by examining both the proliferative capacity and the profile of cytokine secretion of circulating T cell populations from patients with WG.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Seventeen patients with WG were studied. All 19 patients had
biopsy-proven WG, characterized by necrotizing vasculitis,
granulomatous inflammatory changes, or both, in a typical organ system.
In addition, all patients met the American College of Rheumatology 1990
criteria for classification of WG. These patients were participating in
clinical research protocols approved by the National Institute of
Allergy and Infectious Diseases (NIAID) Institutional Review
Board, and the Clinical Director (NIAID) of the Clinical Center of the
National Institutes of Health. All patients provided written informed
consent. The clinical features of the 19 patients are summarized in
Table I
. Healthy volunteers from the
apheresis center of the National Institutes of Health Department of
Transfusion Medicine served as controls.
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PBMCs from WG patients and normal healthy human donor volunteers were isolated by Ficoll-Hypaque density gradient centrifugation of leukocyte concentrates obtained by the apheresis center of the National Institutes of Health by automated apheresis, as described previously (19). T cell-enriched populations from PBMCs were prepared by rosette formation with neuraminidase-treated sheep RBC, followed by recentrifugation over Ficoll-Hypaque gradient. Highly purified PB CD4+ or PB CD8+ T cells were prepared by negative selection using mAbs attached to immunomagnetic beads, as described previously (12). In brief, PB T cell populations were suspended at 2 x 107 cells/ml in calcium-free PBS with 1% FCS (coating medium) to which dilutions of ascites fluid containing the mAbs, anti-CD8, anti-MHC class II, anti-CD14, and anti-CD21 were added. The hybridoma cell lines OKT8 (anti-CD8), IVA12 (anti-MHC class II), 63D3 (anti-CD14), and THB5 (anti-CD21) were obtained from American Type Culture Collection (Rockville, MD), and the hybridoma cell lines 3G8 (anti-CD16) and 10F7 (anti-erythroglycoprotein) were obtained from Dr. Scott Fritz (NIAID, Frederick, MD). Each ascites sample was used at a dilution of 1:350 except IVA12, which was used at a dilution of 1:250. These Abs were prepared as murine ascites and filtered as described previously (20). The cells were incubated at 4°C for 30 min, washed twice, and resuspended in coating medium. The Ab-coated cell populations were then removed by an initial incubation with immunomagnetic beads coated with anti-murine IgG Ab (Advanced Magnetics, Cambridge, MA), followed by a subsequent incubation with immunomagnetic beads coated with anti-murine IgG Ab obtained from Dynal (Oslo, Norway). The resultant T cell population contained >95% CD4+ T cells, as assessed by flow cytometric analysis. For use in flow cytometry studies, anti-CD3 (Leu 4), anti-CD4 FITC (Leu 3a + 3b), anti-CD8 phycoerythrin (Leu 2a), anti-CD14 (Leu M3), anti-CD20 (Leu 16), and control goat anti-mouse IgG FITC/phycoerythrin were purchased from Becton Dickinson (San Jose, CA). Purified monocytes (>95% pure) were isolated from normal human leukocyte concentrates (see above) using counterflow centrifugal elutriation. Purified monocytes were characterized by FACS analysis using fluoresceinated mAb (Becton Dickinson) with specificity for the following cell surface markers: Leu-M5 (monocytes), CD3 (T cells), CD57 (NK cells), and CD20 (B cells).
Reagents and mAbs
Cell cultures were performed in complete medium consisting of
RPMI 1640 (BioWhittaker, Walkersville, MD) supplemented with 3 mM
L-glutamine, 10 mM HEPES buffer, 10 mg/ml gentamicin
(BioWhittaker), 100 U/ml penicillin, and 10% heat-inactivated FCS. LPS
isolated from Escherichia coli 01127:BS was obtained from
Sigma Chemical Co. (St. Louis, MO) and used at 1 µg/ml. PMA was
obtained from Calbiochem (San Diego, CA) and was used at 20 ng/ml;
ionomycin was obtained from Sigma and was used at 100 ng/ml. Trimeric
human CD40 ligand (CD40L)/leucine-zipper fusion protein was obtained
from Immunex (Seattle, WA). Heat-killed, formalin-fixed
Staphylococcus aureus, Cowan I strain (SAC) was obtained
from Calbiochem. Recombinant IFN- (Genzyme, Cambridge, MA) was used
at 1 µg/ml. Anti-CD28 Ab was the gift of Dr. Carl June (Bethesda
Naval Research Institute, Bethesda, MD) and was used at a final
concentration of 1 µg/ml. The anti-CD2 Ab pair T112
and T113, used to stimulate T cells (12, 21), was provided
by Dr. Ellis Reinherz (Dana-Farber Cancer Institute, Boston, MA) and
was used at a dilution of 1:1000 each.
Proliferation assays
To measure proliferation, 5 x 104 cells were cultured in 0.2 ml of complete medium with different stimuli in flat-bottom 96-well microtiter plates (Costar, Cambridge, MA). Plates were incubated at 37°C in a humidified incubator containing 6% CO2 for 72 h. One mCi of [3H]thymidine (DuPont NEN, Boston, MA) was added to each microwell 16 h before terminating the culture. Finally, cells were harvested onto glass filter paper with an automated multisample harvester (PHD cell harvester; Cambridge Technology, Cambridge, MA) and counted in a liquid scintillation counter.
Lymphokine production assays
To measure lymphokine production, PBMCs, T cells, or monocytes
were cultured at 106 cells/well in 1 ml of complete
medium with different stimuli in 24-well tissue culture plates
(Costar). Plates were incubated at 37°C in a humidified incubator
containing 6% CO2 for 8 to 48 h as indicated, after
which supernatants were collected and assayed for IL-4, IL-5, IL-10,
IL-12, TNF-, or IFN- using commercially obtained ELISA kits
(BioSource International, Camarillo, CA). Methods used for these ELISAs
were provided by the manufacturer.
Statistical analysis
Descriptive statistics and testing for significance of differences were assessed by Student’s t test using the StatWorks and Microsoft Excel statistical analysis computer programs.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In initial studies, we determined proliferative responses of PBMCs
from WG patients with both active and inactive disease as well as from
healthy donors. As shown in Figure 1A, PBMCs from WG patients
with active disease stimulated with PMA/ionomycin exhibited a twofold
higher proliferative response after 72 h of culture (mean
[3H]thymidine incorporation, 2.24 x
104) compared with that of patients with inactive disease
or healthy donors (mean [3H]thymidine incorporation,
0.73 x 104 and 0.52 x 104,
respectively; p < 0.01). In addition, as also shown in
Figure 1A, when stimulated via the CD2/CD28 signaling
pathway, PB T cells from patients with active WG exhibited an
approximately sevenfold higher proliferative response than did T cells
from patients with inactive disease or normal controls. To determine
whether this increased proliferative response was due to T cells
previously activated in vivo, we isolated
CD4+HLA-DR- T cells by negative selection and
stimulated them with PMA/ionomycin or anti-CD2/anti-CD28. As
depicted in Figure 1B, the proliferative response of
CD4+HLA-DR- T cells did not differ between
patients and controls. Taken together, these results indicate that
patients with active WG have circulating, previously activated,
CD4+ T cells that exhibit a heightened proliferative
response.
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In the next set of studies, we determined the pattern of cytokine
responses by stimulated PBMCs from patients with both active and
inactive WG. PBMCs were stimulated with either PMA/ionomycin or
anti-CD2/anti-CD28, and cytokine secretion into culture
supernatants at 48 h was evaluated by ELISA (see Materials
and Methods). As shown in Figure 2A, PBMCs from patients with
active WG produced 10-fold higher amounts of IFN- than did those of
healthy controls when stimulated in vitro with either PMA/ionomycin or
anti-CD2/anti-CD28 (p < 0.001). In
contrast, as shown in Figure 2A, PBMCs from patients with
inactive WG produced increased amounts of IFN- in only three of
seven cases when stimulated by PMA/ionomycin and normal amounts of
IFN- when stimulated by anti-CD2/anti-CD28.
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production was limited to previously activated T
cells, since, as shown in Figure 2
, B and C,
anti-CD2/anti-CD28 stimulation of
CD4+HLA-DR+ T cells from patients with active
WG led to a 10-fold higher IFN- secretion than did stimulation of
cells from normal controls (p < 0.0001; Fig. 2B). Similar stimulation of
CD4+HLA-DR- T cells did not lead to higher
IFN- secretion. Parallel studies of T cells stimulated with
PMA/ionomycin also tended to show higher mean secretion of IFN- in
cultures from patients with active WG than in those of normal controls,
but in this case, the difference was no longer statistically
significant (Fig. 2C). The above abnormality in
IFN- secretion was limited to CD4+ T cells, since
purified CD8+ T cells from patients with active WG and
normal controls produced similar amounts of IFN- when stimulated
with anti-CD2/anti-CD28 or PMA/ionomycin (data not shown).
While there was a strong correlation between proliferative responses
and IFN- production in active WG patients (results not shown), there
was no correlation between these parameters in inactive WG patients. In
addition, we were not able to identify any clinical differences between
the inactive WG patients who had relatively high IFN- production
(when stimulated with PMA/ionomycin) and those with relatively low
IFN- production.
In a final set of cytokine secretion studies, we also determined the
ability of PBMCs and purified T cells from patients with active WG to
secrete Th2 cytokines. As shown in Figure 3, no difference between WG patients and
controls was found for IL-4 secretion from either PBMCs or purified
CD4+ T cells. Similarly, there was no significant
difference in the amount of IL-5 secreted by the different groups (data
not shown).
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and by normal
production of IL-4 and IL-5.
T cells, but not monocytes, from patients with active WG secrete
increased amounts of TNF-
TNF- is another Th1-type cytokine that is potentially important
in the pathogenesis of granulomatous inflammatory vascular lesions.
Therefore, in the next set of studies, we evaluated TNF- secretion
by T cells and monocytes from patients with active WG. Purified
CD4+ T cells were stimulated either with
PMA/ionomycin, with LPS + 3% human serum, or directly with
anti-CD2/anti-CD28. As shown in Figure 4A, CD4+ T cells
from patients with active WG secreted significantly more TNF- when
stimulated with either LPS or anti-CD2/anti-CD28 than did
CD4+ T cells from normal controls
(p < 0.002). In contrast, similar amounts of
TNF- were found in T cell supernatants from the two groups after
PMA/ionomycin stimulation. Interestingly, as shown in Figure 4B, freshly isolated and purified monocytes (see
Materials and Methods) from active WG patients did
not secrete increased amounts of TNF- compared with monocytes of
normal controls when stimulated with either PMA/ionomycin or LPS. These
results suggest that T cells, but not monocytes, isolated from the PB
of patients with active WG secrete enhanced amounts of TNF-.
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In view of the above findings of increased secretion of Th1
cytokines in patients with active WG, we next determined whether
monocytes from patients with WG exhibited increased production of
IL-12, the major inducer of IFN-. For these studies, we first
stimulated cryopreserved, purified monocytes from patients with
inactive WG and normal controls either with LPS alone, LPS and IFN-,
SAC and IFN-, or CD40L and IFN-. As shown in Figure 5A, monocytes that had been
isolated from patients with inactive WG secreted increased amounts of
IL-12 compared with normal donor monocytes in response to all of the
stimulants tested. In further studies, we determined IL-12 production
by stimulated monocytes isolated from two patients with active disease.
As shown in Figure 5B, both of the patients studied secreted
significantly increased amounts of IL-12 compared with normal controls
(p < 0.0001). Thus, IL-12 production by
circulating monocytes is enhanced in both clinically inactive and
active patients with WG.
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secretion
It was demonstrated in previous studies that IL-10 can prevent the
development of a Th1 response and reduce IFN- production, most
likely by inhibiting IL-12 secretion (22, 23, 24). To determine whether
IL-10 can also inhibit increased IFN- secretion in patients with
active WG, we cultured anti-CD2/anti-CD28 stimulated
PBMCs from patients with active WG in the presence of
increasing amounts of IL-10. As shown in Figure 6, IL-10 had a dose-dependent blocking
effect on IFN- production by PBMCs isolated from patients with
active WG. Finally, to determine whether an abnormality of IL-10
secretion accounts for the increased IFN- secretion in patients with
active WG, we evaluated IL-10 production both by PBMCs and by purified
monocytes from patients with active WG; as shown in Table II, these cell populations were found to
secrete normal amounts of IL-10.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Immunohistochemical analyses have shown that the inflammatory lesions in WG contain significant numbers of CD4+ T cells along with macrophages and neutrophils (29, 30). In the present study, we examined the function of circulating T cells on the assumption that disease-inducing T cells traffic through the peripheral circulation before localizing in sites of granulomatous inflammation. The feasibility of this approach is supported by our unpublished observations, as well as those of others, showing that patients with active WG have increased numbers of circulating HLA-DR+ and CD25+ T cells (31). In addition, we show in the present study that circulating T cells from patients with active WG (but not from patients with inactive disease) exhibit increased proliferative responses, and that the subpopulation of cells that accounts for this increased response is in the HLA-DR+ subset. These results, taken together, suggest that these circulating HLA-DR+ T cells are representative of the disease-inducing T cells present at sites of granulomatous inflammation.
The major finding of this study is that previously activated
CD4+HLA-DR+ T cells in the circulation of
patients with active WG produce vastly increased amounts of IFN-
when stimulated by the T cell-specific anti-CD2/anti-CD28
stimulus. This finding, plus the observation that the same
CD4+ T cell population secretes normal amounts of IL-4 and
IL-5 following stimulation, strongly suggests that the activated T
cells associated with the granulomatous inflammation of WG are skewed
toward a Th1 cytokine pattern. An additional potentially important
finding is that circulating T cells, but not monocytes/macrophages,
from patients with active WG secrete increased amounts of TNF-. The
latter cytokine is also produced by Th1 cells, and its overproduction
by CD4+ T cells provides further support for the hypothesis
that an aberrant Th1 response may be associated with the granulomatous
inflammatory lesion in WG. Findings leading to a similar conclusion
have recently been reported with respect to giant cell arteritis and
show that cells in lesional tissue were synthesizing mRNA for IFN-,
but not for IL-4 and IL-5. It is noteworthy, in polymyalgia rheumatica,
that temporal artery tissue samples were not found to contain mRNA for
IFN- (18). Thus, assuming that the cell populations in these patient
groups are compatible, a skewed Th1 cytokine secretion pattern appears
to be a phenomenon limited to the granulomatous vasculitides.
Increased production of IFN- and TNF- by circulating, previously
activated T cells (and, presumably, by lesional T cells in active WG)
may help to further define some of the clinical and pathologic features
of the disease. In particular, such increased production provides a
potential explanation for the generation of the granulomatous lesions
in WG via their effects on cellular recruitment and cellular activation
in developing lesions. With regard to cellular recruitment, Th1
cytokines such as IFN- and TNF- up-regulate not only the
expression of adhesion molecules that are critical to the entry of
cells into inflammatory sites but also to the costimulation of the
cells that have entered these sites (32). For example, in the rabbit
model of granulomatous vasculitis, increased expression of the adhesion
molecules ICAM-1 and VCAM-1 has been found to be an early and
persistent feature of the inflammatory lesion (33). In addition,
IFN- is the first cytokine appearing at lesional sites, followed by
TNF- and IL-1. In WG, increased ICAM-1 and VCAM-1 expression can be
demonstrated in renal biopsy specimens, and soluble forms of these
molecules are elevated in patients with active disease (34, 35, 36, 37, 38).
Similarly, in T cells isolated from the lesions of giant cell
arteritis, the expression of LFA-1 and VLA-2 (the ligands of ICAM-1 and
VCAM-1, respectively) is increased. Finally, in TNF--induced
experimental hemorrhagic vasculitis, soluble TNF- receptor treatment
inhibits both granuloma formation and ICAM-1 expression (39).
With regard to cellular activation in lesional tissue, it is now well
established that IFN- and TNF- act synergistically in vitro to
induce activation of monocytes/macrophages and their production of
proinflammatory cytokines. In addition, in various animal models of
granulomatous disease such as that caused by Leishmania
infection, mice with a high capacity for IFN- production manifest
granuloma formation and monocyte activation, which clears the
infection. In contrast, mice with a low capacity for IFN- production
lack monocyte activation and develop progressive and often fatal
disease (40, 41, 42, 43, 44).
Polymorphonuclear (PMN) cells are also significant contributors to the
inflammatory lesion in WG, either directly, via the release of toxic
materials, or because of an autoimmune response to PMN cell granular
proteins. With regard to the latter, Abs against the neutrophil
cytoplasmic Ag proteinase-3 (cANCA) are uniquely associated with WG and
are frequently elevated during periods of increased disease activity
(45, 46, 47, 48, 49, 50, 51). While it is unlikely that these Abs play a primary role in
the generation of granulomatous lesions, they can conceivably
contribute to tissue injury in a secondary fashion. With regard to the
present discussion, aberrant production of Th1 cytokines such as
IFN- and TNF- may enhance autoantibody production in WG by
several mechanisms. First, these cytokines have been shown to induce
surface expression of proteinase-3 on endothelial cells and neutrophils
(52, 53). Second, these cytokines may facilitate macrophage uptake and
presentation of proteinase-3 that has been released from neutrophils
and endothelial cells or that has been generated by cells in the
lesions undergoing apoptosis. This, in turn, could lead to T
cell-dependent B cell production of autoantibodies reactive with
proteinase-3. Furthermore, it has recently been shown that neutrophils
can be a potential source of IL-12 and, therefore, it is conceivable
that during the initial influx of neutrophils they not only are
attracting mononuclear cells to the inflammatory site but also
promoting a Th1 cytokine response (54).
The finding that WG lesions are associated with T cells markedly skewed
toward Th1 cell differentiation implies an abnormality in the
regulation of IL-12, the APC-derived cytokine that is the primary
inducer of T cells producing IFN-. The most important data bearing
on this point came from studies of WG monocytes/macrophages showing
that monocytes isolated from patients with WG produced greatly
increased levels of IL-12 when stimulated with any of a variety of
stimulants. Interestingly, while the highest levels of IL-12 production
were obtained with monocytes from patients with active disease,
monocytes from patients with inactive disease also produced increase
amounts of IL-12. This finding implies that the increase in IL-12
production is not a secondary effect to the inflammatory process
itself, but rather a primary feature of WG. Also bearing on this issue
of the relation of IL-12 to the increased IFN- secretion was the
demonstration that IL-10 exerts a dose-dependent inhibition of IFN-
production in culture of WG T cells. Since IL-10 down-regulates IFN-
production via a more primary inhibitory effect on IL-12 production
(55, 56), this finding provides further substantiation to the concept
that the increased Th1 response in active WG is mediated by excess
IL-12 production. The observation that WG is associated with an
IL-12-driven Th1 T cell response is parallel to the finding in
sarcoidosis, another granulomatous inflammatory disease in which it has
been demonstrated that cells in bronchoalveolar lavage fluids exhibit
increased IL-12 production associated with a Th1-like cytokine
profile (57).
The cytokine studies described here allow us to postulate a series of
pathologic events in WG responsible for the granulomatous vasculitis
that characterizes the disease. The initial event is an exposure to an
environmental Ag(s) (perhaps an infectious agent) that induces an
excessive macrophage IL-12 response and leads to unbalanced T cell
response characterized by overproduction of IFN- and TNF-. This
is followed by the establishment of a granulomatous inflammation via
changes in cellular adhesion and activation of monocytes and T cells,
as described above. The final event is inflammation-induced tissue
breakdown with the release of intracellular materials from infiltrating
cells, such as proteinase-3, which causes further autoimmune responses
that amplify the primary lesion. The environmental Ag(s) capable of
initiating this cascade is presently unknown. The earlier suggestion
that it was proteinase-3 seems unlikely (at least in relation to the
granuloma formation), since proteinase-3 expression is not strictly
related to disease activity, and we have found that purified
proteinase-3 does not stimulate T cells from WG patients to undergo
either proliferation or cytokine secretion (our unpublished
observations). Another candidate is a superantigen associated with a
respiratory pathogen; this would explain both the initiation of disease
in the respiratory area and the exacerbation of disease related to the
occurrence of infection.
The findings reported here have important implications for the treatment of WG. In particular, they suggest that any of a variety of approaches to the down-regulation of the Th1 T cell pathway and IL-12 production at the time of disease initiation or exacerbation may be effective in aborting the inflammation. One obvious possibility along these lines is the administration of IL-10 to patients; we are currently exploring this possibility.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: WG, Wegener’s granulomatosis; NIAID, National Institute of Allergy and Infectious Diseases; PB, peripheral blood; SAC, Staphylococcus aureus Cowan I strain; PMN, polymorphonuclear; CD40L, CD40 ligand.
Received for publication September 17, 1997. Accepted for publication December 5, 1997.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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P. Lamprecht, J. Voswinkel, T. Lilienthal, B. Nolle, M. Heller, W. L. Gross, and A. Gause Effectiveness of TNF-{alpha} blockade with infliximab in refractory Wegener's granulomatosis Rheumatology, November 1, 2002; 41(11): 1303 - 1307. [Abstract] [Full Text] [PDF]
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G. Heine, U. Sester, M. Sester, J. E. Scherberich, M. Girndt, and H. Kohler A shift in the Th1/Th2 ratio accompanies the clinical remission of systemic lupus erythematosus in patients with end-stage renal disease Nephrol. Dial. Transplant., October 1, 2002; 17(10): 1790 - 1794. [Abstract] [Full Text] [PDF]
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L. Kamesh, L. Harper, and C. O. S. Savage ANCA-Positive Vasculitis J. Am. Soc. Nephrol., July 1, 2002; 13(7): 1953 - 1960. [Full Text] [PDF]
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 A. Komocsi, P. Lamprecht, E. Csernok, A. Mueller, K. Holl-Ulrich, U. Seitzer, F. Moosig, A. Schnabel, and W. L. Gross Peripheral Blood and Granuloma CD4+CD28- T Cells Are a Major Source of Interferon-{gamma} and Tumor Necrosis Factor-{alpha} in Wegener's Granulomatosis Am. J. Pathol., May 1, 2002; 160(5): 1717 - 1724. [Abstract] [Full Text] [PDF]
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 J. Soltys, T. Bonfield, J. Chmiel, and M. Berger Functional IL-10 Deficiency in the Lung of Cystic Fibrosis (cftr-/-) and IL-10 Knockout Mice Causes Increased Expression and Function of B7 Costimulatory Molecules on Alveolar Macrophages J. Immunol., February 15, 2002; 168(4): 1903 - 1910. [Abstract] [Full Text] [PDF]
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 P Lamprecht, F Moosig, E Csernok, U Seitzer, A Schnabel, A Mueller, and W L Gross CD28 negative T cells are enriched in granulomatous lesions of the respiratory tract in Wegener's granulomatosis Thorax, October 1, 2001; 56(10): 751 - 757. [Abstract] [Full Text] [PDF]
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 A. E. Dixon, J. B. Mandac, P. J. Martin, R. C. Hackman, D. K. Madtes, and J. G. Clark Adherence of adoptively transferred alloreactive Th1 cells in lung: partial dependence on LFA-1 and ICAM-1 Am J Physiol Lung Cell Mol Physiol, September 1, 2000; 279(3): L583 - L591. [Abstract] [Full Text] [PDF]
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U. Sester, M. Sester, M. Hauk, H. Kaul, H. Kohler, and M. Girndt T-cell activation follows Th1 rather than Th2 pattern in haemodialysis patients Nephrol. Dial. Transplant., August 1, 2000; 15(8): 1217 - 1223. [Abstract] [Full Text] [PDF]
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 D. Vassilopoulos and G. S. Hoffman Clinical Utility of Testing for Antineutrophil Cytoplasmic Antibodies Clin. Vaccine Immunol., September 1, 1999; 6(5): 645 - 651. [Full Text] [PDF]
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C. A Langford and G. S Hoffman Rare diseases bullet 3: Wegener's granulomatosis Thorax, July 1, 1999; 54(7): 629 - 637. [Full Text]
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B. Bussolati, F. Mariano, L. Biancone, R. Foa, S. David, V. Cambi, and G. Camussi Interleukin-12 Is Synthesized by Mesangial Cells and Stimulates Platelet-Activating Factor Synthesis, Cytoskeletal Reorganization, and Cell Shape Change Am. J. Pathol., February 1, 1999; 154(2): 623 - 632. [Abstract] [Full Text] [PDF]
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J. Grunewald, E. Halapi, J. Wahlstrom, R. Giscombe, S. Nityanand, C. Sanjeevi, and A.-K. Lefvert T-Cell Expansions With Conserved T-Cell Receptor beta Chain Motifs in the Peripheral Blood of HLA-DRB1*0401 Positive Patients With Necrotizing Vasculitis Blood, November 15, 1998; 92(10): 3737 - 3744. [Abstract] [Full Text] [PDF]
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; n = 7) disease compared with
healthy donors (
; n = 12); *p <
0.001. Similarly, IFN-
