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-Deficient Mice1
*
Medical and Research Services, Veterans Affairs Medical Center, and Renal Division, Department of Medicine, Emory University, Atlanta, GA 30033; and
Pathology and Laboratory Medicine, Veterans Affairs Medical Center and State University of New York, Buffalo, NY 14215
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Abstract |
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confers susceptibility to
immunologically mediated tissue injury. To test this hypothesis, we
compared the intensity of accelerated anti-glomerular basement
membrane glomerulonephritis between wild-type (IFN-+/+)
and IFN- gene knockout (IFN--/-) mice. This disease
model is initiated by binding of heterologous (sheep)
anti-glomerular basement membrane Abs to the glomeruli of mice
preimmunized with sheep IgG. The secondary cellular and humoral immune
responses to the planted Ag then lead to albuminuria and glomerular
pathology. We found that IFN--/- mice or
IFN-+/+ mice injected with IFN--neutralizing Ab
develop worse albuminuria and glomerular pathology than
IFN-+/+ mice. The humoral response to sheep IgG (serum
mouse anti-sheep IgG titers and intraglomerular mouse IgG deposits)
was comparable in the IFN-+/+ and
IFN--/- groups. In contrast, IFN--/-
mice mounted a stronger cellular immune response (cutaneous
delayed-type hypersensitivity reaction) to sheep IgG than
IFN-+/+ mice. These findings provide evidence that
endogenous IFN- has a protective role in immunologically mediated
glomerulonephritis initiated by foreign Ags. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, produced
by Th1-type lymphocytes, is thought to promote immunologically mediated
renal injury because of its immunostimulatory and proinflammatory
actions (11, 12). These actions include up-regulating MHC
molecules, enhancing the expression of adhesion molecules, activating
lymphocytes and macrophages, and stimulating the release of
inflammatory mediators (11). However, a direct
relationship between IFN- production and susceptibility to
glomerulonephritis induced by a foreign Ag has not been
established.
In this study, we tested whether endogenous IFN- confers
susceptibility to experimental glomerulonephritis by comparing the
intensity of glomerular injury between wild-type
(IFN-+/+) and IFN- gene knockout
(IFN--/-) mice following the induction of
accelerated antiglomerular basement membrane (GBM) nephritis.
Accelerated anti-GBM nephritis is initiated by binding of
heterologous (sheep) anti-GBM Abs to the glomeruli of mice
previously immunized with sheep IgG (10, 13). The
secondary cellular and humoral immune responses to the planted Ag then
lead to albuminuria and glomerular pathology. Progression to glomerular
crescents and glomerular fibrosis may occur, thus resembling certain
forms of human proliferative glomerulonephritis (1). We
report in this work that IFN--deficient mice are more susceptible to
accelerated anti-GBM nephritis than
IFN-+/+ mice. Furthermore, we report that DTH
response to the heterologous Ab is exaggerated in the
absence of IFN-. These findings provide evidence that endogenous
IFN- has a protective role in immunologically mediated renal
disease.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Six- to eight-week-old male C57BL/6
IFN-+/+ and C57BL/6
IFN--/- mice were purchased from The Jackson
Laboratory (Bar Harbor, ME). Mice were housed at the Veterans Affairs
Medical Center/Emory University (Atlanta, GA) animal facility in
microisolators supplied with sterile food and water. Mice were injected
s.c. in each flank with 0.3 mg of sheep IgG (Sigma, St. Louis, MO)
mixed 1:1 with CFA (Sigma). Seven days later, they were injected i.p.
with a subnephritogenic dose (2 mg) of purified sheep anti-rat GBM
Ab that cross-reacts with mouse GBM (provided by Drs. K. F. Badr
and K. A. Munger, Emory University). An additional group of
IFN-+/+ mice received 250 µg hamster
anti-mouse IFN- mAb (Genzyme, Boston, MA) i.p. 1 day before
immunization with sheep IgG, and the same dose was given again 1 day
before injecting the anti-GBM Ab. Control mice were immunized with
sheep IgG, as described above, but received heat-inactivated, nonimmune
sheep serum (NSS) (Sigma) 7 days later. Mice were then housed
individually, and spot urine was collected daily for 4 consecutive
days. Baseline urine sample was collected 1 day before injecting sheep
anti-rat GBM Ab. Mice were sacrificed at the end of the fourth day,
and serum and renal tissue were saved for analysis. Urinary albumin
concentrations were quantitated by a colorimetric method (Sigma).
Urinary creatinine concentrations were quantitated by the picric acid
colorimetric method (Sigma). Albuminuria was reported as the ratio of
urinary albumin to creatinine concentration (Ualb/Ucr)
(9).
Histopathology
Kidney sections were fixed in B5 solution (Great Lakes Diagnostics, Troy, MI), followed by 10% neutral-buffered Formalin (Fisher Scientific, Pittsburgh, PA), and embedded in paraffin wax. Staining with periodic acid-Schiff (PAS) was performed on 4-µm sections. Light-microscopic examination was performed in a blinded fashion by a pathologist (F.K.B.). Glomerular pathology was assessed by examining at least 100 glomeruli per animal. The extent of glomerular cellularity was reported as the average number of cells per glomerulus.
RNA isolation and RT-PCR
Kidneys were flushed with ice-cold PBS, snap frozen in liquid
nitrogen, and stored at -80°C. Total kidney RNA was extracted in
guanidinium salt solution and purified by the cesium chloride method
(9). RNA samples with OD260/280 <
1.6 were rejected. Five micrograms of total RNA were reverse
transcribed using oligo(dT) primers and Superscript reverse
transcriptase, according to the manufacturer’s instructions (Life
Technologies, New Haven, CT). Ten percent of cDNA was then subjected to
35 cycles of PCR amplification (total volume of reaction = 100
µl) in a Perkin-Elmer Thermocycler 480 (Perkin-Elmer, Foster City,
CA) using mouse IL-4- and mouse IFN--specific primers
(9). RT-PCR controls included "no RNA" (blank) and
"no reverse-transcriptase" reactions. Fifteen microliters of each
RT-PCR were electrophoresed on 2% SeaKem LE agarose (American
Bioanalytical, Natick, MA) gels and stained with ethidium bromide.
RT-PCR of a housekeeping gene (hypoxanthine phosphoribosyltransferase)
was performed to verify equal RNA and cDNA loading in the RT and
PCR reactions, respectively.
Immunofluorescence
Fresh kidney tissue was mounted in OCT compound (Miles Diagnostics, Elkart, IN) and frozen in liquid isopentane (Sigma) cooled on dry ice, and 5-µm cryostat sections were prepared using a microtome (Leica, Nussloch, Germany). Direct immunofluorescence studies were performed by fixing frozen sections in acetone, followed by washing with PBS and blocking with 10% normal rabbit serum (Dako, Carpenteria, CA). Tissue samples were then stained with FITC-conjugated rabbit anti-sheep IgG (Zymed, South San Francisco, CA), FITC-conjugated rabbit anti-mouse IgG (Zymed), FITC-conjugated monoclonal rat anti-mouse CD11b (Harlan/Serotec, Indianapolis, IN), or FITC-conjugated monoclonal rat anti-mouse CD3 (Harlan/Serotec). After washing with PBS, sections were studied under a fluorescence microscope in a blinded fashion. The average number of intraglomerular monocytes/macrophages/neutrophils (CD11b+ cells) and T lymphocytes (CD3+ cells) was determined by examining at least 100 glomeruli per animal. The binding of FITC-conjugated rabbit anti-sheep and rabbit anti-mouse Ab to the glomeruli was graded on a scale of 0–4 by a pathologist (F.K.B.) in a blinded fashion.
Measurement of circulating mouse anti-sheep IgG Ab titers
Microtiter wells (Nunc, Roskilde, Denmark) were coated with 1 mg/ml normal sheep IgG (Sigma) in carbonate/bicarbonate buffer (pH 9.5) by incubation overnight at 4°C, washed twice in wash buffer (0.1% Tween-20 in PBS), and blocked with 2% BSA in wash buffer for 1 h at room temperature (7). Wells were washed twice before incubation overnight with triplicate serial dilutions of mouse serum. After three washes, wells were incubated with horseradish peroxidase-conjugated rabbit anti-mouse IgG (Sigma) (1:2000), anti-mouse IgG1 (Zymed) (1:1000), or anti-mouse IgG2b (Zymed) (1:2000) for 2 h. Wells were finally washed six times and incubated with 0.1 M of the substrate 2,2'-azino-di-3-ethylbenzthiazoline sulfonate (ABTS; Boehringer Mannheim, Indianapolis, IN) in 0.02% H2O2 for 1 h at room temperature. The reaction was stopped by adding an equal volume of 0.01% sodium azide in 0.1 M citric acid solution, and absorbance at 405 nm (OD405) was read immediately in a microplate reader (Bio-Rad, Richmond, CA). Control serum was obtained from nonimmunized mice.
Delayed-type hypersensitivity
Mice were immunized s.c. in each flank with 0.3 mg of sheep IgG
(Sigma) mixed 1:1 with CFA. Seven days later, 50 µg of sheep IgG in
30 µl PBS was injected intradermally in the right footpad. The left
footpad (control) was injected with 50 µg of BSA in 30 µl PBS.
Twenty-four and 48 h later, right and left footpad thickness was
measured in a blinded fashion using a dial gauge (Starrett, Small
Parts, Miami Lakes, FL). The DTH response was determined by subtracting
the left footpad thickness from that of the right footpad (
footpad
thickness).
Urinary nitric oxide
Nitric oxide (NO) concentrations in mouse urine samples were measured by a colorimetric assay kit, according to the manufacturer’s instructions (Biomol Quantizyme Assay System, Biomol Research Laboratories, Plymouth Meeting, PA). This assay measures the total concentration of nitrates and nitrites, stable breakdown products of NO, following the addition of the enzyme nitrate reductase to the samples. Total nitrate and nitrite concentrations were divided by the creatinine concentration in each urine sample to adjust for variations in urine collection.
Statistical analysis
Analysis of variance (Fisher’s protected least significant difference and/or Scheffe’s test) or unpaired t test was used to compare differences between groups. The confidence interval was set at 95%.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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+/+ and IFN--/- mice
To study the role of IFN- in the pathogenesis of experimental
glomerulonephritis induced by foreign Ag, we compared the
susceptibility to accelerated anti-GBM nephritis between
IFN-+/+ and IFN--/-
mice. Following the induction of nephritis, two deaths each were
observed in the IFN-+/+ group
(n = 22) and in the IFN-+/+
group treated with IFN--neutralizing Ab (n = 8).
There was no mortality in the IFN--/- group
(n = 19) or in any of the control groups. Dead mice
were excluded from further analysis. At the end of the experiment, body
weights (mean ± SD) were comparable: 23 ± 2 g, 20
± 2 g, and 24 ± 1 g in the
IFN-+/+ group,
IFN--/- group, and
IFN-+/+ group treated with
IFN--neutralizing Ab, respectively. IFN--deficient mice were more
susceptible to accelerated anti-GBM nephritis than
IFN-+/+ mice, as measured by the following
parameters:
Albuminuria.
There were no differences in baseline urinary albumin excretion (day 0)
between the different groups. Albuminuria (Ualb/Ucr) was significantly
higher in IFN--/- mice (n =
19) than IFN-+/+ mice (n = 20)
on days 2, 3, and 4 following disease induction (Fig. 1
A). Like the
IFN--/- group,
IFN-+/+ mice treated with IFN--neutralizing
Ab (n = 6) had worse albuminuria on day 2 than the
wild-type group. Control animals injected with NSS (n =
4/group) had minimal albuminuria without significant differences
between IFN-+/+ and
IFN--/- mice (Fig. 1B).
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-/- mice (31%; n = 13
mice analyzed) and three IFN-+/+ mice treated
with IFN--neutralizing Ab (50%; n = 6 mice
analyzed) developed diffuse renal changes characterized by moderate
extracapillary glomerular hypercellularity, mesangial expansion,
increased glomerular size, intracapillary PAS+
deposits, and intratubular PAS+ casts (Fig. 2). In contrast, only one
IFN-+/+ mouse (7%; n = 14
mice analyzed) had comparable renal pathology (Fig. 2). The
remaining mice in each group developed minimal renal pathology.
Glomerular crescent formation was not observed in any of the mice.
IFN--/- or IFN-+/+
mice injected with NSS had normal renal histology (Fig. 2).
Commensurate with the histopathological changes, we found that average
glomerular cellularity in the IFN--/- group
was significantly higher than that in the
IFN-+/+ group following the induction of
anti-GBM nephritis (Fig. 3).
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-deficient and IFN-+/+ mice following
anti-GBM Ab or NSS injection.
Cytokine mRNA expression in IFN-+/+ and
IFN--/- kidneys
Because Th1 and Th2 lymphocyte-derived cytokines regulate immune
and inflammatory responses, we studied the expression of IFN- and
IL-4 mRNA in the kidneys of IFN-+/+ and
IFN--/- mice after the induction of
accelerated anti-GBM nephritis. As shown in Fig. 4, RT-PCR analysis revealed the complete
absence of IFN- mRNA in IFN--/- kidneys,
while IL-4 mRNA expression was comparable in the
IFN-+/+ and IFN--/-
groups. These data suggest that worse albuminuria and glomerular
pathology occur in IFN--/- mice despite the
expression of IL-4, a Th2 cytokine that has antiinflammatory actions
(9).
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+/+ and
IFN--/- mice
Because albuminuria and glomerular pathology in accelerated
anti-GBM nephritis was initiated by binding of autologous mouse Abs
to heterologous sheep IgG planted along the GBM (4, 5), we
investigated the presence of sheep and mouse IgG in
IFN-+/+ and IFN--/-
glomeruli 4 days following disease induction. As shown in Fig. 5, linear deposits of sheep IgG were
detected along the GBM of IFN-+/+ and
IFN--/- mice, indicating that sheep
anti-rat GBM Abs bind to mouse glomeruli. Linear deposits of mouse
IgG (autologous Ab) were also observed in both groups. Although the
staining intensity for mouse IgG in IFN--/-
glomeruli appears stronger than that in
IFN-+/+ glomeruli in the photomicrograph shown
in Fig. 5, blinded immunohistochemical grading of kidneys from 12 mice
in each group did not reveal significant differences (mean ±
SD = 2.7 ± 1.1 and 2.6 ± 0.9 in the
IFN-+/+ and IFN--/-
groups, respectively).
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+/+ and IFN--/- mice
To quantitate the secondary Ab response to sheep IgG, we measured
the serum titer of total mouse IgG directed against sheep IgG 4 days
following anti-GBM Ab injection (n = 6/group). The
titration curves of IFN-+/+ and
IFN--/- sera were comparable (Fig. 6A). Moreover, there were no
significant differences in IgG isotype (IgG1 and IgG2b) production
between the two groups (Fig. 6, B and C). Control
sera from nonimmunized mice had minimal Ab to sheep IgG.
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Cell-mediated immune responses, such as DTH, play a critical role
in the pathogenesis of murine accelerated anti-GBM nephritis
(6, 7). To investigate whether enhanced susceptibility to
accelerated anti-GBM nephritis in
IFN--/- mice is related to enhanced
cell-mediated mechanisms, we compared the cutaneous (footpad) DTH
response to sheep IgG between immunized
IFN-+/+ and IFN--/-
mice (n = 12/group). Immunized
IFN--/- mice mounted a
significantly greater DTH reaction than
IFN-+/+ mice, measured at either 24 or 48
h after rechallenging with sheep IgG in the footpad (Fig. 7). Control mice that were not immunized,
but were injected with sheep IgG in their footpads, did not mount a
DTH response.
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+/+ and IFN--/- mice
It is postulated that renal NO production, which occurs
immediately following the induction of anti-GBM nephritis, protects
against heavy proteinuria by lowering intraglomerular capillary
pressure (14, 15). We therefore measured the concentration
of nitrates and nitrites, stable breakdown products of NO, in urine
samples collected from IFN-+/+ and
IFN--/- mice before and after the induction
of glomerulonephritis. We found that the total urinary nitrate and
nitrite level increased by 2.7-fold above baseline in the
IFN-+/+ group 1 day after disease induction,
but failed to increase in the IFN--/- group
(n = 12/group, p < 0.05) (Fig. 8). Fold increase in total urinary
nitrate and nitrite level was still higher in
IFN-+/+ than
IFN--/- mice on day 2, but the difference
did not reach statistical significance (Fig. 8).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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confers
susceptibility to immunologically mediated renal disease. Surprisingly,
we found that IFN--/- mice or
IFN-+/+ mice treated with neutralizing
anti-IFN- Abs develop worse albuminuria and glomerular pathology
than IFN-+/+ mice following the induction of
accelerated anti-GBM nephritis. These observations indicate that
endogenous IFN- plays a protective role in experimental
glomerulonephritis and are consistent with other experimental models in
which endogenous IFN- was found to limit immunological tissue injury
induced by foreign Ags. For example, gene knockout mice lacking
the IFN--receptor (IFN-R-/-) are more
susceptible to collagen-induced arthritis than wild-type mice
(16, 17). Moreover, injecting IFN--neutralizing Abs
accelerates the onset and severity of arthritis in wild-type mice
(17). Similarly, IFN--/- or
IFN-R-/- mice exhibit exaggerated morbidity
and mortality following the induction of experimental autoimmune
encephalomyelitis (18, 19). Tarrant et al. also found that
IL-12 administration protects mice from experimental autoimmune uveitis
by increasing IFN- production (20).
We also investigated in this study the mechanisms by which endogenous
IFN- could protect from immunologically mediated glomerulonephritis.
Because susceptibility to accelerated anti-GBM nephritis is
determined by the humoral and cellular immune responses to the foreign
Ag planted in the kidney (5, 6, 7), we compared the Ab and
DTH responses to sheep IgG between IFN-+/+ and
IFN--/- mice. We found that the Ab response,
assessed by the extent of mouse anti-sheep IgG deposits in
glomeruli and by mouse anti-sheep IgG serum titers, was comparable
between the two groups. In contrast, IFN--/-
mice mounted a stronger cutaneous DTH response to sheep IgG than
IFN-+/+ mice. Exaggerated DTH response has
been observed in IFN--/- mice stimulated
with allogeneic cells (21). Conversely, DTH response to a
protein Ag is suppressed when wild-type mice are treated with IL-12,
which increases IFN- production in vivo (20). Enhanced
DTH responses in the absence of IFN- could result from increased T
cell proliferation, from decreased macrophage apoptosis, or both.
Several investigators have shown that endogenous IFN- is critical
for limiting the proliferation of activated T cells in vitro and in
vivo (19, 22, 23, 24). Munn et al. have demonstrated that
IFN- is critical for activation-induced apoptosis of macrophages
(25).
Despite enhanced cutaneous DTH response to sheep IgG in
IFN--/- mice, we did not observe increased T
cell and macrophage accumulation in their glomeruli following the
induction of nephritis. This raises the possibility that other
mechanisms contribute to increased glomerular cellularity and
albuminuria in the absence of IFN-. Johnson et al. found that
IFN- administration inhibits mesangial cell proliferation in the
anti-Thy-1 glomerulonephritis model (26), suggesting
that mesangial cell expansion in experimental glomerulonephritis may be
regulated by IFN-. Several investigators have demonstrated
intrarenal inducible NO synthase expression and NO production following
the induction of anti-GBM nephritis (27, 28).
Inhibition of NO production in nephritic animals leads to increased
intraglomerular capillary pressure and, subsequently, increased
proteinuria (14, 15). Because
IFN--/- mice do not up-regulate inducible NO
synthase expression in response to inflammatory stimuli (29, 30), it is possible that reduced NO production contributes to
heightened albuminuria during accelerated anti-GBM nephritis in
these mice. In this manuscript, we provided evidence that
IFN--/- mice fail to up-regulate renal NO
production, as measured by total urinary nitrate and nitrite
concentration, following the induction of glomerulonephritis. In
contrast, IFN-+/+ mice exhibited up to
2.7-fold increase in total urinary nitrate and nitrite production.
These data, however, do not identify the cellular and enzymatic sources
of NO in our experimental model.
Studies in lupus-prone mice have shown that IFN- is essential for
the pathogenesis of autoimmune glomerulonephritis
(31, 32, 33, 34, 35). MRL/lpr mice bred onto the
IFN--/- phenotype develop significantly
milder renal pathology than IFN-+/+
MRL/lpr mice (31, 32). Similarly, IFN- is
necessary for the genesis of mercury chloride-induced autoimmunity and
experimental autoimmune myasthenia gravis in mice (36, 37). In contrast, we observed that IFN--deficient mice are
more susceptible to glomerulonephritis initiated by the binding of
foreign Ag to the kidney. Our findings underscore the regulatory role
that IFN- plays in immunologically mediated tissue injury triggered
by foreign Ags.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Fadi G. Lakkis, VAMC and Emory University, Research 151N, 1670 Clairmont Road, Atlanta, GA 30033. E-mail address:
3 Abbreviations used in this paper: DTH, delayed-type hypersensitivity; GBM, glomerular basement membrane; NSS, nonimmune sheep serum; PAS, periodic acid-Schiff; Ualb/Ucr, ratio of urinary albumin to creatinine concentration.
Received for publication March 3, 1999. Accepted for publication June 2, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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receptor deletion prevents autoantibody production and glomerulonephritis in lupus-prone (NZB x NZW)F1 mice. J. Immunol. 160:3713. receptor signaling is essential for the initiation, acceleration, and destruction of autoimmune kidney disease in MLR-Fas(lpr) mice. J. Immunol. 161:494. is required for lupus-like disease and lymphoaccumulation in MLR-lpr mice. J. Clin. Invest. 101:364.[Medline]
but not Th1/Th2 imbalance. J. Immunol. 161:234. (IFN-) is necessary for the genesis of acetylcholine receptor-induced clinical experimental autoimmune myasthenia gravis in mice. J. Exp. Med. 186:385.This article has been cited by other articles:
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