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Receptor in the Regulation of Renal MHC Expression
*
Department of Medicine, Division of Nephrology and Immunology, University
of Alberta, Edmonton, Alberta, Canada.
Department of Medical Microbiology and Immunology, University of Alberta,
Edmonton, Alberta, Canada.
Correspondence to Dr. Philip F. Halloran, Division of Nephrology and Immunology, University of Alberta, #303, 8249-114 Street, Edmonton, Alberta T6G 2R8 Canada. Phone: 780-407-8880; Fax: 780-431-0461; E-mail: phil.halloran{at}ualberta.ca
 |
Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(IFN-)
receptor 1 (IFN-R1) was investigated in the regulation of MHC
expression in kidney in the basal state, in response to potent inflammatory
stimuli, and after renal injury. In this study, MHC regulation in mice lacking
IFN-R due to targeted disruption of the IFN-R1 gene (GRKO mice)
was compared with regulation in 129Sv/J mice with wild-type IFN-R1
genes. Basal class I expression was reduced by approximately 45% in kidneys of
GRKO mice, while basal class II expression was confined to interstitial cells
and was not reduced in GRKO kidneys. Recombinant IFN- administration
induced widespread expression of class I and II in renal tubules, arterial
endothelium, and glomeruli of 129Sv/J mice, but produced no change in kidneys
of GRKO mice. Potent systemic inflammatory stimuli (injections of allogeneic
cells, skin sensitization with oxazolone, and injection of bacterial
lipopolysaccharide) significantly induced both class I and class II expression
in 129Sv/J mice, but not in GRKO mice. Acute renal injury increased local
expression of class I and II in both 129Sv/J and GRKO mice, but the induction
in GRKO mice was reduced compared with 129Sv/J mice. Thus, the IFN-
receptor plays a unique and nonredundant role in the regulation of renal MHC
in the response to inflammation, in the response to renal injury, and in the
basal state. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(IFN-) potently induces the expression of MHC genes and thus affects
antigen presentation and potential immune targets in disease states. MHC
induction by inflammatory stimuli is reduced or absent in mice lacking
IFN- (3). IFN- or
IFN-R has been shown to regulate a variety of renal diseases including
autoimmune systemic lupus erythematosus in mice
(4,5),
but not anti-glomerular basement membrane crescentic nephritis
(6). IFN- also affects
both early and late events in organ transplants
(7,
8,
9).
IFN- signals via the IFN- receptor (IFN-R) complex
composed of a ligand-binding chain R1 and an accessory chain R2, which are
members of the type II cytokine receptor family that includes
IFN-
/ß R and IL-10R
(10,
11,
12,
13). In the
IFN-/IFN-R structure, there is possible contact between the
IFN-R2 accessory chain and the IFN- homodimer
(14). To date, in
vitro studies have not shown persistent IFN--dependent effects
through R2 when R1 is disrupted. However, the issue has not been addressed
in vivo. Humans and mice with disrupted genes for IFN-,
IFN-R1, or IFN-R2 display severe defects in IFN--mediated
responses and some defects in host defense
(15,
16,
17). However, there has been
no systematic comparison of the phenotypes produced by disruption of the genes
for IFN-, IFN-R1, and IFN-R2 in vivo. Each of
these phenotypes should be established independently in vivo,
particularly because the IFN-R is widely distributed in most resting
cells and has potential for multiple and massive effects on a variety of cell
types. One reported discrepancy between IFN-R1 deficiency
versus IFN- deficiency is that mice with disrupted
IFN-R1 genes (GRKO mice) express MHC class II on their renal tubules
in vivo in response to bacterial lipopolysaccharide (LPS)
(18), whereas mice with
disrupted IFN- gene (GKO mice) show little class II induction after LPS
(3). This apparent discrepancy
could reflect either phenotypic differences between the GRKO and GKO mice due
to previously unsuspected redundancies between IFN- and its R1 and R2
mutations induced by the gene disruption protocol, and/or background genetic
differences or potential variance in experimental design.
Since GRKO mice are becoming important models for immunologic renal disease
and transplantation (4,
5,
6), it is important to
establish their renal phenotypes and to explore potential differences between
GRKO and GKO mice. In the present study, we examined the MHC phenotype of
kidneys of GRKO mice compared with wild-type mice and the previously described
phenotype of GKO mice
(3,19).
We studied three states of MHC expression: the basal state without
stimulation, after potent inflammatory stimulation or recombinant IFN-
(rIFN-), and after local renal injury. Basal class I but not class II
expression was reduced in kidneys from GRKO mice. Systemic inflammatory
stimuli induced little or no MHC mRNA or products, and GRKO mice showed no
response to injections of rIFN-. Renal injury induced MHC expression in
GRKO mice, but the level of induction was reduced compared with control
129Sv/J mice. Our results also suggest that class II induction is greatly
reduced in GRKO mice given bacterial LPS, consistent with our previous studies
of GKO mice. Thus, the IFN-/IFN-R pathway plays an essential
role in basal class I expression, in the intense systemic MHC expression that
accompanies inflammation, and in the local MHC induction in injured tissue.
The results are consistent with the exclusive and essential roles of
IFN- and IFN-R1 in basal and induced renal MHC expression in
vivo, but also confirm that acute renal injury can induce MHC expression
by a pathway independent of IFN- or IFN-R1.
|
Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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R1
genes was generated by gene targeting in murine embryonic stem cells
(17). The gene was disrupted
by inserting the neomycin-resistance gene (neor) into exon
V, which encodes an extracellular domain. Homozygous 129Sv/Ev mice were
provided by Dr. Michel Aguet (University of Zurich, Zurich, Switzerland).
Control Mice with Wild-Type IFN-R1 Genes
129Sv/J mice with wild-type IFN-R1 genes were obtained from Jackson
Laboratories (Bar Harbor, ME) and used as controls. The mice were maintained
in the Health Sciences Laboratory Animal Services at the University of Alberta
and were kept on acidified water. All experiments conformed to approved animal
care protocols.
rIFN- Treatment
The rIFN- was generously provided by Genentech, Inc. (South San
Francisco, CA). A dose of 50,000 IU in saline, or saline alone as a control,
was intraperitoneally injected in each animal on day 0 and day 1, and mice
were sacrificed on day 3.
P815 Tumor Allografts
Murine mastocytoma tumor cell line P815 (American Type Culture Collection,
Rockville, MD) was passaged in DBA/2(H-2d) mice from Jackson
Laboratories (Bar Harbor, ME). After P815 cells were collected from the
ascites fluid, approximately 20 x 106 cells, or an equivalent
volume of saline as a control, were injected intraperitoneally into mice. The
tissues of experimental mice were examined 7 d later.
Oxazolone Skin Painting
A total of 100 µl of 25% oxazolone (4-ethoxymethylene-2 phenol-2
oxazolin-5-one) in acetone was painted onto the shaved back of mice on day 0.
On day 4, 25 µl of 5% oxazolone in acetone was again applied to the same
area. Sham mice were treated with 100 µl of acetone onto the shaved back on
day 0 and then repeated with 25 µl of acetone on day 4. Mouse tissues were
harvested on day 6.
LPS Injections
LPS of Salmonella minnesota dissolved in sterile saline at 250
µg/ml and heated at 56°C for 5 h, or a saline control, was injected
intraperitoneally on day 0, and the mice were sacrificed on day 3.
Acute Toxic Injury
Mice were subcutaneously injected with gentamicin (250 mg/kg three times a
day) or with a sham saline injection on two consecutive days. Mice were killed
and their tissues were examined on day 7.
Acute Tubular Necrosis
Unilateral ischemic injury has been widely reported
(3,20,21).
Briefly, mice 8 to 12 wk of age were anesthetized with 2,2,2-tribromoethanol
in tert-butyl alcohol (Avertin, Department of Surgery, University of Alberta,
Edmonton, Alberta, Canada) by intraperitoneal injection. The left renal
pedicle was identified through a midline incision and occluded with a
micro-bulldog clamp for 60 min. Before closure, the kidney was inspected to
ensure reperfusion, and the abdominal cavity was filled with warm saline.
Sham-operated control mice underwent a simple laparotomy under identical
conditions. Each group had between 5 and 10 mice, and the tissues were
harvested at day 7.
Antibodies
Monoclonal antibodies (mAb) were purified in our laboratory from
supernatants of hybridoma cell lines. The lines were AF 6-120.1.2 (mouse IgG
against mouse I-Ab), 20-8-4S (mouse IgG against mouse
H-2KbDb), M1/42.3.9.8 (rat IgG2a against all
mouse H-2 haplotypes), and M5/114.15.20 (rat IgG2b against mouse
I-Ab,d,q and I-Ed,k), obtained from American Type
Culture Collection (Rockville, MD). Briefly, the hybridoma cell lines were
maintained in tissue culture, and the supernatants containing AF 6-120.1.2
(anti-I-Ab) and 20-8-4S (anti-H-2KbDb) were
purified by protein A chromatography. The supernatants containing M1/42.3.9.8
(anti-H-2 antigens, all haplo-types) and M5/114.15.20
(anti-I-Ab,d,q and I-Ed,k) were ammonium
sulfate-precipitated, and then the antibodies were purified with a DE52 anion
exchanger column (Whatman, Hillsboro, OR) and by concentration with Amicon
ultrafiltration. The protein concentration was adjusted to 1 mg/ml and
maintained at -70°C. Peroxidase-conjugated goat IgG against rat IgG and
peroxidase-conjugated goat IgG against mouse IgG were supplied by Organon
Teknika (Scarborough, Ontario, Canada).
Radiolabeled Antibody Binding Assay
Anti-H-2KbDb mAb and anti-I-Ab mAb were
radiolabeled with [125I]-iodide using the Iodogen method (Pierce
Chemical Co., Rockford, IL)
(22). Tissues of individual
mice were prepared as described previously
(22,23).
The tissue concentration was adjusted to 20 mg/ml. A total of 5 mg of kidney
tissue was aliquoted in triplicate and spun. The pellets were incubated on ice
with 125I-labeled mAb in 10% normal mouse serum (100,000 cpm per
100 µl) with agitation for 1 h. After washing, the pellets were counted in
a gamma counter and the nonspecific binding of a negative tissue was
subtracted.
Staining of Tissue Sections
Flash-frozen cryostat sections were fixed in acetone, then incubated with
normal goat serum. The slides were incubated with rat mAb against class I (M1)
and class II (M5) or controls. The slides were then incubated with
affinity-purified peroxidase-conjugated goat anti-rat IgG
F(ab')2 fragment. Antibody binding was visualized by the use
of 3'3-diaminobenzidine tetrahydrochloride and hydrogen peroxide for the
color reaction and then counterstained with hematoxylin.
Northern Blot Analysis
Total RNA was extracted from pooled samples of 4 M guanidinium
isothiocyanate followed by centrifugation in 5.7 M cesium chloride as
described previously (3). Total
RNA (10 µg) was electrophoresed in a 1.5% agarose gel in the presence of
2.2 M formaldehyde, transferred to a nitrocellulose filter, and hybridized
with 32P-labeled cDNA probes for H-2K (class I) or chain of
I-A (class II) and with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) or
ß-actin for loading control. After hybridization, the blots were exposed
to Kodak X-Omat AR film at -70°C with an intensifying screen.
Statistical Analyses
Statistical significance between experimental groups was performed using
ANOVA, and MHC fold increases were determined from cpm counts using a standard
curve.
|
Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Response to rIFN-
We assessed the renal response to IFN- in GRKO and 129Sv/J mice by
measuring MHC mRNA and protein levels after injecting 100,000 U of
rIFN- or saline (control) intraperitoneally. The rIFN- treatment
increased the steady-state levels of MHC class I and II mRNA significantly in
129Sv/J, but not in GRKO kidneys (Figure
2A). IFN- also increased expression of MHC products in
tissue homogenates in 129Sv/J but not GRKO kidneys
(Figure 2B). When plotted on a
standard curve, the changes in 129Sv/J kidneys corresponded to an approximate
14-fold increase in class I expression and a two-fold increase in class II
expression after IFN- treatment. Thus, kidneys of GRKO mice have no MHC
changes in response to rIFN-.
|
Effect of Remote Proinflammatory Stimuli on Renal MHC Expression in
GRKO Mice
MHC expression is induced in kidney during inflammation at remote sites,
due to systemic circulation of cytokines. We compared these MHC responses in
GRKO and 129Sv/J mice.
Allogeneic Stimulation. Mice inoculated with allogeneic P815 ascites
tumor cells develop intense IFN--dependent MHC expression in kidney
(3). GRKO and control mice were
challenged with an intraperitoneal injection of allogeneic P815 cells. The
steady-state MHC mRNA (Figure
3A) increased in 129Sv/J mice but not in GRKO mice. As assessed by
RABA (Figure 3B), MHC product
expression was increased 28-fold (class I) and 12-fold (class II) in kidneys
of 129Sv/J mice. There was no increase in MHC expression in GRKO mice.
|
Skin Sensitization with Oxazolone. We induced a local skin hypersensitivity response to oxazolone and assessed the induction of MHC class I and class II mRNA expression and products by Northern blot analysis and RABA, respectively. Oxazolone induced less skin inflammation in GRKO mice, as reported previously (24) (data not shown). Kidneys of 129Sv/J mice with oxazolone skin reactions exhibited increased steady-state mRNA levels for class I and class II. GRKO kidneys showed essentially no increase of MHC mRNA expression after oxazolone treatment (Figure 4A). Similarly, the RABA showed a striking increase in MHC products in 129Sv/J but not GRKO kidney homogenates (Figure 4B). This corresponded with approximate six- and threefold increases in class I and II expression, respectively.
|
Lipopolysaccaride. LPS induces MHC products in kidney by an
IFN--dependent pathway
(25). Haas et al.
(18) reported that LPS induced
MHC class II in renal tubular epithelium of GRKO mice. In the present
experiments, LPS induced expression of class I and class II mRNA in kidney of
129Sv/J mice but not GRKO mice (Figure
4A). We also examined the expression of class I and class II
molecules in kidney of 129Sv/J and GRKO mice in response to LPS treatment
(Figure 4C). LPS induced class
I and class II products in kidney of 129Sv/J—a fivefold increase in
class I expression and a two-fold increase in class II expression in 129Sv/J
mice on a standard curve—but no increase in GRKO mice.
Induction of Renal MHC Expression in GRKO Mice after Renal
Injury
Renal injury induces local MHC expression
(26), which is only partially
dependent on IFN-
(3,21).
We induced renal injury with high toxic doses of gentamicin and assessed MHC
expression. Class I mRNA levels in GRKO mice were less than in 129Sv/J mice
(Figure 5A), and class I
product was increased in kidney of 129Sv/J and GRKO mice after toxic renal
injury (Figure 5B). The
induction of class II in GRKO and 129Sv/J mice was not significantly different
(Figure 5, A and B). Both the
class II mRNA and the RABA were increased after toxic renal injury. The
changes in 129Sv/J mice tended to be greater than in the GRKO mice. Acute
injury by ischemia also induced class I expression by RABA but had less effect
in GRKO mice (Figure 5C). Thus,
GRKO mice displayed reduced MHC induction in response to injury, particularly
ischemic injury.
|
Tissue Staining for MHC Class I and II in Kidney
We assessed patterns of MHC expression in kidney sections from 129Sv/J and
GRKO mice by indirect immunoperoxidase staining in four states: the basal
state, after rIFN- administration, after systemic inflammatory stimuli,
and after toxic injury. The staining for basal class I and II in kidney
sections was not significantly different between 129Sv/J and GRKO mice except
that class I staining of the arterial endothelium was stronger in 129Sv/J than
in GRKO mice (reported previously in reference
(27) (data not shown). Basal
class II staining was confined to interstitial cells in 129Sv/J and GRKO mice
(Table 1,
Figure 6, A and B). The
rIFN- strongly induced class I staining of tubules, arterial
endothelium, and glomeruli in 129Sv/J mice but not in GRKO mice
(Table 1,
Figure 7, C and D). The
rIFN- induced class II expression in tubules of 129Sv/J but not GRKO
mice (Table 1,
Figure 6, C and D).
|
|
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Remote and systemic inflammatory stimuli induced MHC in a pattern identical
to that of rIFN- in kidneys of 129Sv/J mice (i.e., class I in
tubules, arterial endothelium, and glomeruli and class II in kidney tubules)
(Table 1,
Figure 7,
Figure 7 [class I], and Figure
6 [class II], E, G and
I). These stimuli had little
effect in GRKO kidney (Table 1,
Figure 7,
Figure 7 [class I], and Figure
6 [class II], F, H and
J). In particular,
heat-inactivated LPS of S. minnesota did not induce class II staining
in the tubules of GRKO mice, in contrast to a previous study
(18). Acute injury by
gentamicin induced more staining for class I in kidney tubules of 129Sv/J than
in GRKO mice (Table 1,
Figure 7, K and L). In
gentamicin-treated 129Sv/J mice, MHC class II antigens were induced in kidney
tubules (Table 1,
Figure 6K). Gentamicin
treatment also induced MHC class II expression in GRKO mice. Class II-positive
interstitial cell staining was also increased in both GRKO and 129Sv/J mice
(Table 1,
Figure 6L) after gentamicin
injection.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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R1 in the
regulation of renal MHC expression. GRKO mice had reduced MHC class I
expression in the basal state, whereas basal class II expression was
independent of IFN-R. MHC expression in GRKO mice was unchanged in
response to rIFN-. However, there remained the potential for other
mechanisms that could bypass the lack of IFN-R, particularly during
complex inflammatory states in which numerous cytokines with potential for MHC
regulation (i.e., IFN-/ß or tumor necrosis
factor-) are produced. The induction of renal MHC class I and II
expression by systemic inflammatory stimuli, which are potent inducers of many
cytokines, was essentially lost in GRKO mice. In contrast, acute renal injury
by gentamicin induced MHC expression in GRKO mice, albeit at reduced levels.
Thus, IFN-R1 in kidney is essential for normal class I expression in
the basal state, for class I and II expression after rIFN- treatment,
and after systemic stimuli that induce IFN- in vivo. Kidney
injury induces at least some MHC expression by an IFN-R1-independent
mechanism (3). The regulation
of MHC gene expression in kidney is becoming a major example of the complex
yet precise mechanisms that regulate gene expression in response to local and
remote influences.
The close agreement of the present studies with earlier results in GKO mice
indicate that both IFN- and IFN-R1 have essential roles in
regulating the expression of MHC genes in the kidney
(3,28).
The principal difference was that GKO responded to rIFN- and GRKO did
not, as expected. These studies confirm that some renal MHC expression is
independent of IFN- and IFN-R1: basal class II, a component of
basal class I expression, and some of the class I and II changes during acute
renal injury. However, the high MHC expression that occurs in response to
systemic inflammation is dependent on IFN-. This does not suggest that
IFN- is the only cytokine operating, because synergy with other
cytokines increases the effect of IFN- on MHC expression
(29,30).
Nevertheless, the high cytokine levels in these inflammatory states apparently
cannot bypass the absence of IFN- or IFN-R1. Because
gene-disrupted mice sometimes reveal unsuspected redundancies, it was
conceivable that in vivo other cytokines might stimulate the
IFN-R in GKO mice or IFN- might stimulate noncognate receptors
in GRKO mice or have weak interactions with IFN-R2 chains.
IFN-R2 does not bind ligand but is required for signal transduction
in vitro (31). GRKO
mice presumably have R2, but on the basis of these results R2 cannot
compensate for the loss of R1 and makes no contribution to MHC regulation in
the absence of R1 in vivo. Thus, IFN- and its receptor play
nonredundant roles in their MHC regulating functions, unlike many other
cytokines.
The surprising role of IFN- in renal MHC expression in the basal
state has several implications. First, IFN- must be constantly present
in sufficient quantities in unstimulated mice to induce genes in the arterial
endothelium, raising the question of whether this is also a feature of human
endothelium. However, some class I is expressed in the absence of IFN-
or its receptor, either due to constitutive expression or to induction by
non-IFN- stimuli. Mouse class II is more difficult to induce by
IFN- than class I, and this may explain (as illustrated here in the
response to rIFN-) why class I is induced but class II is not. This may
be relevant to the human kidney, in which class II is present on many
endothelial cells in vivo. We suggest that class II expression in
human endothelium, but not mouse endothelium, reflects either higher
IFN- production in the basal state in humans or greater sensitivity of
human class II genes to basal IFN- production. Because IFN-
potentiates atherosclerosis in the apolipoprotein E knockout mouse
(32), the fact that basal
IFN- production can affect gene expression in renal endothelium is
potentially relevant to renal atherosclerosis.
Renal injury induces increased expression of MHC genes by mechanisms both
dependent on and independent of IFN-/IFN-R1, confirming our
previous conclusions
(3,32)
and raising the question of the mechanisms. We presume that the
IFN-/IFN-R1-dependent component is mediated by natural killer
cells, which are major sources of IFN- production and will be recruited
to injured areas by the chemokine response. Antigen nonspecific recruitment
and activation of T cells may also play a role. In contrast, we suspect that
the IFN-/IFN-R1-independent component of this response seen in
our gentamicin toxicity experiments may represent an intrinsic response of the
stressed and regenerating epithelium (i.e., to changes in integrin
signals from extracellular matrix), but may also reflect non-IFN-
cytokines from inflammatory cells. In short, the mechanisms of injury-mediated
inflammation and the immune response have yet to be well defined
(33). The ability of injury to
induce renal MHC expression bears no obvious relationship to the nature of the
inducing stimulus. For example, it is not dependent on reperfusion injury as
we first proposed when we and others observed this effect after renal ischemia
(20,21,34).
The injury-induced increases in antigen presentation could be a link between
renal injury and both autoimmunity and transplant rejection
(33,35).
The differences between our results with LPS (class II induction was
IFN--dependent) and those of Haas et al.
(18) (class II induction was
independent of IFN-) probably reflect variations in experimental
protocol. Haas et al. studied MHC induction by staining tissues 4 d
after injection of 50 µg of LPS from Escherichia coli, noting that
LPS induced MHC class II expression in renal tubules of GRKO mice. They
concluded that IFN- is not absolutely required for induction of class
II after LPS treatment. We found little or no class II induction by S.
minnesota LPS in GRKO tubules, compared with 129Sv/J controls. One
possible mechanism for the induction of class II by LPS in GRKO mice in the
studies of Haas et al. is that they used an LPS protocol that induced
some renal injury and thus led to the type of class II expression that follows
acute tubular injury. We selected heat-inactivated LPS from S.
minnesota to avoid the stress response and injury, and thus the only
effects we elicited were those related to IFN- production.
The congruence between the phenotypes of GKO and GRKO mice confirms the
unique dependency of IFN- on IFN-R1 and vice versa, and
the unique role of the IFN-/IFN-R1 unit in renal MHC regulation
in vivo. Certain effects of IFN- on immune regulation as well
as the host defense problems encountered by humans and mice with IFN-
and IFN-R deficiencies may reflect the defects in antigen presentation
and MHC regulation, rather than direct effects on lymphocytes. The role of the
tubular epithelium in antigen presentation has been explored elsewhere
(36,
37,
38,
39) but remains unresolved.
Regulation is not limited to class II, since class I and many other components
of the antigen presenting system are also induced in kidney
(40). It will thus be
instructive to explore how the high responsiveness of the kidney to stimuli,
both through the IFN-/IFN-R system and independent of it,
impacts the propensity toward autoimmune diseases
(41).
|
Acknowledgments |
|---|
. We thank Dr. Marjan Afrouzian for
reviewing the pathology and Ms. Lina Kung for reviewing the manuscript. We
also wish to thank Ms. Pam Publicover for her skilful secretarial
assistance. This work is supported by operating grants from The Medical Research Council of Canada, The Kidney Foundation of Canada, The Muttart Chair in Clinical Immunology, the Royal Canadian Legion, Fujisawa Canada, Novartis Pharmaceuticals Canada, and Hoffmann-La Roche Canada; Dr. Yutaka Takei was supported by a grant from the International Council for Canadian Studies; Tasha N. Sims is supported by a Studentship from the Alberta Heritage Foundation for Medical Research.
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O. Takeuchi, T. N. Sims, Y. Takei, V. Ramassar, K. S. Famulski, and P. F. Halloran Differential Usage of Class II Transactivator Promoters PI and PIV during Inflammation and Injury in Kidney J. Am. Soc. Nephrol., November 1, 2003; 14(11): 2823 - 2832. [Abstract] [Full Text] [PDF]
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 P. L. Kimmel, D. J. Cohen, A. A. Abraham, I. Bodi, A. M. Schwartz, and T. M. Phillips Upregulation of MHC class II, interferon-{alpha} and interferon-{gamma} receptor protein expression in HIV-associated nephropathy Nephrol. Dial. Transplant., February 1, 2003; 18(2): 285 - 292. [Abstract] [Full Text] [PDF]
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A. C. Wiseman, B. A. Pietra, B. P. Kelly, G. R. Rayat, M. Rizeq, and R. G. Gill Donor IFN-{gamma} Receptors Are Critical for Acute CD4+ T Cell-Mediated Cardiac Allograft Rejection J. Immunol., November 1, 2001; 167(9): 5457 - 5463. [Abstract] [Full Text] [PDF]
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 P. F. Halloran, M. Afrouzian, V. Ramassar, J. Urmson, L.-F. Zhu, L. M. H. Helms, K. Solez, and N. M. Kneteman Interferon-{{gamma}} Acts Directly on Rejecting Renal Allografts to Prevent Graft Necrosis Am. J. Pathol., January 1, 2001; 158(1): 215 - 226. [Abstract] [Full Text] [PDF]
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