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*
Department of Immunobiology, DNAX Research Institute, Palo Alto, CA 94304;
Department of Pediatrics and Biomedical Research Center, Heinrich Heine University, Düsseldorf, Germany
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-chain receptor, IL-7 is unique in its effect on the T-
and B-cell lineages (1). The mechanism of IL-7 function has now been
linked to the bcl-2 anti-apoptosis pathway, indicating a
role in the maintenance of lymphocyte viability (2, 3), particularly at
the developmental point of Ag receptor rearrangement (4). Aside from the role for IL-7 on T and B cells, little is known about the in vivo actions of IL-7 on other cell types. It has been established that IL-7 stimulates myeloid colony formation in vitro (5), regulates Janus kinase-3 phosphorylation in human monocytes (6), induces cytokine secretion and tumoricidal activity by human monocytes (7), stimulates NK cells (8), and has a supportive effect on eosinophil progenitors (9). As a pharmacologic agent in vivo, IL-7 administration mobilizes myeloid progenitor cells from the mouse bone marrow to peripheral sites (10, 11). Despite these findings, no obvious abnormality in myelopoietic cells or cells of the NK lineage was apparent in IL-7-deficient (IL-7-/-)5 mice under normal conditions.
The intestinal epithelium as well as intestinal human goblet cells have been identified as prominent sites for the expression of IL-7 (12). A relatively common pathologic condition at this anatomical site is inflammatory bowel disease (IBD), a heterogeneous disease occurring in 0.2% of humans (13). It is generally believed that this disease involves an altered or aberrant intestinal immune response, perhaps in the context of certain micro-organisms (14). This concept is supported by findings that a wide variety of mutant mice that harbor mutations affecting the inflammatory or immune response have a complex spectrum of pathologic abnormalities in the digestive tract (15). Typically these disorders do not occur in germfree animals (16, 17), establishing the importance of a microbial trigger that may subvert the altered immune response toward chronic pathology (18). In particular, Helicobacter hepaticus has been shown to cause colitis in immunodeficient mice, such as SCID, but causes no intestinal pathology in immunocompetent animals (19). Moreover, H. hepaticus has been detected in immunocompetent mice from major mouse vendors (20).
One approach to understanding this etiologically diverse disease in humans is to determine which molecules, pathways, and mechanisms are operating in genetically modified disease models. Herein we describe a T cell- and B cell-independent inflammation in the colon and cecum of RAG-2-deficient mice colonized with H. hepaticus (Hh flora+), akin to the pathology described in SCID mice (19), and show that the initiation and/or maintenance of this disease are dependent on IL-7. We characterize the cell populations responding in the disease state by in situ immunofluorescence and FACS analysis, and show that rIL-10 protein therapy is also an effective method of preventing the occurrence of colitis.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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All animals were derived from one common breeder pair on a 129 SvEv/129 Ola hybrid background. Genomic DNA was isolated from tails and was digested with either EcoRI and XbaI for screening of RAG-2 deficiency or with BamHI and XbaI for screening of IL-7 deficiency as described in the original publications of the single gene-targeted mice (1, 21). All mice were housed in a specific pathogen-free barrier facility in enhanced microisolator cages and screened quarterly for viral, bacterial, and parasitic agents at the Research Animal Diagnostic and Investigative Laboratory in Columbia, MO. The DNAX animal facility is an American Association for the Accredidation of Laboratory Animal Care-accredited institution. Treatment and care of the animals were in accordance with the institutional guidelines.
H. hepaticus screening by PCR
DNA from fecal samples were prepared by first homogenizing the sample with a QIAshredder (Qiagen, Hilden, Germany) and then processing it through a QIAamp column (QIAamp Tissue Kit, Qiagen). DNA amounts were equalized by comparing genomic DNA intensities in ethidium bromide-stained gels. PCR was performed following the protocol of Shames et al. (20). The primer sequences chosen were specific for H. hepaticus (5', 5'-GCA TTT GAA ACT GTT ACT CTG-3'; 3', 5'-CTG TTT TCA AGC TCC CCG AAG-3'). A 417-bp PCR product indicated the presence of H. hepaticus.
Hh flora exposure
Exposure to Hh flora of PCR-negative mice was accomplished by using the natural means of transmission. Either newborn mice from Hh flora- mothers were marked, mixed, and then raised by known infected, Hh flora+ foster parents, or Hh flora- adult mice from both strains were cohoused and exposed weekly to bedding from cages of Hh flora+ mice. The acquisition of H. hepaticus was confirmed in each case by PCR.
Antibiotic treatment
Animals were treated with 50 mg/kg/day amoxicillin via addition to the drinking water for 14 days following the suggested treatment of Russel et al. (22). Treatment was started after weaning at age 21 days. This treatment ablated the presence of H. hepaticus in RAG-2-/- and IL-7/RAG-2-/- mice shown by H. hepaticus-specific PCR and of the inflammatory pathology in the RAG-2-/- group.
Peripheral blood analysis
Blood samples were obtained via the tail vein. Blood cell concentrations were assessed using an automated cell counter (model 901, Serono-Baker Diagnostics, Allentown, PA). For differential counts, blood smears were stained with Wright-Giemsa stain and counted under a light microscope. Serum amyloid A (SAA) levels were measured by ELISA using a kit supplied by BioSource International (Camarillo, CA) according to the manufacturer’s direction.
Histologic analysis
Cecums were removed, trimmed of fat and connective tissue, fixed in 10% neutral buffered formalin, routinely processed, sectioned at 5 µm, and stained with either hematoxylin and eosin or Steiner’s silver stain (23) for light microscopic examination.
Immunofluorescence labeling of tissue sections
Colon tissue was immersed in Tissue-Tek embedding
compound (Miles Scientific, Elkhart, IN) and snap-frozen on liquid
nitrogen. Sections (4 µm) were cut using a Reichert-Jung Frigocut
cryostat (Cambridge Instruments, Buffalo, NY) and immediately air-dried
onto glass microscope slides. Tissue sections were simultaneously
stained with specific mAb and anti-cytokeratin using a two-step
protocol as previously described (24). The mAb used were rat
anti-mouse F4/80 tissue culture supernatant (clone A3-1; 1/50
dilution: BMA, Westerbury, NY), rat anti-mouse MTS6 (anti-I-A,
I-E; 1/10 dilution: provided by Dr. R. L. Boyd, Monash University,
Melbourne, Australia), and rabbit anti-bovine cytokeratin (broad
spectrum antiserum; 1/100 dilution; Dakopatts, Santa Barbara, CA).
Second-step Ab were goat anti-rat IgG (+L)-FITC (8 µg/ml;
Caltag, Burlingame, CA) and rhodamine isothiocyanate-conjugated goat
anti-rabbit IgM and IgG (H+L) (25 µg/ml; Southern Biotechnology
Associates, Birmingham, AL).
Flow cytometric analysis
Peritoneal lavage cells were collected by washing the peritoneal cavity with 10 ml of cold PBS supplemented with 10% FCS. After washing, cells were incubated with CD16/CD32 mAb (1/50; PharMingen, San Diego, CA) for 10 min at 4°C to block nonspecific binding. Three-color staining was then performed using biotinylated F4/80 mAb (1/100; Caltag), phycoerythrin-conjugated DX-5 mAb (1/100; PharMingen), and FITC-conjugated anti-CCR-3 mAb (1/200; DNAX, Palo Alto, CA) followed by staining with Tri-Color-conjugated streptavidin (1/100; Caltag). Cell washes and Ab dilutions were performed in PBS containing 2% FCS. Each incubation was performed at 4°C for 20 min. Cells were analyzed on a FACSCalibur flow cytometer (Becton Dickinson, San Jose, CA) equipped with CellQuest software (Becton Dickinson). Cell sorting was performed using a FACStar Plus (Becton Dickinson); sorted populations were >99% pure upon reanalysis.
Treatment with rIL-10
Hh flora+ RAG-2-/- mice received daily i.p. injections of 20 µg of rIL-10 beginning at 3 wk of age and were cohoused with untreated litter mates. Mice were killed after 6 wk of treatment for pathologic evaluation. Production and purification of rIL-10 were previously described (25).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Routine breeding of RAG-2-/- and IL-7/Rag-2-/- revealed rectal prolapse formation in a large percentage of RAG-2-/- mice, but not in IL-7/RAG-2-/- mice. Comprehensive screening of animals from both colonies for a large panel of viruses, parasites, and bacteria showed H. hepaticus colonization, but no other unusual findings (data not shown).
This observation prompted us to design studies to examine a potential
pathologic role for IL-7 in the development of this inflammatory
disorder. A PCR assay (20) was employed to survey for the status of
H. hepaticus colonization. Two methods were then used to
control the status of H. hepaticus colonization in
experimental groups of animals. First, mice of both genotypes that were
H. hepaticus PCR positive, but before the onset of
pathology, were treated with amoxicillin according to established
protocols (22). The amoxicillin treatment resulted in a conversion of
the PCR signal from positive to negative. Subsequent re-exposure to Hh
flora was accomplished by cohousing PCR-negative animals with
PCR-positive mice (Fig. 1
A).
Second, newborn litters of each genotype were marked, then mixed to
nurse on mothers known to harbor Hh flora. PCR analysis was performed
each week for 2 wk and showed a similar acquisition of H.
hepaticus in both groups (Fig. 1B). By these two
designs, experimental groups of animals could acquire the flora that
contained H. hepaticus by a natural mode of transmission.
Animals are hereafter referred to as Hh flora+ or Hh
flora-.
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shows a
significant increase in all these parameters in the
RAG-2-/- Hh flora+ group of mice
compared with normal values in RAG-2-/- Hh
flora- mice. In contrast (and relative to the data from
RAG-2-/- mice),
IL-7/RAG-2-/- Hh flora+ mice showed
only a minimal increase in WBC counts, a moderate increase in platelet
counts, and no increase in SAA compared with
IL-7/RAG-2-/- Hh flora- mice. In a
separate experiment with animals treated in the same way, the
differential subpopulations of WBC were investigated (Table I). While WBC and platelet counts were
elevated, the percent WBC composition was not significantly different,
indicating a generalized hemopoietic response in the blood. Identical
results were obtained when PCR- adult animals became Hh
flora+ (data not shown).
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A). In contrast, all
RAG-2-/- Hh flora+ mice showed
severe pathologic changes, consisting of markedly hyperplastic
epithelia, a depletion of goblet cells, and focal epithelial necrosis
and ulceration. Areas underlying and adjacent to the ulcerations were
expanded by edema and were infiltrated with inflammatory cells
consisting of macrophages, neutrophils, and eosinophils (Fig. 3C). The pathology occurred in discontinuous patches along
the colon (data not shown). In contrast, pathologic changes were not
observed in the IL-7/RAG-2-/- mice regardless
of whether the animals were Hh flora- (Fig. 3B)
or Hh flora+ (Fig. 3D). Cecum tissue sections
stained with Steiner’s silver stain (23) from
RAG-2-/- Hh flora+ (Fig. 4A) or
IL-7/RAG-2-/- Hh flora+ (Fig. 4B) showed characteristic helical organisms that were
indicative of H. hepaticus. Both groups of mice had similar
patterns of staining for these organisms, providing an additional
method to compare and monitor acquisition of the Hh flora.
Interestingly, the inflamed nature of the tissue in
RAG-2-/- mice showed closer contact and a
deeper penetration of the bacteria into the crypt structures compared
with tissues from IL-7/RAG-2-/- Hh
flora+ mice.
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A hallmark of colitis is the up-regulation of MHC class II,
particularly expression by colonic epithelial cells (26). Using in situ
immunofluorescent techniques, RAG-2-/- Hh
flora- mice, which have normal intestinal physiology,
showed MHC class II staining in patches, primarily at the luminal
epithelial surface (Fig. 5A).
In contrast, intense MHC class II staining was observed throughout the
entire tissue section in RAG-2-/- Hh
flora+ mice (Fig. 5C). Large numbers of
infiltrating cells were MHC class II positive, as were most epithelial
cells. Neither group of IL-7/RAG-2-/- mice,
whether Hh flora- or Hh flora+, showed an
up-regulation of MHC class II expression (Fig. 5, B and
D, respectively). The occurrence of infiltrating macrophages
was also assessed using the F4/80 mAb. Only diseased mice,
RAG-2-/- Hh flora+ animals, showed
a markedly enhanced frequency of F4/80-positive cells infiltrating into
the tissue (Fig. 5, E–H). Further characterization of cell
populations from the peritoneal cavity showed an unusual
F4/80low subset, present only in
RAG-/- Hh flora+ animals (Fig. 6A). To investigate the nature
of these cells we sorted the F4/80low population by flow
cytometry, followed by cytospinning and staining with Wright-Giemsa
stain. All cells were eosinophils (data not shown). To further
investigate these cells we performed a three-color FACS analysis using
the mAb F4/80, a mAb to the eosinophil chemokine receptor
CCR-3,6 and the mAb DX-5,
which recognizes NK cells. F4/80 bright cells (macrophages) were
excluded from analysis by gating, and the staining pattern for the
remaining cells is shown in Fig. 6B. The
DX-5+/CCR-3+/F4/80low phenotype
defined the eosinophil population. Only
RAG-2-/- Hh flora+ mice with
colitis showed robust eosinophilia, in contrast to the
IL-7/RAG-2-/- mice, regardless of the Hh flora
status. To our knowledge, DX-5 staining on eosinophils has not
previously been described. It is unclear whether this is an unusual
feature of IL-7/RAG-2-/- mice or a more
generalized feature of mouse eosinophils. The number of
DX-5+/CCR-3-/F4/80- NK cells
(Fig. 6B) in the peritoneal lavage was similar for both
genotypes of Hh flora- and Hh flora+ animals.
Attempts to detect DX-5-positive cells with an NK cell morphology in
inflamed colon tissue sections were unsuccessful.
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The anti-inflammatory properties of IL-10 are well documented
(27), and IL-10-deficient mice develop colitis (17, 28). In light of
these data and the nature of the inflammation in the
RAG-2-/- Hh flora+ mice, we
investigated the potential of rIL-10 protein therapy to protect against
IL-7-dependent colitis in the model described herein. Weanling
RAG-2-/- Hh flora+ untreated
control mice and RAG-2-/- Hh flora+
mice treated with rIL-10 for 6 wk were investigated for a blood
response and intestinal pathology. WBC and platelet counts showed that
rIL-10 therapy reduced the disease-associated WBC count to normal and
reduced, at least to a moderate degree, the platelet count (data not
shown). Histology revealed that rIL-10 therapy completely protected all
the treated animals, whereas all the control animals developed disease,
as shown in the representative Fig. 7,
A and B, respectively. Given the well-established
down-regulatory effects of rIL-10 on macrophages, these data suggest a
critical role for macrophages in this disease.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Both genetic and environmental factors are implicated in human IBDs (29). Aberrant immune or inflammatory responses triggered by microbial organisms may be important in the sequence of events leading to pathology. However, it is also clear that defects in epithelial cell factors can predispose mice toward colitis (30). Given the complexity of potential interactions of the various cell populations that are likely to be involved in human IBD, one approach to understanding disease mechanisms is to take advantage of the controlled genetics and environmental conditions afforded by mouse models.
A variety of mouse models of colitis have recently been characterized
(31), many involving gene knockout studies. While all these models are
unlikely to represent genetic replicas of the human disease, each may
point to a mechanistic pathway worthy of pursuit in understanding the
nature of the disease. Indeed, most of the gene knockout models that
develop colitis, such as IL-10-deficient (17), IL-2-deficient (16), and
TCR
-deficient mice (32) unexpectedly developed intestinal pathology,
emphasizing the complex and poorly understood immune and inflammatory
regulation along the digestive tract.
While most mouse models established the importance of T cells in the disease, the occurrence of colitis in SCID mice offered a different perspective (19). It is clear that the intestinal pathophysiology, similar to that in the T cell-driven models, can occur independently of T cells. Furthermore, in relation to human IBD, numerous studies have implied that the presence of particular microbial flora correlates with disease incidence (14). This conclusion was supported by the finding that antibiotic treatment of postsurgery human patients with metronidazole had shown efficacy (33). Within the context of T cell-independent chronic inflammation and microbial organisms, we describe herein a myeloid response in RAG-2-/- Hh flora+ animals that is either directly or indirectly dependent on IL-7.
The acquisition and colonization of RAG-2-/- mice by Hh flora resulted in a peripheral increase in WBC and platelets. In the cecum and colon, a substantial infiltration of macrophages and granulocytes accompanied the chronic disease. In contrast, the colonization of IL-7/RAG-2-/- mice with Hh flora did not result in any signs of disease or inflammation. The development of IL-7-dependent colitis invoked a number of potentially new and unexplored mechanisms. For example, IL-7 may be involved in initiating migratory events to the bowel, although IL-7 alone did not appear to be directly chemotactic for these cell populations (our unpublished observations). However, other cytokines have been characterized as an initiating signal for chemokine gene expression (34). Alternatively, IL-7 might be involved in maintaining an inflammatory state in the colon, perhaps by acting as a cell maintenance factor for myeloid cells, in a manner comparable to the IL-7 bcl-2-dependent maintenance of lymphocytes (4). Indeed, IL-7 has been shown to effectively stimulate the monocyte and macrophage lineage (5). The proximity of IL-7 production by mucosal epithelia (12) and its potential interaction with infiltrating F4/80 positive cells further the hypothesis that IL-7 may regulate inflammation via macrophages.
IL-10 is well appreciated for its anti-inflammatory activities and its inhibitory effect on macrophages (27). These data combined with the observation of colitis in IL-10-deficient mice have formed the basis of human clinical trials using rIL-10 as a therapeutic protein for Crohn’s disease patients (35). In the colitis model described herein, rIL-10 administration is able to prevent the occurrence of disease, further supporting the idea of a primary role for macrophages in this disease model.
It was recently reported (36) that mice expressing an IL-7 transgene in
the colonic mucosa develop colitis, consistent with the data in this
paper indicating a pathogenic role for IL-7. The model presented here
indicates a previously unsuspected and dominant role for IL-7 in
driving inflammation promoted by gut flora, but only in the absence of
lymphocytes. While this function may be surprising for IL-7, these data
suggest that complex interactions are occurring between distinct cell
types that may depend on similar molecules for intestinal homeostasis.
For example, the 
T cell population in a normal mouse intestine
is strictly dependent on the presence of IL-7 (37), implying that
normal T cell populations may be required to keep innate inflammatory
mechanisms in check. In this sense, it is reasonable to hypothesize
that variations in the adaptive immune response may lead to the lack of
appropriate control of innate inflammatory mechanisms in addition to
the more traditional concept of an aggressive and pathogenic T cell.
This type of adaptive cell loss of function may include pathways that
mediate anti-inflammatory properties. Ultimately, the lessons
learned from the approach of mouse genetics and disease modeling may
allow for a broader understanding of the mechanistic complexities of
this ill-defined disease in humans.
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Acknowledgments |
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Footnotes |
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2 Current address: Eos Biotechnology, Inc., 225A Gateway Blvd., South San Francisco, CA 94080.
3 Current address: Children’s Hospital Medical Center and BioCenter, University of Halle-Wittenberg, 06097 Halle, Germany.
4 Address correspondence and reprint requests to Dr. Rich Murray, Eos Biotechnology, Inc., 225A Gateway Blvd., South San Francisco, CA 94080. E-mail address:
5 Abbreviations used in this paper: IL-7-/-, IL-7 deficiency; IBD, inflammatory bowel disease; Hh flora, Helicobacter hepaticus-containing flora; RAG-2-/-, recombination-activating gene-2 deficiency; IL-7/RAG-2-/-, IL-7 and recombination-activating gene-2 deficiency; SAA, serum amyloid A; WBC, white blood cells.
6 J. C. Grimaldi, N. Yu, G. Grunig, B. W. P. Seymour, F. Cottrez, D. S. Robinson, N. Hosken, W. G. Ferlin, X. Wu, H. Soto, A. O’Garra, K. S. Soo, M. C. Howard, and R. L. Coffman. Depletion of eosinophils in mice using antibodies specific for C-C chemokine receptor 3 (CCR3). Submitted for publication.
Received for publication May 5, 1998. Accepted for publication July 13, 1998.
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