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The Journal of Immunology, 1998, 161: 1069-1073.
Copyright © 1998 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Curative Treatment of an Experimentally Induced Colitis by a CD44 Variant V7-Specific Antibody1

Bianca Wittig*, Christoph Schwärzler{dagger}, Nicole Föhr*, Ursula Günthert{dagger} and Margot Zöller2,*

* Department of Tumor Progression and Immune Defense, German Cancer Research Center, Heidelberg, Germany; and {dagger} Basel Institute for Immunology, Basel, Switzerland


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Inflammatory bowel disease is a quite severe chronic inflammation, treated mainly by immunosuppression, which often has serious side effects. As CD44 is important in lymphocyte activation and migration, we asked whether Abs against CD44 isoforms influence trinitrobenzenesulfonic acid (TNBS)-induced colitis in mice. A lethal colitis (73/111 mice) could be prevented in 69 of 97 mice by anti-CD44v7 (CD44 variant isoform v7), whereas anti-CD44s (CD44 standard isoform) and anti-CD44v6 had no effect. Upon receiving anti-CD44v7 after the disease had been fully exacerbated, >90% of the mice recovered. TNBS plus anti-CD44v7-treated mice developed early signs of inflammation, with infiltration of leukocytes in the lamina propria and increased IFN-{gamma} production. However, while control mice developed a severe pancolitis, the intestine fully regenerated in anti-CD44v7-treated mice. Locally and systemically, a strong increase in IL-10 production was noted. Thus, anti-CD44v7 can be regarded as a highly efficient and specific therapeutic reagent in chronic colitis, which probably functions by regulating an overshooting Th1 reaction.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Chronic inflammatory bowel diseases (IBD),3 such as colitis ulcerosa and Crohn’s disease, are of major concern because of the severity of the symptoms, high incidence, and onset at a relatively young age (1). Many trials have recently been undertaken to define new modes of therapeutic intervention that may be less harmful than the conventional immunosuppressive treatment (2, 3). Progress in the field has been much accelerated by recently available animal models such as TNBS- or dextran sodium sulfate-induced colitis. Furthermore, mice deficient in IL-2 or IL-10 spontaneously develop IBD (4, 5, 6, 7). TNBS-induced colitis (6, 7) has been well characterized as an overshooting Th1 response accompanied by a strong up-regulation of IFN-{gamma} production (8). Successful trials of therapeutic interference by, for example, anti-IFN-{gamma}, anti-IL-10, and anti-TNF-{alpha} have strengthened the importance of Th1 cytokines in IBD (9, 10, 11).

CD44 variant isoforms are transiently up-regulated or exclusively expressed during lymphocyte activation (12). Their involvement has been suggested in signal transduction (13, 14). In particular, CD44v6 and CD44v7 have been shown to be involved in delayed-type hypersensitivity reactions (15). Here, we present evidence that a CD44v7-specific Ab can prevent and cure TNBS-induced colitis by interfering with an ongoing Th1 response.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Mice and treatment of mice

BALB/c mice were obtained from Charles River (Sulzfeld, Germany). One day before treatment, mice were transferred from specific pathogen-free to conventional conditions. They received 200 µl TNBS (2.5% w/v) in 50% ethanol intrarectally (10) and, where indicated, anti-CD44s, anti-CD44v7, or anti-CD44v6.

Antibodies

The following mAb were used: anti-CD44v6 (clone LN6.1, mIgG2a), anti-CD44v7 (clone LN7.1, mIgG1; Schwärzler et al., manuscript in preparation), anti-CD44s (IM-7, rIgG2b), anti-IFN-{gamma} (R4-6A2, anti-rIgG), anti-µ (131.12, rIgG2b), anti-CD3 (145-2C11, rIgG) (American Type Culture Collection, Manassas, VA), anti-Thy1.2 (YTS154.7.7.10, rIgG2b), anti-CD4 (YTA3.2.1, rIgG2b), anti-CD8 (YTS169.4.1, rIgG2b), and anti-Mac-1 (YBM6.1.1, rIgG2a) (European Collection of Animal Cell Cultures, Wiltshire, England (ECACC)). Purified mAb were used in vitro at a concentration of 10 µg/ml. Pairs of anti-IL-10, anti-IL-12, and anti-IFN-{gamma} were obtained commercially (PharMingen, Hamburg, Germany). For flow cytometry, FITC- and phycoerythrin-labeled isotpye-specific secondary Abs were used. For FACS analysis, 3 x 105 cells were stained according to routine procedures. When cytokine production was evaluated, cells were fixed (3% formaldehyde) and permeabilized (1% Tween 20). Fluorescence was determined with an EPICS XL (Coulter, Hialeah, FL).

Preparation of lymphoid cells

Lymphoid organs were prepared under sterile conditions. Lymphocytes from the lamina propria (LPL) were isolated by flushing the gut several times with PBS containing penicillin and streptomycin and 2 times for 10 min with 0.7 mM EDTA and 1 mM DTT in PBS to remove intraepithelial lymphocytes. The tissue was minced and incubated three times for 30 min at 37°C with a mixture of collagenase (50 U/ml) and DNase (27 U/ml), and cells in the supernatants were collected. T cells were enriched by depletion of plastic-adherent cells (2 x 1 h) and of B cells by panning on anti-mouse Ig-coated plates. The nonadherent cells were collected, incubated with anti-CD4 and/or anti-CD8, washed, and seeded on anti-rat IgG-coated plates. The adherent cells stained to >95% with anti-CD4 or anti-CD8.

ELISA and ELISpot assay

Standard procedures were used for these assays. For measuring cytokine secretion, lymphocytes (4 x 106/ml) were cultured in RPMI 1640 supplemented with 10% FCS, antibiotics, 10-3M HEPES buffer, and 2 x 10-5 M 2-ME in the presence of 100 µg TNP-OVA/ml. After 3 days, supernatants (50 µl) were seeded on the coated plates. For the ELISpot assay, freshly harvested lymphocytes or lymphocytes derived from bulk cultures were added to the coated plates, lysing the cells after 24 h of incubation.


   Results and Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
CD44 isoforms encoding exon v6 and v7 were not detected on spleen cells, lymph node cells (LNC), PBL, Peyer’s patch lymphocytes, and peritoneal exudate cells. Only on LPL was a low level of expression seen, which may be indicative of a continuous state of activation (16). After antigenic stimulation in vitro or in vivo (Table IGo), expression of CD44v6 was noted on subpopulations of CD4+ and, predominantly, on CD8+ T cells. CD44v7 was expressed at a low level on T as well as non-T cells.


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  		Table I. Expression of CD44v6 and CD44v7 on activated lymphocytes

 
Because of the restricted expression of CD44v6 and CD44v7, we speculated that CD44v6/CD44v7-specific Abs might be promising candidates for therapeutic interference with chronic inflammatory reactions such as TNBS-induced experimental colitis.

In the first set of experiments, anti-CD44s, anti-CD44v6, and anti-CD44v7 were instilled intrarectally 2 h after application of TNBS (Fig. 1Go). The incidence of colitis following TNBS treatment was 100%. Ninety-six percent (107/111) of the mice developed a wasting disease and 66% (73/111) became moribund within 5 to 12 days. Neither anti-CD44s nor anti-CD44v6 exerted any major effect on the survival rate. Instead, only 27% (28/97) of mice showed signs of severe colitis after anti-CD44v7 treatment. Intravenous injection of anti-CD44v7 had the same effect. Animals survived in 80% of the cases without any obvious symptoms. This was confirmed by macroscopic inspection (data not shown) and histologic examination of the gut (Fig. 2Go). After 4 days, an increase in inflammatory cells and partial destruction of the epithelial layer were seen in TNBS- as well as in TNBS plus anti-CD44v7-treated animals. Whereas in TNBS only-treated mice, inflammation progressed toward severe ulcerative destruction of the epithelium and the lamina propria as well as the muscle layers, 10 days after treatment with TNBS plus anti-CD44v7, the epithelium and the lamina propria were intact, and the number of infiltrating cells matched that in healthy mice. In the lamina propria, Peyer’s patch, mesenteric lymph nodes, and spleen, the distribution of subpopulations of lymphocytes (B cells, CD4+ and CD8+ T cells, and {gamma}{delta} and {alpha}ß T cells) was essentially unaltered in TNBS- as well as in TNBS plus anti-CD44v7-treated mice. Expression of CD44v6 and CD44v7 on LPL was comparable in TNBS- and TNBS plus anti-CD44v7-treated mice (data not shown).



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  		FIGURE 1. Influence of anti-CD44 Ab on disease progression after TNBS treatment. A, Weight loss (mean ± SD) and B, survival time and rate of BALB/c mice (10/group), which received control IgG, anti-CD44s, anti-CD44v6, or anti-CD44v7 (150 µg/mouse) intrarectally 2 and 24 h after TNBS treatment; C, survival time and rate after i.v. injection of control IgG or anti-CD44v7 (200 µg/mouse).

 


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  		FIGURE 2. Histologic examination of the colon in TNBS- and TNBS plus anti-CD44v7 Ab-treated mice. Sections through the colon of TNBS-treated mice (a and b) and of TNBS plus anti-CD44v7-treated mice (c and d) at 3 (a and c) and 7 (b and d) days after treatment: the colon was excised, shock frozen, cut into 5-µm sections, and stained with hematoxylin-eosin.

 
As anti-CD44v7 did not influence the early events of response, it appeared unlikely that the Ab functioned by directly protecting epithelial cells in the crypts of the gut from a destructive immune intervention. This interpretation was strengthened by the fact that neither anti-CD44s nor anti-CD44v6 were protective. Thus, we speculated that anti-CD44v7 interfered with the functional activity of the molecule on the few CD44v7+-activated lymphocytes.

TNBS-induced colitis is accompanied by an overshooting Th1 reaction (8), which may be suppressed by anti-CD44v7. To test this hypothesis, cytokine production of TNBS- vs TNBS plus anti-CD44v7-treated mice was followed during exacerbation of the disease (Fig. 3Go). The number of IFN-{gamma}-producing and -secreting cells increased in a comparable manner in both groups, which excludes a direct blockade of Th1 cells by anti-CD44v7. However, 3 to 5 days after application of anti-CD44v7, IL-10 production was up-regulated and IL-12 production was down-regulated in gut-associated as well as splenic lymphocytes. Interestingly, IL-10 has been produced predominantly by non-T cells. Only after a delay was the up-regulation of IL-10 accompanied by a gradual decrease in IFN-{gamma} production.



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  		FIGURE 3. Influence of anti-CD44v7 Ab on cytokine production. Cytokine production (IL-2, IL-4, IL-10, IFN-{gamma}, and TNF-{alpha}) has been evaluated in LPL and spleen cells. Production of IL-2, IL-4, and TNF-{alpha} were not influenced by anti-CD44v7 treatment (data not shown). A, The number of cytokine-producing LPL (FACS) at 4 to 10 days after intrarectal application of TNBS and TNBS plus anti-CD44v7; B, Relative cytokine production (mean + SD of triplicates) by LPL (5 x 104) that had been cultured in the presence of TNP-OVA for 3 days. The culture supernatants were transferred to ELISA plates coated with anti-cytokine Abs; C, Numbers of cytokine-producing (FACS) and -secreting (ELISpot) cells (mean + SD of triplicates) as well as relative amount of cytokine secretion (ELISA) (mean ± SD of triplicates) in the spleen of TNP-OVA (200 µg in adjuvant, s.c.)- and TNBS (intrarectally)-treated mice; D, The percentage of cytokine-producing (FACS) T cells and non-T cells in freshly harvested spleen cells of untreated, TNBS-, and TNBS plus anti-CD44v7-treated mice.

 
Thus, anti-CD44v7 did not prevent Th1 activation but redirected the ongoing immune response. If this interpretation is correct, the Ab should interfere efficiently with disease progression at a time when the gut is already severely injured. Indeed, when anti-CD44v7 was given to the mice 5 and 6 days after TNBS treatment (Fig. 4Go), the animals recovered and the gut appeared unaltered a few days later.



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  		FIGURE 4. TNBS-induced colitis can be cured by anti-CD44v7 Ab. Survival time and rate of BALB/c mice (10 per group) that received anti-CD44v7 or mouse IgG (150 µg/mouse) 5 and 6 days after TNBS treatment.

 
This proves that a severe form of IBD could be prevented and cured by a CD44v7-specific Ab. Anti-CD44v7 modulated the ongoing immune response, marked by a significant increase in IL-10 secretion. For the following reasons, we assume that anti-CD44v7 functions bidirectionally by actively stimulating IL-10 production and by blocking a signaling cascade that amplifies the production of Th1 cytokines.

The most straightforward explanation would be a direct stimulation of IL-10-producing cells by anti-CD44v7. CD44v7 is expressed on T as well as non-T cells, and IL-10 is produced predominantly by non-T cells. IL-10 is known to interfere via IL-12 with the perpetuation of IFN-{gamma} production (16, 17). In fact, IL-12 production was found to be severely impaired in TNBS plus anti-CD44v7-treated mice. A similar regulatory circuit has recently been described (18) in which CD4+ cells produced IL-10 in the presence of "B cell help." Our observation that costimulation of LNC via cross-linking of CD3 and CD44v7 did not induce up-regulation of IL-10 (data not shown) is in line with this finding and strengthens the view of an involvement of non-T cells in the anti-CD44v7-induced production of IL-10.

However, stimulation of IL-10 production may not have been the only mechanism of action because: 1) mice unable to express CD44v7 by targeted deletion (Günthert et al., manuscript in preparation) do not develop TNBS-induced colitis; and 2) TNBS-treated CD44v7 knockout mice do not produce elevated levels of IFN-{gamma}, although IL-12 production is unimpaired (B. Wittig et al., unpublished observation). Therefore, we suppose that anti-CD44v7 also blocks costimulatory activity of CD44v7. In APC, CD40L-CD40 interactions rapidly induce transcription of CD44, which functions as the ligand of a powerful, so far undefined costimulatory molecule (13). CD40L-CD40 interactions are known to activate Th1 more efficiently than Th2 (19), Th1 cytokine production being further supported by the stimulation of IL-12 production (17, 20, 21). An involvement of CD44v7 in CD40-CD40L-initiated costimulatory circuits could explain the resistance of CD44v7 knockout mice toward TNBS-induced colitis and may be responsible, in part, for the delayed decrease in IFN-{gamma} production in anti-CD44v7-treated mice.

Without question, anti-CD44v7 modulates an overshooting Th1 reaction. Experiments are in progress to elucidate whether CD44v7, indeed, displays dual activity as a signaling molecule on APC and as part of a costimulatory circuit. Since a selective and significant up-regulation of CD44v7 is also seen in the PBL of patients with IBD,4 it is tempting to speculate that a blockade of CD44v7 could be of therapeutic value in chronic inflammatory processes as well as in autoimmune diseases accompanied by hyperactivity of the Th1 subset.


   Acknowledgments
 
We gratefully acknowledge comments and suggestions on the manuscript made by Drs. M. Kopf, M. Salio, and S. Matzku.


   Footnotes
 
1 This work was supported by the Deutsche Forschungsgemeinschaft, Grant MZ40-5/2 (M.Z.) and the Curt-Engelhorn Grant (B.W.). The Basel Institute for Immunology was founded and is supported by F. Hoffmann-La Roche, Inc., Basel, Switzerland. Back

2 Address correspondence and reprint requests to Dr. Margot Zöller, Department of Tumor Progression and Immune Defense, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. E-mail address: Back

3 Abbreviations used in this paper: IBD, chronic inflammatory bowel disease; TNBS, trinitrobenzenesulfonic acid; TNP, trinitrophenyl; LPL, lamina propria lymphocytes; LNC, lymph node cells; CD44s, CD44 standard isoform; CD44v, CD44 variant isoform; ELISpot, enzyme-linked immunospot; CD40L, CD40 ligand. Back

4 B. Wittig, S. Seiter, D. S. Schmidt, M. Zuber, M. Neurath, and M. Zöller. Selective up-regulation of CD44 variant isoforms on peripheral blood leukocytes of patients with chronic inflammatory bowel disease. Submitted for publication. Back

Received for publication April 3, 1998. Accepted for publication May 26, 1998.


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