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DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, CA 94304
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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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In addition to inhibiting Ag-specific responses, we have shown that IL-10 induces long lasting Ag-specific anergy in human CD4+ T cells (10) and that repetitive Ag-specific activation of both human and mouse CD4+ T cells in the presence of IL-10 leads to the differentiation of a new subset of regulatory cells called T regulatory cells 1 (Tr1) (11). These suppressive and antiinflammatory activities of IL-10 suggest its potential clinical use as an immunosuppressant in allogeneic transplantation and autoimmune diseases (12). However, some studies have shown IL-10 unable to suppress an immune response in vivo. For example, IL-10 was not able to prevent (13), and in some situations even exacerbated, graft-vs-host disease (14) when administered either at the same time or after the bone marrow transplant. The discrepancy between these in vivo effects of IL-10 may be due to the fact that IL-10 also stimulate activated CD8+ T cells (15).
To determine the effects of increased IL-10 production specifically by APCs in vivo, we generated IL-10 TG mice (TG+) in which the human IL-10 cDNA was regulated by the mouse MHC class II Ea promoter and expressed only by MHC class II-positive cells. Human IL-10 is fully active in the mouse, but the species difference allows the transgene encoded, but not host IL-10, to be specifically neutralized by anti-hIL-10 Abs. With these TG mice, the consequences of elevated IL-10 in the differentiation of T cells and the induction of tolerance were evaluated by well-characterized immunization protocols. The impact of chronic exposure to IL-10 and its effect on monocyte-mediated protection were analyzed in two intracytoplasmic models of infection, Listeria monocytogenes and Leishmania major. Finally, the potential immunostimulatory role of IL-10 in tumor rejection was analyzed in the P815 melanocytoma model.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The class II MHC Ea promoter sequences (16) (Ea position -2172 to +12) was cloned upstream of a human IL-10 cDNA sequence. The construct was injected into eggs from BALB/cJ females, and TG founders were backcrossed three generations to BALB/cAnN mice. Presence of the transgene was confirmed using Southern blot analysis with a probe encompassing the human IL-10 cDNA and by PCR with human IL-10-specific cDNA primers. TG mice on the BALB/cAnN, (DBA2 x BALB/c)F1, (C57BL/6 x BALB/c) backgrounds were bred at DNAX (Palo Alto, CA). Control mice were either nontransgenic littermates or were purchased from Simonsen Laboratories (Gilroy, CA).
Cell lines, culture, and reagents
All assays were conducted in Yssel’s medium (17) supplemented with 10% FCS. Mice were immunized with 10 µg/mice of OVA (Sigma, St. Louis, MO) with either alum (Sigma) injected i.p. or with CFA (Sigma) injected at the base of the tail. Spleen cells suspension were treated with 0.83% ammonium chloride to lyse red blood cells, washed, and resuspended in culture medium. CD4+ T cells were purified from the spleen or lymph nodes of mice by negative depletion using anti-B220, anti-Mac-1, and anti-CD8 mAbs (PharMingen, San Diego, CA) and sheep anti-rat-coated Dynabeads (Dynabeads, Robbins Scientific, Mountain View, CA). Resident peritoneal macrophages were collected as described (8), and contaminant B and T cells were removed with anti-B220, anti-CD4, and anti-CD8 MAb (PharMingen) and sheep anti-rat-coated Dynabeads.
The P815 (H-2d) mastocytoma cell line, derived from a DBA/2 mouse, is highly tumorigenic in syngeneic mice. OVA was purchased from Sigma and used at 500 µg/ml in proliferative and cytokine assays. The neutralizing anti-hIL-10 9D7 was previously described (18).
PCR analysis
cDNA synthesis was performed as described previously (19). PCR analysis was conducted as described previously (19). PCR cycles were 30 s at 94°C, 30 s at 60°C, and 30 s at 72°C, with 35 cycles using the primers 5'-GGA TGC ACA GCT CAA GCA CTG CT and 3'-ACT AGG ATC CTC AGT TCG TAT CTT CAT TG for IL-10, and for 30 cycles using the primers 5'-GTA ATG ATC AGT CAA CGG GGG AC and 3'-CCA GCA AGC TTG CAA CCT TAA CCA for HPRT. PCR products were analyzed on agarose gels stained with ethidium bromide.
Cytokine ELISAs
Cytokine levels in supernatants were detected by two-site
sandwich ELISAs as previously described for mIFN-
(20), mIL-4 and
mIL-10 (18), and hIL-10 (10). Samples were assayed in duplicate and
quantitated by comparison with standard curves of purified recombinant
or natural cytokine.
Ig isotype ELISAs
Serum samples were assayed for Ig concentration by a two-site sandwich ELISA according to the manufacturer’s instruction (Pierce, Rockford IL) and OVA-specific Ig isotype as described (21).
Flow cytometry
For analysis, splenocytes were stained with FITC or phycoerythrin (PE)-conjugated mAbs (PharMingen). Flow cytometry analysis was performed on a FACScan flow cytometer (Becton Dickinson, Mountain View, CA).
Parasite infections and L. major antigen preparation
L. major (WHO strain designation WHOM/-/173), a kind gift from Dr. R. Locksley, were cultured as promastigotes in M199 (Life Technologies, Grand Island, NY) containing 30% FCS (J. R. Scientific, Woodland, CA), 2 mM L-glutamine, and 100 U/ml each of penicillin and streptomycin. Promastigotes were harvested from stationary phase cultures and washed in PBS. Mice were infected with 1.5 x 107 viable promastigotes, injected s.c. into the left hind footpad. L. major Ag, used for in vitro restimulations (LmAg) was prepared by four cycles of freezing and thawing of the parasites, followed by centrifugation. The Ag preparation was added to culture wells at an equivalent of 2 x 106 organisms/ml. Parasite loads were determined by limiting dilution culture of cell suspensions from lesion-draining lymph nodes. The remainder of each lymph node suspension was used for in vitro stimulation of CD4+ T cells as described below.
Recall responses to LmAg in vitro
CD4+ T cells were purified from lesion-draining
popliteal lymph nodes and restimulated with LmAg (equivalent to 2
x 106 organisms/ml) and nontransgenic BALB/c splenic APC.
APC were prepared by depletion of CD4+ and CD8+
T cells from spleen cell suspensions followed by 1000 rad of
-irradiation. CD4+ T cells (5 x
105/ml) and APC (2 x 106/ml) were
cultured with Ag for 72 h, and the supernatants were harvested for
assay of cytokines.
L. monocytogenes infection
Mice were injected i.v. with 5 x 104 live L. monocytogenes organisms. For the death curves, each group contained five animals, which were monitored daily for survival. Anti-hIL-10 mAb (9D7) was administered at day -1, day 0, and day 7 (1 mg/mouse i.p.).
Tumor production
P815 cells (1 x 106) were injected s.c. in a volume of 0.1 ml into the right flanks of (DBA/2 x BALB/c)F1 IL-10 TG or nontransgenic mice. Tumor size was measured every 3 days as the product of tridimensional parameters.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The class II MHC Ea promoter used in the TG construct has been
successfully used to generate other TG mice in which the protein of
interest was expressed with a tissue and cell-type specificity
indistinguishable from that of the endogenous MHC class II genes (16).
A transient transfectant of 3T3 cells bearing the hIL-10 construct
could be induced to secrete hIL-10 following incubation with IFN-
(not shown). Analyses with purified cells from TG mice showed hIL-10 in
the supernatants of activated splenocytes or B cells, but not in the
supernatants of activated T cells (Fig. 1
a). This observation was
confirmed by hIL-10-specific RT-PCR experiments performed on cDNA
obtained from purified T cells, B cells, or macrophages (Fig. 1b). hIL-10 was also detectable in the serum of the hIL-10
TG mice at levels of 400–700 pg/ml.
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Although hIL-10 TG mice had an impaired T cell development in the
thymus (M. Rouleau, manuscript in preparation), the number of T cells
contained in the peripheral organs was not decreased (Table I), and the ratio of CD4/CD8 was similar
to that of nontransgenic littermates (Table I). Moreover, no difference
in the proliferative capacity to polyclonal mitogens was observed
between T cells from hIL-10 TG and nontransgenic littermates
(Fig. 2a).
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). However, the relative percentage of activated B
cells was not different between hIL-10 TG mice and littermate controls,
as observed by flow cytometry profile using B cell activation markers
(Table I). The levels of the different IgG isotypes and of IgM were not
significantly different in TG and nontransgenic mice (Fig. 2b).
IL-10 has been shown to down-regulate the expression of costimulatory
molecules at the surface of monocytes/macrophages. However, no
difference in the expression of MHC molecules, ICAM-1, or CD86
molecules was observed in splenic macrophages from IL-10 TG compared
with nontransgenic littermates (Table I).
hIL-10 TG mice have a defective response to OVA
To determine the effect of altered IL-10 expression in the TG mice
on T cell differentiation in vivo, mice were immunized with OVA in the
presence of two different adjuvants: alum, which favors a Th2
response, or CFA, which favors development of a predominant Th1
response. One week after the second weekly injection of OVA in the
presence of alum or CFA, the amounts of the different Ig isotypes
specific for OVA were measured (Fig. 3
a). Reduced OVA-specific Ab responses were observed in the
IL-10 TG mice, as compared with nontransgenic littermates, regardless
of the type of adjuvant used (Fig. 3a). This inhibition of
both Th1- and Th2-type responses in IL-10 TG mice was confirmed by the
analysis of the proliferative response or the production of cytokines
by either splenocytes or draining lymph node cells from immunized mice.
For example, no significant proliferative response was observed in
purified CD4+ T cells from IL-10 TG mice immunized with OVA
in alum after restimulation in vitro with OVA presented by irradiated
wild-type BALB/c splenocytes (Fig. 3b). In contrast,
purified CD4+ T cells from nontransgenic littermates
immunized with OVA in alum proliferated after in vitro restimulation
(Fig. 3b). Similarly, the IFN- levels observed after in
vitro restimulation of CD4+ T cells purified from popliteal
lymph nodes of mice immunized with OVA in CFA were greatly reduced in
the IL-10 TG mice as compared with the nontransgenic siblings (Fig. 3c).
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To investigate the role of IL-10 in bacterial infections, IL-10 TG
mice and control animals were infected with varying doses of L.
monocytogenes. The IL-10 TG animals displayed a 100% mortality
rate within 2 wk of inoculation with 5 x 104
bacteria, a dose that was sublethal in wild-type animals (Fig. 4). The sensitivity of the IL-10 TG mice
was completely reverted by the administration of anti-hIL-10 mAb
(at day -1, day 0, and day 7 of infection; Fig. 4) whereas IL-10 TG
mice treated with an isotype control Ab remained susceptible (not
shown).
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The consequence of overproduction of IL-10 on chronic infection
with an intracellular pathogen was examined in mice infected with the
protozoan parasite, L. major. Cutaneous infection of
resistant mouse strains induces a highly polarized Th1 response that
leads to resolution of the localized lesion and resistance to
infection (23). The principal effector mechanism in mice is the
IFN--dependent production of NO by macrophages. Since IL-10 is both
a potent inhibitor of IFN- production by T cells as well as NO
production by macrophages, higher levels of IL-10 might be expected to
inhibit control of parasite growth and enhance disease progression.
Since BALB/c mice are themselves highly susceptible to L.
major infection, TG BALB/c mice were crossed with resistant
C57BL/6J to produce a resistant F1 background. TG CB6F1
mice developed progressive footpad lesions that closely resembled the
lesions in susceptible BALB/c mice (not shown), whereas nontransgenic
littermates were quite resistant to the infection (Fig. 5). The greatly enhanced susceptibility
to L. major was completely reversed by treating the mice
with a neutralizing anti-hIL-10 Ab beginning 1 day before the
infection, demonstrating that the TG IL-10 was acting during infection
rather than acting on lymphocyte development before the infection.
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). Although high
parasite counts and progressive lesion development are characteristic
of mice with a predominant Th2 response to L. major, T cells
from both TG and nontransgenic CB6F1 mice produced similar, Th1-like
cytokine responses to LmAg in vitro (Table II).
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The role of IL-10 in tumor rejection and the generation of CTL
responses remains controversial, and both positive or negative effects
have been reported. To analyze the CTL response against tumor cells in
IL-10 TG mice we used the immunogenic P815 H-2d
mastocytoma. In syngeneic DBA/2 or in (DBA/2 x
BALB/c)F1 mice, P815 is a highly tumorigenic
mastocytoma cell line. Tumor-associated transplantation Ags present in
P815 have been identified and are able to induce CTL responses in
syngeneic mice that specifically kill P815 in vitro (24). In spite of
this, the antitumor response was not fully effective, and the tumors
grew progressively, resulting in death within 20–30 days (Fig. 6). Treating mice with anti-CD8 mAb
resulted in a more acute and rapid growth of the tumor in vivo (Fig. 6a). In IL-10 TG mice, injection of P815 resulted in a very
rapid growth of the tumor cells in the first 2 wk. Injection of the
anti-hIL-10 mAb 24 h prior to tumor cell injection enabled the
IL-10 TG mice to control the growth of the transplanted tumors, whereas
delayed injection of anti-hIL-10 Abs (at day 10) had no effects in
controlling the growth of the tumor (Fig. 6b). However, in
untreated IL-10 TG mice after 3 wk, the tumor cells were completely
eliminated whereas the tumor continued to grow in the nontransgenic
controls and in IL-10 TG mice treated after 10 days with
anti-hIL-10 Abs. This late protective mechanism observed in IL-10
TG mice seems to be mediated, in part, by IL-10-activated
CD8+ T cells since treatment of IL-10 TG mice with
anti-CD8 mAb or anti-hIL-10 injected after 10 days resulted in
the development of a tumor growth pattern similar to that observed in
anti-CD8 mAb-treated nontransgenic siblings.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). No major difference in the number of T
cells and in the ratio of CD4/CD8 T cells was observed, and no major
differences were apparent in the serum Ig profiles (Fig. 2c). Neither could the substantially reduced responses to
immunization be attributed to altered development of T and B cells. All
of the immune functions that were altered in the IL-10 TG mice were
reversible by anti-hIL-10 mAb treatment only during the period of
Ag challenge. IL-10 has been shown to be a significant inhibitor of macrophage functions, especially NO production, that are essential for the control of intracellular pathogens such as Listeria and Leishmania. (9, 25, 26). This inhibition has been studied extensively in vitro, but less is known about the consequences of elevated IL-10 production on pathogen control in vivo. Two well-characterized models of intracellular infection were used to study the effects of elevated IL-10 in IL-10 TG mice. Nontransgenic mice readily controlled infection with moderate doses of L. monocytogenes, whereas TG littermates did not control the infection and died as early as 7 days after infection. At the dose used in these experiments, 5 x 104 organisms/ml, one-half of the TG mice died within 2 wk and all were dead 4 wk after infection. This time course suggests inhibitory effects on both the innate and Ag-specific components of the response to Listeria and is consistent with the previously reported inhibition of the innate response by recombinant IL-10 (25). Treatment with anti-hlL-10 beginning just before infection reversed this increased susceptibility, demonstrating that it was a direct result of hIL-10 produced during the course of the infection.
In a more chronic model of infection, using the protozoan parasite, L. major, TG IL-10 also caused a marked inhibition of parasite control in genetically resistant CB6F1 mice. This was suggested by the progressive development of the footpad lesion and was confirmed by direct measurements of the parasite burden in the lesion-draining lymph node. Although the lesion progression and parasite counts were similar to those usually seen in highly susceptible BALB/c mice (not shown), the actual T cell response was quite different. Instead of the predominantly Th2 cytokine response of BALB/c mice, CB6F1 Tg+ mice developed a Th1-like response similar in magnitude to the nontransgenic controls. That this Th1 response was not able to control the infection in TG mice strongly suggested that IL-10 was acting principally to inhibit the microbiocidal effector functions of this Th1 response. This view was confirmed by the demonstration that anti-hIL-10 Ab treatment could reverse this increased susceptibility. Preliminary experiments suggest that lesion development in TG mice can be changed from progressive to resolving, even in mice not treated with anti-hIL-10 mAb until 4 wk after infection (data not shown). Thus, high levels of IL-10 in vivo are capable of inhibiting Th1 responses to such an extent as to render ineffective a normally protective Th1 response to these intracellular pathogens. A recent description of a different IL-10 TG mouse showed no significant inhibition of control of an infection with L. major (27). A possible difference is that the IL-10 transgene in that report was controlled by the IL-2 promoter, and there could be significant differences in the levels of IL-10 produced in these two mice, especially in the case of a chronic infection.
The injection of tumorigenic P815 cells into IL-10 TG mice showed a biphasic action of IL-10. In the initial phase, the growth of the tumor was not controlled in IL-10 TG mice as compared with nontransgenic siblings. This mechanism was inhibited by the addition of anti-hIL-10 Abs at day -1 and reflected the inhibitory activities of IL-10 as previously observed in the IL-2 promoter-driven mIL-10 TG mice (27). However, in a second phase, when the tumor expanded rapidly in the nontransgenic littermates, it was completely rejected in hIL-10 TG mice. This second phase seemed to rely on the activation of CTL since no rejection of the tumor was observed in IL-10 TG mice previously treated with depleting anti-CD8 mAb or treated with anti-hIL-10 Abs after 10 days. Indeed, the results concerning the effects of IL-10 on CD8+ CTL activation and tumor rejection are controversial. On one hand, IL-10 has been shown to inhibit allogeneic mixed lymphocyte reaction in human (28), to decrease monocyte activation (7), to induce local anergy to allogeneic and syngeneic tumor (29), or to protect target cells against cytolysis (30). In contrast, IL-10 increases the proliferative response of activated human CD8+ T cells (15), the frequency of CTL after polyclonal activation (31), or Ag-specific activation in vivo (32). Our results shed some light on the contradictory results obtained with IL-10 in the treatment of tumors in mouse models and suggest that IL-10 might have beneficial effects when injected after the onset of the tumor to activate cytotoxic CD8+ T cells.
The poor immune response observed after immunization of IL-10 TG mice
could be due to several mechanisms. IL-10 has been shown to inhibit the
Ag-presenting capability of monocytes (3) mainly by down-regulating
costimulatory molecules (5, 6). However, no change in the expression of
MHC molecules or CD80, CD86, or ICAM-1 was observed on macrophages from
IL-10 TG mice (Table I). Moreover, no difference in the Ag-presenting
capacity of purified splenic macrophage from hIL-10 TG mice was
observed in vitro (not shown).
A second hypothesis to explain the absence of T cell responses after immunization of IL-10 TG mice would be the induction of anergy in T cells and the development of Tr1-type cells. Indeed, we have previously shown that activation of human CD4+ T cells in the presence of IL-10 resulted in the induction of a long-term Ag-specific anergy (10). Moreover, we have recently shown that both human and mouse CD4+ T cells, repeatedly stimulated in the presence of IL-10, differentiate into a new subset of CD4+ T cells different from the classical Th1 and Th2 T cell clones. These cells, termed Tr1 (T regulatory 1) have a poor proliferative response and secrete no IL-2 or IL-4, but do produce high levels of IL-10 and inhibit the proliferative response of bystander cells both in vitro and in vivo (11). The development of Tr1 cells in IL-10 TG mice would result in the absence of T cell-mediated response in vivo and in the absence of recall stimulation in vitro, as observed in the present study. The injection of CD4+ T cells bearing a TG OVA TCR from DO11-10 mice into IL-10 TG mice will be used to test this hypothesis.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Hervé Groux, Institut National de la Santé et de la Recherche Médicale U343, Hôpital de l’Archet, Route de Saint Antoine de Ginestière, 06200 Nice, France. E-mail address:
3 Present address: Telethon Institute for Gene Therapy, San Raffaele Hospital, Via Olgettina 58, 20132 Milan, Italy.
4 Abbreviations used in this paper: NO, nitric oxide; Tr1, T regulatory cells 1; TG, transgene, hIL-10, human IL-10; HPRT, hypoxanthine phosphoribosyltransferase; mIL-10, murine IL-10; LmAg, Leishmania major Ag.
Received for publication April 24, 1998. Accepted for publication October 26, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß peptide complexes at the plasma membrane of monocytes by affecting arrival and recycling. Immunity 7:861.[Medline]
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S. Mendez, S. K. Reckling, C. A. Piccirillo, D. Sacks, and Y. Belkaid Role for CD4+ CD25+ Regulatory T Cells in Reactivation of Persistent Leishmaniasis and Control of Concomitant Immunity J. Exp. Med., July 19, 2004; 200(2): 201 - 210. [Abstract] [Full Text] [PDF]
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 E. Lech-Maranda, L. Baseggio, J. Bienvenu, C. Charlot, F. Berger, D. Rigal, K. Warzocha, B. Coiffier, and G. Salles Interleukin-10 gene promoter polymorphisms influence the clinical outcome of diffuse large B-cell lymphoma Blood, May 1, 2004; 103(9): 3529 - 3534. [Abstract] [Full Text] [PDF]
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N. B. Norsworthy, J. Sun, D. Elnaiem, G. Lanzaro, and L. Soong Sand Fly Saliva Enhances Leishmania amazonensis Infection by Modulating Interleukin-10 Production Infect. Immun., March 1, 2004; 72(3): 1240 - 1247. [Abstract] [Full Text] [PDF]
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U. M. Padigel, J. Alexander, and J. P. Farrell The Role of Interleukin-10 in Susceptibility of BALB/c Mice to Infection with Leishmania mexicana and Leishmania amazonensis J. Immunol., October 1, 2003; 171(7): 3705 - 3710. [Abstract] [Full Text] [PDF]
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N. Noben-Trauth, R. Lira, H. Nagase, W. E. Paul, and D. L. Sacks The Relative Contribution of IL-4 Receptor Signaling and IL-10 to Susceptibility to Leishmania major J. Immunol., May 15, 2003; 170(10): 5152 - 5158. [Abstract] [Full Text] [PDF]
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 A. S. Yang and E. C. Lattime Tumor-induced Interleukin 10 Suppresses the Ability of Splenic Dendritic Cells to Stimulate CD4 and CD8 T-Cell Responses Cancer Res., May 1, 2003; 63(9): 2150 - 2157. [Abstract] [Full Text] [PDF]
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D. Berrebi, S. Bruscoli, N. Cohen, A. Foussat, G. Migliorati, L. Bouchet-Delbos, M.-C. Maillot, A. Portier, J. Couderc, P. Galanaud, et al. Synthesis of glucocorticoid-induced leucine zipper (GILZ) by macrophages: an anti-inflammatory and immunosuppressive mechanism shared by glucocorticoids and IL-10 Blood, January 15, 2003; 101(2): 729 - 738. [Abstract] [Full Text] [PDF]
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S. Ahmed, M. Colmenares, L. Soong, K. Goldsmith-Pestana, L. Munstermann, R. Molina, and D. McMahon-Pratt Intradermal Infection Model for Pathogenesis and Vaccine Studies of Murine Visceral Leishmaniasis Infect. Immun., January 1, 2003; 71(1): 401 - 410. [Abstract] [Full Text] [PDF]
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C. G. Feng, M. C. Kullberg, D. Jankovic, A. W. Cheever, P. Caspar, R. L. Coffman, and A. Sher Transgenic Mice Expressing Human Interleukin-10 in the Antigen-Presenting Cell Compartment Show Increased Susceptibility to Infection with Mycobacterium avium Associated with Decreased Macrophage Effector Function and Apoptosis Infect. Immun., December 1, 2002; 70(12): 6672 - 6679. [Abstract] [Full Text] [PDF]
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 I Y Rosenblum and A D Dayan Carcinogenicity testing of IL-10: principles and practicalities Human and Experimental Toxicology, July 1, 2002; 21(7): 347 - 358. [Abstract] [PDF]
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 K. J. Erb, C. Trujillo, M. Fugate, and H. Moll Infection with the Helminth Nippostrongylus brasiliensis Does Not Interfere with Efficient Elimination of Mycobacterium bovis BCG from the Lungs of Mice Clin. Vaccine Immunol., May 1, 2002; 9(3): 727 - 730. [Abstract] [Full Text] [PDF]
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R. Dorsey, N. Kundu, Q. Yang, C. S. Tannenbaum, H. Sun, T. A. Hamilton, and A. M. Fulton Immunotherapy with Interleukin-10 Depends on the CXC Chemokines Inducible Protein-10 and Monokine Induced by IFN-{gamma} Cancer Res., May 1, 2002; 62(9): 2606 - 2610. [Abstract] [Full Text] [PDF]
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P. Launois, A. Gumy, H. Himmelrich, R. M. Locksley, M. Rocken, and J. A. Louis Rapid IL-4 Production by Leishmania Homolog of Mammalian RACK1-Reactive CD4+ T Cells in Resistant Mice Treated Once with Anti-IL-12 or -IFN-{gamma} Antibodies at the Onset of Infection with Leishmania major Instructs Th2 Cell Development, Resulting in Nonhealing Lesions J. Immunol., May 1, 2002; 168(9): 4628 - 4635. [Abstract] [Full Text] [PDF]
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D. E. Jones, M. R. Ackermann, U. Wille, C. A. Hunter, and P. Scott Early Enhanced Th1 Response after Leishmania amazonensis Infection of C57BL/6 Interleukin-10-Deficient Mice Does Not Lead to Resolution of Infection Infect. Immun., April 1, 2002; 70(4): 2151 - 2158. [Abstract] [Full Text] [PDF]
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R. Lang, R. L. Rutschman, D. R. Greaves, and P. J. Murray Autocrine Deactivation of Macrophages in Transgenic Mice Constitutively Overexpressing IL-10 Under Control of the Human CD68 Promoter J. Immunol., April 1, 2002; 168(7): 3402 - 3411. [Abstract] [Full Text] [PDF]
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B. Hondowicz and P. Scott Influence of Parasite Load on the Ability of Type 1 T Cells To Control Leishmania major Infection Infect. Immun., February 1, 2002; 70(2): 498 - 503. [Abstract] [Full Text] [PDF]
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 Y. Murata, T. Shimamura, and J. Hamuro The polarization of Th1/Th2 balance is dependent on the intracellular thiol redox status of macrophages due to the distinctive cytokine production Int. Immunol., February 1, 2002; 14(2): 201 - 212. [Abstract] [Full Text] [PDF]
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I. J. Fuss, M. Boirivant, B. Lacy, and W. Strober The Interrelated Roles of TGF-{beta} and IL-10 in the Regulation of Experimental Colitis J. Immunol., January 15, 2002; 168(2): 900 - 908. [Abstract] [Full Text] [PDF]
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B. M. Segal, D. D. Glass, and E. M. Shevach Cutting Edge: IL-10-Producing CD4+ T Cells Mediate Tumor Rejection J. Immunol., January 1, 2002; 168(1): 1 - 4. [Abstract] [Full Text] [PDF]
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Y. Belkaid, K. F. Hoffmann, S. Mendez, S. Kamhawi, M. C. Udey, T. A. Wynn, and D. L. Sacks The Role of Interleukin (IL)-10 in the Persistence of Leishmania major in the Skin after Healing and the Therapeutic Potential of Anti-IL-10 Receptor Antibody for Sterile Cure J. Exp. Med., November 19, 2001; 194(10): 1497 - 1506. [Abstract] [Full Text] [PDF]
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S.-i. Fujii, K. Shimizu, T. Shimizu, and M. T. Lotze Interleukin-10 promotes the maintenance of antitumor CD8+ T-cell effector function in situ Blood, October 1, 2001; 98(7): 2143 - 2151. [Abstract] [Full Text] [PDF]
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V. Dheenadhayalan, S. Shanmugalakshmi, S. Vani, P. Muthuveeralakshmi, G. Arivarignan, A. D. Nageswari, and R M. Pitchappan Association of Interleukin-10 Cytokine Expression Status with HLA Non-DRB1*02 and Mycobacterium bovis BCG Scar-Negative Status in South Indian Pulmonary Tuberculosis Patients Infect. Immun., September 1, 2001; 69(9): 5635 - 5642. [Abstract] [Full Text] [PDF]
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S. Kawamoto, Y. Nitta, F. Tashiro, A. Nakano, E. Yamato, H. Tahara, K. Tabayashi, and J.-i. Miyazaki Suppression of Th1 cell activation and prevention of autoimmune diabetes in NOD mice by local expression of viral IL-10 Int. Immunol., May 1, 2001; 13(5): 685 - 694. [Abstract] [Full Text] [PDF]
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S. Corinti, C. Albanesi, A. la Sala, S. Pastore, and G. Girolomoni Regulatory Activity of Autocrine IL-10 on Dendritic Cell Functions J. Immunol., April 1, 2001; 166(7): 4312 - 4318. [Abstract] [Full Text] [PDF]
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S. Bhattacharyya, S. Ghosh, P. L. Jhonson, S. K. Bhattacharya, and S. Majumdar Immunomodulatory Role of Interleukin-10 in Visceral Leishmaniasis: Defective Activation of Protein Kinase C-Mediated Signal Transduction Events Infect. Immun., March 1, 2001; 69(3): 1499 - 1507. [Abstract] [Full Text] [PDF]
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M. T. Liu, D. Armstrong, T. A. Hamilton, and T. E. Lane Expression of Mig (Monokine Induced by Interferon-{{gamma}}) Is Important in T Lymphocyte Recruitment and Host Defense Following Viral Infection of the Central Nervous System J. Immunol., February 1, 2001; 166(3): 1790 - 1795. [Abstract] [Full Text] [PDF]
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M. M. Kane and D. M. Mosser The Role of IL-10 in Promoting Disease Progression in Leishmaniasis J. Immunol., January 15, 2001; 166(2): 1141 - 1147. [Abstract] [Full Text] [PDF]
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B. Balasa, A. La Cava, K. Van Gunst, L. Mocnik, D. Balakrishna, N. Nguyen, L. Tucker, and N. Sarvetnick A Mechanism for IL-10-Mediated Diabetes in the Nonobese Diabetic (NOD) Mouse: ICAM-1 Deficiency Blocks Accelerated Diabetes J. Immunol., December 15, 2000; 165(12): 7330 - 7337. [Abstract] [Full Text] [PDF]
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A. G.S. van Halteren, B. Mosselman, B. O. Roep, W. van Eden, A. Cooke, G. Kraal, and M. H. M. Wauben T Cell Reactivity to Heat Shock Protein 60 in Diabetes-Susceptible and Genetically Protected Nonobese Diabetic Mice Is Associated with a Protective Cytokine Profile J. Immunol., November 15, 2000; 165(10): 5544 - 5551. [Abstract] [Full Text] [PDF]
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I. V. Lyadova, E. B. Eruslanov, S. V. Khaidukov, V. V. Yeremeev, K. B. Majorov, A. V. Pichugin, B. V. Nikonenko, T. K. Kondratieva, and A. S. Apt Comparative Analysis of T Lymphocytes Recovered from the Lungs of Mice Genetically Susceptible, Resistant, and Hyperresistant to Mycobacterium tuberculosis-Triggered Disease J. Immunol., November 15, 2000; 165(10): 5921 - 5931. [Abstract] [Full Text] [PDF]
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F. N. Lauw, D. Pajkrt, C. E. Hack, M. Kurimoto, S. J. H. van Deventer, and T. van der Poll Proinflammatory Effects of IL-10 During Human Endotoxemia J. Immunol., September 1, 2000; 165(5): 2783 - 2789. [Abstract] [Full Text] [PDF]
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B. Balasa, K. Van Gunst, N. Jung, D. Balakrishna, P. Santamaria, T. Hanafusa, N. Itoh, and N. Sarvetnick Islet-Specific Expression of IL-10 Promotes Diabetes in Nonobese Diabetic Mice Independent of Fas, Perforin, TNF Receptor-1, and TNF Receptor-2 Molecules J. Immunol., September 1, 2000; 165(5): 2841 - 2849. [Abstract] [Full Text] [PDF]
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Y. Belkaid, S. Mendez, R. Lira, N. Kadambi, G. Milon, and D. Sacks A Natural Model of Leishmania major Infection Reveals a Prolonged ""Silent"" Phase of Parasite Amplification in the Skin Before the Onset of Lesion Formation and Immunity J. Immunol., July 15, 2000; 165(2): 969 - 977. [Abstract] [Full Text] [PDF]
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H. D. Brightbill, S. E. Plevy, R. L. Modlin, and S. T. Smale A Prominent Role for Sp1 During Lipopolysaccharide- Mediated Induction of the IL-10 Promoter in Macrophages J. Immunol., February 15, 2000; 164(4): 1940 - 1951. [Abstract] [Full Text] [PDF]
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L. Li, M. Crowley, A. Nguyen, and D. Lo Ability of a Nondepleting Anti-CD4 Antibody to Inhibit Th2 Responses and Allergic Lung Inflammation Is Independent of Coreceptor Function J. Immunol., December 15, 1999; 163(12): 6557 - 6566. [Abstract] [Full Text] [PDF]
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 M. R. Stämpfli, M. Cwiartka, B. U. Gajewska, D. Alvarez, S. A. Ritz, M. D. Inman, Z. Xing, and M. Jordana Interleukin-10 Gene Transfer to the Airway Regulates Allergic Mucosal Sensitization in Mice Am. J. Respir. Cell Mol. Biol., November 1, 1999; 21(5): 586 - 596. [Abstract] [Full Text]
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S. Sharma, M. Stolina, Y. Lin, B. Gardner, P. W. Miller, M. Kronenberg, and S. M. Dubinett T Cell-Derived IL-10 Promotes Lung Cancer Growth by Suppressing Both T Cell and APC Function J. Immunol., November 1, 1999; 163(9): 5020 - 5028. [Abstract] [Full Text] [PDF]
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D. J. Cua, H. Groux, D. R. Hinton, S. A. Stohlman, and R. L. Coffman Transgenic Interleukin 10 Prevents Induction of Experimental Autoimmune Encephalomyelitis J. Exp. Med., March 15, 1999; 189(6): 1005 - 1010. [Abstract] [Full Text] [PDF]
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