Published online before print August 11, 2003, doi: 10.1161/01.CIR.0000089083.61317.A1
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(Circulation. 2003;108:1232.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
Induction of a Regulatory T Cell Type 1 Response Reduces the Development of Atherosclerosis in Apolipoprotein E–Knockout Mice
From the Institut National de la Santé et de la Recherche Médicale, INSERM U541, Institut Fédératif de Recherche Circulation Paris VII, Hôpital Lariboisière, Paris, France (Z.M., A.G., B.E., A.T.); INSERM U343 (H.G., N.F., F.C.); and TxCell, Bat. ARC (V.B.), Hôpital de l’Archet, Nice, France.
Correspondence to Ziad Mallat, MD, PhD, or Alain Tedgui, PhD, INSERM U541, Hôpital Lariboisière, 41 Bd de la chapelle, 75010 Paris, France. E-mail mallat{at}larib.inserm.fr or tedgui@larib.inserm.fr
Received June 3, 2003; de novo received July 9, 2003; accepted July 21, 2003.
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Abstract |
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Background— T helper type 1 (Th1) response plays a permissive role in atherosclerosis. We hypothesized that adoptive transfer of a novel subtype of T lymphocytes called regulatory T cells type 1 (Tr1) would inhibit Th1 responses by inducing a bystander immune suppression and therefore limit the development of atherosclerosis.
Methods and Results— Clones of ovalbumin (OVA)–specific Tr1 cells expanded in vitro were administered intraperitoneally (106 cells per mouse) with their cognate antigen (50 µg of OVA subcutaneously in complete Freund’s adjuvant [CFA]) to female apolipoprotein E–knockout mice. A group of mice received only (OVA/CFA) immunization without Tr1 cells. Two other control groups received no immunization and were injected with either Tr1 cells or saline. After 9 weeks of treatment, mice injected with (OVA/CFA)+OVA-specific Tr1 cells showed a significant decrease in Th1 responses, as revealed by a decrease in OVA-specific IgG2a serum levels (P<0.0001), a decrease in the production of interferon-
(P<0.001), and an increase in interleukin-10 production (P<0.001) by cultured spleen and lymph T cells compared with controls. In addition, cytokine production by concanavalin A–stimulated spleen cells showed a clear switch to a regulatory immune response in mice treated with (OVA/CFA)+Tr1. This was associated with a significant reduction in atherosclerotic lesion size in both the thoracic aorta and aortic sinus of mice treated with (OVA/CFA)+Tr1 compared with controls (P=0.002 to P<0.0001). Plaques of mice injected with (OVA/CFA)+Tr1 showed significantly lower accumulation of macrophages and T cells than plaques of control mice.
Conclusions— Tr1-type regulatory immune response reduces the development of experimental atherosclerosis.
Key Words: atherosclerosis • inflammation • immunity • lymphocytes • immunization
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Introduction |
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Atherosclerosis is a chronic disease of the arterial wall in which both innate and adaptive immunoinflammatory mechanisms are involved.1–3 The profile of the T-cell response in atherosclerosis is of the T helper type 1 (Th1),3 whose proatherogenic potential has been demonstrated in experimental models of atherosclerosis.4–10 As in other chronic immunoinflammatory diseases, it has been suggested that the development and progression of atherosclerosis may result from an imbalance between Th1 and Th2 responses.3,11 However, evidence is now accumulating for a novel functionally distinct subpopulation of T cells, called regulatory T cells, that exert important regulatory functions in various immunoinflammatory diseases (see Groux et al,12 Roncarolo et al,13 and McGuirk et al14 for review). Several subsets of regulatory T (Tr) cells with distinct phenotypes and distinct mechanisms of action have now been identified. These include Tr1 cells,15–20 which secrete high levels of interleukin (IL)-10 and low to moderate levels of transforming growth factor (TGF)-ß; Th3 cells,21,22 which secrete primarily TGF-ß; and CD4+CD25+ T cells, which inhibit immune responses through cell-to-cell contact.23 We have shown that repeated stimulation of naive T cells from ovalbumin (OVA) T-cell receptor–transgenic mice with OVA and IL-10 results in the generation of T-cell clones with a unique cytokine profile distinct from that of Th0, Th1, or Th2 cells.15 These Tr1 cells produce IL-10 and some IL-5 and interferon-
(IFN-) with or without TGF-ß but with little or no IL-2 or IL-4 and proliferate poorly after polyclonal T-cell receptor–mediated activation. Functional studies on Tr1 cells have indicated that Tr1 cells have immunosuppressive properties and have been shown to prevent the development of Th1-mediated autoimmune diseases.15 Coculture of naive CD4+ T cells and human Tr1 clones in the presence of allogenic antigen-presenting cells results in the suppression of proliferative responses.15 Similarly, Tr1 clones specific for filamentous hemagglutinin from Bordetella pertussis suppress proliferation and cytokine production by a Th1 clone against an unrelated antigen, influenza virus hemagglutinin.20 In both cases, the suppressive effects of Tr1-cell clones are reversed by neutralizing IL-10, suggesting that regardless of their antigen specificities, Tr1 cell suppression is a bystander effect mediated through the production of IL-10. Here, we tested the hypothesis that transfer of such Tr1 cells to apolipoprotein (apo) E–knockout mice will inhibit pathogenic Th responses and reduce the development of atherosclerosis. |
Methods |
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Generation, Expansion, and Transfer of OVA-Specific Tr1 Clones
The mouse T-cell clones were obtained from DO11-10 BALB/c mice after in vitro differentiation as described previously.15 Naive (MEL-14bright) CD4+, KJ-1.26+ cells were stimulated repeatedly with OVA peptide 323–339 every week for 3 weeks in the presence of IL-10. T-cell clones were generated as described previously.15 Clones were expanded and analyzed for cytokine secretion after activation with antigen-presenting cells and OVA peptide. Selected clones were then stimulated with irradiated splenocytes and OVA peptide every 2 weeks and further expanded with IL-2 (R&D Systems). T-cell clones were used at least 10 days after the last stimulation. Here, we used clone A-10-9, which has been described previously and shown to prevent Th1- and Th2-mediated immune responses.15,24
Fifteen-week-old female apoE-knockout C57Bl/6 mice (Charles River, Orleans, France) were immunized subcutaneously with either saline (n=11) or 50 µg of OVA in complete Freund’s adjuvant (CFA) (both from Sigma) (n=18) every 12 days for 9 weeks. The saline-treated mice were then divided into 2 groups that at day 0 received, in addition to subcutaneous saline, a unique intraperitoneal injection (200 µL) of either saline (n=5) or 106 OVA-specific Tr1 cells without OVA/CFA (n=6). The OVA/CFA-immunized group was divided into 2 other groups of mice that at day 0 received an intraperitoneal injection (200 µL) of either saline (OVA/CFA group, n=9) or 106 OVA-specific Tr1 cells (OVA/CFA+Tr1 group, n=9).
Cytokine Assays
In brief, ELISA plates (Polylabo) were coated with the appropriate coating anti-cytokine monoclonal antibodies (11B11, 2A5, TRFK4, and XGM-1 for IL-4, IL-10, IL-5, and IFN-, respectively) in carbonate buffer and incubated at 4°C overnight. Sandwich ELISAs were performed as described previously.24 Plates were read on an ELISA reader at a wavelength of 405 nm after color development (Labsystems iEMS reader).
Analysis of OVA-Specific Serum IgE, IgG1, and IgG2a
OVA-specific Ig levels were measured by use of a 2-step sandwich ELISA as described.24 To detect IgG1 and IgG2a, we used biotinylated rat monoclonal antibody (A85-1 and R19-15 for IgG1 and IgG2a, respectively; Becton Dickinson) at 2 µg/mL. Standards for OVA-specific IgG1 were pooled sera from hyperimmunized BALB/c mice.
Purification and Culture of Spleen and Lymph Node Cells
T cells were purified from spleen or draining lymph nodes by negative selection with anti-CD11b (M1/70), anti-B220, and anti-NK cells (DX5) followed by depletion with a mixture of magnetic beads coated with anti-rat Ig (Dynal).
For cytokine measurements, purified T cells (105) were mixed with irradiated splenic antigen-presenting cells (4x105) and OVA/CFA (0.25 mg/mL) concanavalin A (conA) (2 µg/mL) in 96-well plates. Supernatants were collected at 24 hours (for IL-4 measurements) and at 48 hours (for IL-5, IL-10, and IFN- measurements) and assayed for cytokine levels by ELISA as described previously.24
For the cell proliferation assay, purified T cells were mixed with irradiated splenic cells and conA or OVA. [3H]-Thymidine (1 µCi; Perkin Elmer) was added for the last 12 hours of cell culture.
Analysis of Atherosclerotic Plaque Size and Composition
Mice were killed at 24 weeks of age. Plasma total and HDL cholesterol were measured with a commercially available cholesterol kit (Sigma). Morphometric and immunohistochemical studies were performed in the aortic sinus and the thoracic aorta (spanning from the brachiocephalic artery to the renal arteries and including the first 3 mm2 of the brachiocephalic artery) as described previously.9
Collagen fibers were stained with Sirius red. Immunohistochemical analysis was performed as described previously.9 The following primary antibodies were used: MOMA-2 (BioSource International) as a specific marker for macrophages; anti-mouse CD3-
(Santa Cruz), anti–
-smooth muscle actin, alkaline phosphatase conjugate, clone 1A4 (Sigma), and anti–IL-10 antibody (Santa Cruz). At least 4 sections per animal were analyzed for each immunostaining. Morphometric analysis was performed with an automated image processor (Histolab, Microvision) as described previously.9
Statistical Analysis
The effects of treatment on lesion area, plaque composition, serum Ig levels, and cytokine production by spleen and lymph T cells were evaluated by ANOVA and Bonferroni/Dunn’s test or Student’s t test. A value of P<0.05 was considered to be statistically significant.
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Results |
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Transfer of Tr1 Cells With Their Cognate Antigen Induces Immune Suppression
As expected (Table 1), treatment with OVA in CFA resulted in elevated serum levels of OVA-specific antibodies, predominantly IgG2a, and to a much lesser extent IgE, in comparison with the saline-treated group, in which OVA-specific IgGs were undetectable. Treatment of mice with OVA/CFA induced a Th1-like response, as revealed by the production of high levels of IFN-
(Th1 cytokine) but low levels of IL-10 and no IL-4 (Th2 cytokines) by OVA-stimulated lymph T cells (Table 1). Injection of regulatory Tr1 cells alone did not alter the immune response (Table 1). However, administration of Tr1 cells to OVA/CFA-immunized animals significantly inhibited the secretion of OVA-specific IgG2a antibodies, as reported previously in a model using alum as an adjuvant.24 Moreover, the suppressive effect of Tr1 cells was confirmed by the marked decrease in IFN- production and proliferative response observed in the (OVA/CFA)+Tr1 group compared with the OVA/CFA after in vitro recall response of T cells (P<0.001). This was associated with enhanced IL-10 production by T cells stimulated with OVA in vitro (P<0.001), suggesting that the transferred OVA-specific Tr1 cells were functionally active (Table 1). TGF-ß in the supernatants was below detectable levels.
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IL-10 is a cytokine with important immunosuppressive effect in vivo. Therefore, to analyze the consequence of high IL-10 secretion in mice transferred with Tr1 cells and treated with OVA/CFA, we analyzed the cytokine response of T cells after polyclonal activation with conA. As expected, conA stimulation induced a Th0 type response in T cells from saline- or Tr1-treated mice and a Th1-type response in mice treated with OVA/CFA (Table 2). In contrast, in mice treated with regulatory Tr1 cells and OVA/CFA, we observed a marked decrease in IFN- production and an increase in IL-10 production by conA-stimulated T cells (Table 2). Interestingly, the ratio of INF- to IL-10 was reduced by 3- to 4-fold in the (OVA/CFA)+Tr1 group compared with the other groups of mice, suggesting that the transfer of regulatory Tr1 cells followed by a systemic delivery of their specific antigen induced a bystander nonspecific regulatory immune response as a result of the chronic stimulation of Tr1 cells with OVA/CFA. However, as shown previously in other inflammatory models, the inhibitory function of Tr1 cells is local,15,25 and chronic stimulation of Tr1 cells did not result in systemic secretion of IL-10 in the serum, because <30 pg/mL of IL-10 was measured in the serum of the 4 different groups of mice.
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Transfer of Tr1 Cells With Their Cognate Antigen Reduces Atherosclerotic Lesion Size in ApoE-Deficient Mice
Serum total cholesterol and HDL levels did not differ between groups (Table 3). Atherosclerotic lesion size in the thoracic aorta did not differ between the saline and Tr1 groups (Table 3). There was a modest but not statistically significant reduction in lesion size in the thoracic aorta of mice treated with OVA/CFA in comparison with the saline or Tr1 group (P=0.09 and P=0.07, respectively). In contrast, there was a marked and highly significant reduction in lesion size in the (OVA/CFA)+Tr1 group in comparison with either OVA/CFA (42% reduction, P=0.008), Tr1 alone, or saline (55% reduction, P
0.001) (Table 3).
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Atherosclerotic lesion size in the aortic sinus did not differ between saline-, Tr1-, and OVA/CFA-treated animals. However, we found a highly significant decrease of plaque size in the (OVA/CFA)+Tr1 group compared with either the saline (P=0.002), Tr1 (P<0.0001), or OVA/CFA group (P=0.001) (Table 3 and Figure 1). Despite the significant decrease in lesion size, plaques of mice treated with (OVA/CFA)+Tr1 showed a marked decrease in relative macrophage infiltration (32% to 46% reduction, Table 3 and Figure 1) and T-cell accumulation (37% to 50% reduction, Table 3), with no change in smooth muscle cell or collagen content (Table 3). In addition, we found intense IL-10 staining in the plaques of mice treated with (OVA/CFA)+Tr1, whereas no or barely detectable levels of IL-10 were found in plaques from the other 3 groups (Figure 2). IL-10 staining was also detected in the adventitia of all study groups but was clearly enhanced in the (OVA/CFA)+Tr1 group (Figure 2). Overall, these results suggest that a regulatory T-cell response is associated with a less pronounced inflammatory plaque phenotype.
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Discussion |
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A substantial body of evidence suggests an important role for Th1-mediated immunoinflammatory responses in the development and progression of atherosclerotic lesions, at least in experimental models of human-like atherosclerosis.3–10 There are also reports from human studies suggesting a strong association between Th1-related responses and plaque instability.9,26–29 Therefore, much of the recent research in the field of atherosclerosis, based on current dogma suggesting that the immunoinflammatory response in atherosclerosis is controlled by distinct Th1 and Th2 subpopulations of T cells, has focused on the potential role of Th2-mediated responses in the modulation of the atherosclerotic process. The finding by several independent groups that IL-10, a Th2-related cytokine, exerts major antiatherogenic effects has particularly reinforced the Th1/Th2 paradigm in immunity to atherosclerosis.11,30–33 However, IL-10 is not specific to Th2 cells. Interestingly, another subtype of T cells, Tr1, with cytokine profiles distinct from either Th1 or Th2 cells, has been identified and shown to play an important role in the regulation of and protection against various Th1- and Th2-mediated immunoinflammatory diseases (see References 12–14 for review). Therefore, we hypothesized that in atherosclerosis, there may be an imbalance between the effector and the regulatory (for instance, Tr1) arms of the immune response and suggested that supplementation with Tr1 cells may lead to the induction of a regulatory immune phenotype and a reduction in Th1- and Th2-mediated responses, ultimately altering plaque development and/or composition.
Here, we showed that these regulatory Tr1 cells, when transferred into mice with their cognate antigen, induced a significant suppression of Th1-mediated responses and led to an increase in IL-10 production by stimulated peripheral T cells. Tr1-mediated immune suppression was observed in response to stimulation with either OVA or conA, suggesting the induction of a systemic bystander immune suppression, which most likely resulted from repeated administration of OVA/CFA. Interestingly, the induction of Tr1 responses was associated with a significant reduction in atherosclerotic plaque size and a marked reduction in the relative accumulation of inflammatory macrophages and T lymphocytes with preservation of smooth muscle cell and collagen contents. It is noteworthy that the transfer and in vivo activation of Tr1 cells led to a profound reduction in the ratio of IFN- to IL-10 compared with the other groups (Table 2) and with the appearance of intense IL-10 staining within the plaques, suggesting that this change in the balance between proatherogenic and antiatherogenic mediators may have contributed to the alterations in lesion development and composition. These results show that modulation of the immune response is achievable by transfer and activation of Tr1 cells and leads to limitation of the development of atherosclerosis in apoE-deficient mice.
It could be argued that our data may simply be compatible with a systemic effect of circulating IL-10 and that such an effect may be independent of any regulatory or immunosuppressive function. Although it is very difficult to separate the regulatory functions of Tr1 clones from their capacity to produce IL-10 (several studies have established the critical contribution of the immunomodulatory cytokine IL-10 to the regulatory potential of Tr1; for review, see References 12 and 13), we believe that several data argue against such a hypothesis. First, we have been unable to detect any substantial production or difference in serum IL-10 levels between the various study groups, whereas IL-10 protein accumulation was increased locally within the plaques of the OVA/CFA+Tr1 group. Second, not all IL-10–producing T cells are regulatory T cells. Pinderski et al33 have recently shown that overexpression of IL-10 by T lymphocytes (IL-10 was placed under the control of the IL-2 promoter) led to a switch toward a Th2 phenotype that is phenotypically and functionally distinct from all Tr1 clones. Unlike the results obtained with the overexpression of IL-10 in the latter study,33 we showed in our work that appropriate activation of Tr1 led to significant reductions in both Th1- (IFN-) and Th2-related (IL-4 and IL-5) cytokines and immunoglobulins (IgG2a and IgE, respectively) (Tables 1 and 2
). This is consistent with previous studies showing that only regulatory T cells, like Tr1, are able to suppress both Th1- and Th2-related responses.12,13,20,24
Another potential limitation to our study is the confounding effect of CFA on atherosclerotic lesion development. Indeed, previously published studies have reported a reduction in atherosclerosis with CFA/IFA.34,35 These reductions in the aortic arch or the thoracic aorta were moderate (18% and 19%) and were accompanied by changes in total and/or HDL cholesterol levels that may have contributed to limitation of plaque progression. It is noteworthy that in our study, the OVA/CFA group showed a reduction in atherosclerotic lesion size in the thoracic aorta (23%) similar to that reported in studies using CFA/IFA, even in the absence of changes in cholesterol levels. However, in our study, the additional transfer of Tr1 cells resulted in a much more important and marked 55% reduction in atherosclerosis.
In conclusion, our results provide the first proof of the concept that cell transfer of a novel subpopulation of T cells with regulatory functions, here Tr1 cells, is able to modulate the in vivo immune response and leads to substantial limitation of plaque size while inducing changes in plaque composition indicative of a less inflammatory plaque phenotype. This work paves the way for the development and testing of novel therapeutic strategies based on the enhancement and/or transfer of specific regulatory immune cells (ie, Tr1 cells specific for a plaque-derived antigen) to limit the development and prevent the complications of atherosclerosis.
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Acknowledgments |
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This work was supported by Action Concertée Incitative Jeunes Chercheurs, Ministère de la Recherche, France (to Dr Mallat), and Fondation de France.
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Footnotes |
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This article originally appeared Online on August 11, 2003 (Circulation. 2003;108:r47–r52).
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H. Ait-Oufella, K. Kinugawa, J. Zoll, T. Simon, J. Boddaert, S. Heeneman, O. Blanc-Brude, V. Barateau, S. Potteaux, R. Merval, et al. Lactadherin Deficiency Leads to Apoptotic Cell Accumulation and Accelerated Atherosclerosis in Mice Circulation, April 24, 2007; 115(16): 2168 - 2177. [Abstract] [Full Text] [PDF]
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 E. J.A van Wanrooij, G. H.M van Puijvelde, P. de Vos, H. Yagita, T. J.C. van Berkel, and J. Kuiper Interruption of the Tnfrsf4/Tnfsf4 (OX40/OX40L) Pathway Attenuates Atherogenesis in Low-Density Lipoprotein Receptor-Deficient Mice Arterioscler Thromb Vasc Biol, January 1, 2007; 27(1): 204 - 210. [Abstract] [Full Text] [PDF]
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 A. Mor, G. Luboshits, D. Planer, G. Keren, and J. George Altered status of CD4+CD25+ regulatory T cells in patients with acute coronary syndromes Eur. Heart J., November 1, 2006; 27(21): 2530 - 2537. [Abstract] [Full Text] [PDF]
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A.-K. L. Robertson and G. K Hansson T Cells in Atherogenesis: For Better or For Worse? Arterioscler Thromb Vasc Biol, November 1, 2006; 26(11): 2421 - 2432. [Abstract] [Full Text] [PDF]
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E. A. Heller, E. Liu, A. M. Tager, Q. Yuan, A. Y. Lin, N. Ahluwalia, K. Jones, S. L. Koehn, V. M. Lok, E. Aikawa, et al. Chemokine CXCL10 Promotes Atherogenesis by Modulating the Local Balance of Effector and Regulatory T Cells Circulation, May 16, 2006; 113(19): 2301 - 2312. [Abstract] [Full Text] [PDF]
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 A. Tedgui and Z. Mallat Cytokines in Atherosclerosis: Pathogenic and Regulatory Pathways Physiol Rev, April 1, 2006; 86(2): 515 - 581. [Abstract] [Full Text] [PDF]
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J. Khallou-Laschet, G. Caligiuri, E. Groyer, E. Tupin, A.-T. Gaston, B. Poirier, M. Kronenberg, J. L. Cohen, D. Klatzmann, S. V. Kaveri, et al. The Proatherogenic Role of T Cells Requires Cell Division and Is Dependent on the Stage of the Disease Arterioscler Thromb Vasc Biol, February 1, 2006; 26(2): 353 - 358. [Abstract] [Full Text] [PDF]
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E. J.A. van Wanrooij, H. Happe, A. D. Hauer, P. de Vos, T. Imanishi, H. Fujiwara, T. J.C. van Berkel, and J. Kuiper HIV Entry Inhibitor TAK-779 Attenuates Atherogenesis in Low-Density Lipoprotein Receptor-Deficient Mice Arterioscler Thromb Vasc Biol, December 1, 2005; 25(12): 2642 - 2647. [Abstract] [Full Text] [PDF]
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 S G Baidya and Q-T Zeng Helper T cells and atherosclerosis: the cytokine web Postgrad. Med. J., December 1, 2005; 81(962): 746 - 752. [Abstract] [Full Text] [PDF]
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M. P.W. Moos, N. John, R. Grabner, S. Nossmann, B. Gunther, R. Vollandt, C. D. Funk, B. Kaiser, and A. J.R. Habenicht The Lamina Adventitia Is the Major Site of Immune Cell Accumulation in Standard Chow-Fed Apolipoprotein E-Deficient Mice Arterioscler Thromb Vasc Biol, November 1, 2005; 25(11): 2386 - 2391. [Abstract] [Full Text] [PDF]
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 M. Shinohara, S. Kawashima, T. Yamashita, T. Takaya, R. Toh, T. Ishida, T. Ueyama, N. Inoue, K.-i. Hirata, and M. Yokoyama Xenogenic smooth muscle cell immunization reduces neointimal formation in balloon-injured rabbit carotid arteries Cardiovasc Res, November 1, 2005; 68(2): 249 - 258. [Abstract] [Full Text] [PDF]
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 B. Nashed, B. Yeganeh, K. T. HayGlass, and M. H. Moghadasian Antiatherogenic Effects of Dietary Plant Sterols Are Associated with Inhibition of Proinflammatory Cytokine Production in Apo E-KO Mice J. Nutr., October 1, 2005; 135(10): 2438 - 2444. [Abstract] [Full Text] [PDF]
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N. R. Veillard, S. Steffens, G. Pelli, B. Lu, B. R. Kwak, C. Gerard, I. F. Charo, and F. Mach Differential Influence of Chemokine Receptors CCR2 and CXCR3 in Development of Atherosclerosis In Vivo Circulation, August 9, 2005; 112(6): 870 - 878. [Abstract] [Full Text] [PDF]
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G. Caligiuri, E. Groyer, J. Khallou-Laschet, A. A. H. Zen, J. Sainz, D. Urbain, A.-T. Gaston, M. Lemitre, A. Nicoletti, and A. Lafont Reduced Immunoregulatory CD31+ T Cells in the Blood of Atherosclerotic Mice With Plaque Thrombosis Arterioscler Thromb Vasc Biol, August 1, 2005; 25(8): 1659 - 1664. [Abstract] [Full Text] [PDF]
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P. A. VanderLaan and C. A. Reardon Thematic review series: The Immune System and Atherogenesis. The unusual suspects:an overview of the minor leukocyte populations in atherosclerosis J. Lipid Res., May 1, 2005; 46(5): 829 - 838. [Abstract] [Full Text] [PDF]
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G. S. Getz Thematic review series: The Immune System and Atherogenesis. Immune function in atherogenesis J. Lipid Res., January 1, 2005; 46(1): 1 - 10. [Abstract] [Full Text] [PDF]
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J. Nilsson, G. K. Hansson, and P. K. Shah Immunomodulation of Atherosclerosis: Implications for Vaccine Development Arterioscler Thromb Vasc Biol, January 1, 2005; 25(1): 18 - 28. [Abstract] [Full Text] [PDF]
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 R. Elhage, P. Gourdy, L. Brouchet, J. Jawien, M.-J. Fouque, C. Fievet, X. Huc, Y. Barreira, J. C. Couloumiers, J.-F. Arnal, et al. Deleting TCR{alpha}{beta}+ or CD4+ T Lymphocytes Leads to Opposite Effects on Site-Specific Atherosclerosis in Female Apolipoprotein E-Deficient Mice Am. J. Pathol., December 1, 2004; 165(6): 2013 - 2018. [Abstract] [Full Text] [PDF]
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N. R. Veillard, S. Steffens, F. Burger, G. Pelli, and F. Mach Differential Expression Patterns of Proinflammatory and Antiinflammatory Mediators During Atherogenesis in Mice Arterioscler Thromb Vasc Biol, December 1, 2004; 24(12): 2339 - 2344. [Abstract] [Full Text] [PDF]
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 L. Mazzolai, M. A. Duchosal, M. Korber, K. Bouzourene, J. F. Aubert, H. Hao, V. Vallet, H. R. Brunner, J. Nussberger, G. Gabbiani, et al. Endogenous Angiotensin II Induces Atherosclerotic Plaque Vulnerability and Elicits a Th1 Response in ApoE-/- Mice Hypertension, September 1, 2004; 44(3): 277 - 282. [Abstract] [Full Text] [PDF]
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A. Tedgui and Z. Mallat Hypertension: A Novel Regulator of Adaptive Immunity in Atherosclerosis? Hypertension, September 1, 2004; 44(3): 257 - 258. [Full Text] [PDF]
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S. Potteaux, B. Esposito, O. van Oostrom, V. Brun, P. Ardouin, H. Groux, A. Tedgui, and Z. Mallat Leukocyte-Derived Interleukin 10 Is Required for Protection Against Atherosclerosis in Low-Density Lipoprotein Receptor Knockout Mice Arterioscler Thromb Vasc Biol, August 1, 2004; 24(8): 1474 - 1478. [Abstract] [Full Text] [PDF]
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