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Function Inflammation Is Independent of Coreceptor to Inhibit Th2 Ability of a Nondepleting Anti-CD4 Antibody to Inhibit Th2 Responses and Allergic Lung Inflammation Is Independent of Coreceptor Function This information is current as of September 25, 2021. Li Li, Mary Crowley, Andrea Nguyen and David Lo J Immunol 1999; 163:6557-6566; ; http://www.jimmunol.org/content/163/12/6557 Downloaded from References This article cites 41 articles, 21 of which you can access for free at: http://www.jimmunol.org/content/163/12/6557.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 25, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 1999 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Ability of a Nondepleting Anti-CD4 Antibody to Inhibit Th2 Responses and Allergic Lung Inflammation Is Independent of Coreceptor Function1 Li Li, Mary Crowley, Andrea Nguyen, and David Lo2 Nondepleting anti-CD4 Abs have been used in vivo to induce Ag-specific immunological tolerance in Th1 responses, including tissue allograft rejection and autoimmune diabetes. To examine whether this Ab (YTS177.9) acts by provoking a Th2 shift, we tested the effect in a mouse model of allergic lung inflammation. Interestingly, nondepleting anti-CD4 treatment induces tolerance to allergens as well, especially when given during initial priming. In vitro studies indicate that the effect of the Ab is independent of CD4 coreceptor function, as Ab treatment also inhibits proliferation and induces a persistent anergy in naive CD4 T cells stimulated by anti-CD3/CD28. Moreover, the Ab stimulated a distinct pattern of tyrosine phosphorylation in T cells even in the Downloaded from absence of TCR triggering, suggesting that signaling through CD4 alone induces significant physiological changes in T cell function. These results show that tolerance induced by anti-CD4 triggering is not a simple shift in Th1/Th2 effector function or depletion of Ag-specific cells, but may instead induce a persistent clonal anergy capable of blocking subsequent immunity. The Journal of Immunology, 1999, 163: 6557–6566. D4 T cells are critical cells in directing effector function fused. The Ag-specific nature of this effect was clear, as it did not http://www.jimmunol.org/ in several kinds of immune responses, including the Ab interfere with subsequent priming to secondary Ags. It was sug- C response to viral infection, cellular immune responses to gested that the anti-CD4 treatment induced a dominant Ag-specific tissue allografts, delayed-type hypersensitivity, and autoimmune tolerance, but the specific mechanism was not clearly defined. One diseases such as type 1 diabetes, thyroiditis, and multiple sclerosis. of the possible mechanisms is the induction of clonal anergy, as Therefore, therapeutic approaches in pathological syndromes are described for superantigen-reactive Vb61 T cells in the bone mar- often aimed toward the modification or modulation of CD4 T cell row transplantation model (7). In this study, bone marrow trans- functions. For example, in the case of type 1 diabetes, this has been plantation with Mls3-1a-positive cells did not significantly deplete achieved through some general approaches such as the in vivo the Mls-reactive Vb61 T cells, but proliferative responses to Mls depletion of cells expressing ab-TCR (1), CD3 (2), or CD4 (3). In were reduced. However, since not all Vb6 cells are superantigen by guest on September 25, 2021 similar fashion, anti-CD4 depletion has been shown to prevent reactive, alterations in the receptor repertoire in the chimeras might lung-allergic inflammation (4, 5). Unfortunately, these approaches also account for this effect. risk generalized immune suppression, predisposing the subjects to Another compelling possible explanation for the effects of the opportunistic infections. Recently, however, a more subtle ap- nondepleting anti-CD4 Ab comes from studies on the nonobese proach has been developed using Abs against CD4 that do not diabetic mouse model of spontaneous autoimmune diabetes. As deplete the T cell pool, but were still found to have significant with tissue allograft rejection, Th1 cells appear to be the main immunomodulatory effects. These effects were not due to gener- effector cells driving pathogenesis, although in this case they are alized immunosuppression, but depended on simultaneous expo- specific for islet b cell Ags. Treatment of nonobese diabetic mice sure of CD41 T cells to a specific Ag, providing for an Ag-specific with the anti-CD4 Ab was able to prevent diabetes in three differ- tolerance. ent situations, including 1) the spontaneous development of dis- In studies by the Waldmann group, an anti-CD4 Ab (YTS177.9) ease (8), 2) adoptive transfer into sublethally irradiated recipients was found to have striking effects in Ag-specific CD4 T cell re- (9), and 3) induction with high doses of cyclophosphamide (10). sponses, without causing a depletion of peripheral CD4 T cells This last observation is most relevant, as cyclophosphamide-in- (reviewed in Ref. 6). When mice were primed to specific Ag dur- duced diabetes has also been shown to correlate with increased ing anti-CD4 treatment, a longstanding Ag-specific tolerance was IFN-g production by T cells (11, 12), essentially a Th1 shift. More- induced that could not be broken even when naive cells were in- over, cyclophosphamide can abrogate the effects of anti-CD4 even in thymectomized mice, suggesting that these reagents have direct and reversible effects on the T cells and their effector function. Department of Immunology IMM-25, The Scripps Research Institute, La Jolla, Thus, the longstanding tolerance in anti-CD4-treated mice may be CA 92037 due to the development of Ag-specific suppressor effector CD4 T Received for publication May 18, 1999. Accepted for publication September cells, most likely with a Th2 phenotype. 27, 1999. In the studies on tissue allograft rejection and autoimmune di- The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance abetes, the highly polyclonal nature of the responding T cell pop- with 18 U.S.C. Section 1734 solely to indicate this fact. ulation made it difficult to closely follow Ag-specific cells to de- 1 This work was supported by Grants AI29689 and AI31583 to D.L. from the National termine the effects of the anti-CD4 treatment. Thus, we have used Institutes of Health, and a grant from the Juvenile Diabetes Foundation International. 2 Address correspondence and reprint requests to Dr. David Lo, Department of Im- munology IMM-25, The Scripps Research Institute, 10550 North Torrey Pines Road, 3 Abbreviations used in this paper: Mls, minor lymphocyte stimulating; BAL, bron- La Jolla, CA 92037. E-mail address: [email protected] choalveolar lavage. Copyright © 1999 by The American Association of Immunologists 0022-1767/99/$02.00 6558 NONDEPLETING ANTI-CD4 AND ALLERGIC LUNG INFLAMMATION Downloaded from http://www.jimmunol.org/ FIGURE 1. Nondepleting anti-CD4 Ab administered during immunization inhibits allergic lung inflammation. Naive BALB/c mice were immunized and boosted with OVA/alum i.p. 1 wk apart, and the anti-CD4 Ab or normal rat Ig as control Ab were given i.p. 1 day before and 1 day after the immunization/ boost. These mice were challenged with OVA intranasally in the third week once per day for 3 days, and were sacrificed 3 h after the last challenge. Their lungs were fixed with Bouin’s and stained with hematoxylin and eosin (HE), or embedded in OCT, and the frozen sections were stained for cyanide-resistant eosinophil peroxidase (EPO) activity for eosinophils (3200). by guest on September 25, 2021 TCR transgenic mice to provide more detailed in vitro information Research Institute), with normal rat Ig (Sigma, St. Louis, MO) as control on whether the Ab will have significant effects on Th2-mediated Ab. Human rIL-2 and mouse rIL-4 were obtained from Pepro Tech (Rocky immunity such as allergic asthma, and whether the primary effect Hill, NJ). Anti-IL-12 was the monoclonal rat IgG clone C17.8.20, obtained as a hybridoma generously provided by Dr. G. Trinchieri (Wistar Institute, on Ag-specific T cells involves a Th1 to Th2 shift or clonal anergy. Philadelphia, PA). Anti-CD3, CD28, CD4, CD8a, B220, and CD62L Abs Our results suggest that anti-CD4 treatment can have potent effects were all obtained from PharMingen (San Diego, CA), and mouse anti-rat 9 in blocking the development of allergic lung inflammation. Con- IgG polyclonal Ab (F(ab )2 fragment) was obtained from Jackson Immu- sistent with this effect, we find that in vitro the anti-CD4 inhibits noResearch (West Grove, PA). Abs and standards for ELISAs measuring cytokines and serum Ig were obtained from PharMingen. proliferation and induces a persistent anergy in primary CD4 T cells; moreover, the induction of anergy is independent of CD4 coreceptor function, and may involve the activation of novel sig- Induction of OVA-specific lung inflammation naling pathways. Thus, anti-CD4 therapy may have broader appli- Naive mice were immunized i.p. with 10 mg chicken egg OVA (Sigma) in cation than generally assumed, and may be an effective method for 100 ml of PBS mixed with the same volume of Imject Alum (Pierce, Rock- inducing anergy in the prevention of allergic diseases, including ford, IL); these mice were then boosted the same way in the following asthma.
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