DOCSLIB.ORG

Finally, Ctla4ig Graduates to the Clinic

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Finally, Ctla4ig Graduates to the Clinic Finally, CTLA4Ig graduates to the clinic Mohamed H. Sayegh J Clin Invest. 1999;103(9):1223-1225. https://doi.org/10.1172/JCI6952. Commentary It has long been known that T cells require two signals for full activation, but the mechanisms of how these signals function have been only recently elucidated (1). The first signal is provided by the T-cell receptor after interacting with the MHC/antigenic peptide complex. This so-called “signal one” confers antigen specificity to the immune response but alone is insufficient for full T-cell activation. Indeed, T cells receiving only signal one are rendered anergic (unresponsive to antigenic rechallenge, with inhibition of proliferation and cytokine production) in vitro (2). The second signal, or “costimulatory signal,” is provided by interactions between specific receptors on the T cell and their respective ligands on antigen-presenting cells (APCs). The CD28/CD152–B7-1/B7-2 T-cell costimulatory pathway is a unique and complex pathway that regulates T-cell activation (recently reviewed in refs. 3 and 4) (Figure 1). Interaction of CD28, constitutively expressed on T cells, with the B7 family of molecules (B7-1 and B7-2), expressed on APCs, provides a second “positive” signal that results in full T-cell activation, including cytokine production, clonal expansion, and prevention of anergy. In addition, CD28 signaling appears to be important in prevention of cell death and promotion of cell survival, presumably by upregulation of T-cell expression of bcl-xl genes (5). Once activated, T cells express another costimulatory molecule (CD152, or CTLA4) that is homologous to CD28, […] Find the latest version: https://jci.me/6952/pdf Finally, CTLA4Ig graduates to the clinic Commentary See related article Mohamed H. Sayegh this issue, pages 1243–1252 Laboratory of Immunogenetics and Transplantation, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA. Phone: (617) 732-5259; Fax: 617-732-5254; E-mail: [email protected]. It has long been known that T cells and 4) (Figure 1). Interaction of CD28, vation that CTLA4 gene knockout mice require two signals for full activation, constitutively expressed on T cells, with develop massive lymphoproliferation but the mechanisms of how these sig- the B7 family of molecules (B7-1 and and early death (10, 11). Furthermore, nals function have been only recently B7-2), expressed on APCs, provides a recent evidence suggests that CTLA4 elucidated (1). The first signal is pro- second “positive” signal that results in negative signaling pathway may be vided by the T-cell receptor after inter- full T-cell activation, including required for the induction of acquired acting with the MHC/antigenic pep- cytokine production, clonal expansion, tolerance (12, 13). Indeed, it has been tide complex. This so-called “signal and prevention of anergy. In addition, hypothesized that CTLA4 may function one” confers antigen specificity to the CD28 signaling appears to be impor- as a “master switch” for peripheral T-cell immune response but alone is insuffi- tant in prevention of cell death and tolerance in vivo (14). cient for full T-cell activation. Indeed, promotion of cell survival, presumably Several years before the regulatory T cells receiving only signal one are ren- by upregulation of T-cell expression of function of CTLA4 was elucidated, dered anergic (unresponsive to anti- bcl-xl genes (5). Linsley et al. first described the creation genic rechallenge, with inhibition of Once activated, T cells express another of a new immunomodulatory agent proliferation and cytokine production) costimulatory molecule (CD152, or that consists of the extracellular in vitro (2). The second signal, or “cos- CTLA4) that is homologous to CD28, domain of the soluble CTLA4 receptor timulatory signal,” is provided by inter- has a higher affinity to B7-1 and B7-2, fused to the heavy chain of human actions between specific receptors on and functions to provide a “negative” sig- IgG1 (6). Other similar agents have the T cell and their respective ligands nal that inhibits cytokine production been subsequently described, including on antigen-presenting cells (APCs). The and arrests cell cycle progression (6–8). a murine form of CTLA4Ig, and several CD28/CD152–B7-1/B7-2 T-cell cos- The importance of CTLA4 as a negative hundred articles have been published timulatory pathway is a unique and regulatory T-cell costimulatory molecule describing the immunomodulatory complex pathway that regulates T-cell in the physiologic termination of T-cell functions of CTLA4Ig in several experi- activation (recently reviewed in refs. 3 responses (9) is highlighted by the obser- mental animal models of transplant Figure 1 Complexity of the CD28/CD152–B7-1/B7-2 T-cell costimulatory pathway. After antigenic stimulation (delivery of signal one through the T-cell recep- tor; not shown here), CD28, expressed on resting T cells, interacts with B7-2, and later with B7-1, both expressed on APCs. This results in transduc- tion of a positive costimulatory signal to the T cell, culminating in cytokine production, clonal expansion, and prevention of anergy and cell death, thus promoting cell survival. Activated T cells then express CTLA4, a molecule that is highly homologous to CD28 but upon interaction with B7-1/ B7-2 delivers a negative signal to the T cell, resulting in inhibition of cytokine production and cell cycle progression arrest, thus physiologically ter- minating immune responses. The use of biologic agents, such as anti-B7 monoclonal antibodies or CTLA4Ig, to block B7 binding to CD28 results in T-cell anergy in vitro, and in anergy, deletion, or induction of regulatory T cells in vivo (4). The Journal of Clinical Investigation | May 1999 | Volume 103 | Number 9 1223 Table 1 immunosuppressive or tolerogenic Human diseases in which CD28/B7 T-cell costimulatory blockade may have promise effects of B7 and/or CD154 blockade (24, 27, 28). Finally, we need to investi- Autoimmune diseases Transplant rejection Asthma gate and better understand the exact Psoriasis Solid organs mechanisms of costimulatory blockade Rheumatoid arthritis Cell transplants (islets, neural cells) in vivo in humans with different dis- Multiple sclerosis Bone marrow eases and to develop surrogate markers Systemic lupus erythematosus to monitor disease activity and Inflammatory bowel diseases response to therapy. In a recent study, Guinan et al. (29) used CTLA4Ig to anergize alloreactive bone marrow T cells ex vivo to prevent rejection, autoimmunity, infections, potential for a prolonged beneficial clin- graft-versus-host disease after hap- asthma, and others (recently reviewed ical effect of therapy even after CTLA4Ig loidentical bone marrow transplanta- in refs. 3 and 4). Although it is clear that serum levels become undetectable. tion. Such studies, and the pioneering CTLA4Ig, because of the higher affinity These cautionary data in particular sug- work by Abrams et al. (23), pave the way of the CTLA4 receptor to B7-1 and B7- gest that CTLA4Ig may be inducing a for the development of new clinical tri- 2, acts as a competitive inhibitor of state of T-cell hyporesponsiveness or als that will further examine the CD28–B7-1/B7-2 costimulation and tolerance in vivo. immunomodulatory functions of novel induces T-cell anergy in vitro, its exact Two interesting observations in this agents that block T-cell costimulatory mechanism of action in vivo remains study again highlight the complexity of activation in several immune-mediated unclear. It has been suggested, however, the CD28/CD152 T-cell costimulatory human diseases. A better understand- that induction of tolerance by B7 block- signaling pathway. First, there is the ing of the mechanisms of these novel ade may be due to anergy (failure of dichotomy between the clinical observa- agents may make the goal of achieving clonal expansion), deletion, or induc- tion indicating that the beneficial effects immunologic tolerance in humans elu- tion of regulatory T cells in vivo (15–21) of CTLA4Ig may be long lasting and the sive no more. (Figure 1). Interestingly, a recent study immunologic studies showing that from our group indicated that an intact fully primed T cell–dependent humoral Acknowledgments CTLA4 negative signaling pathway is immune responses were not affected, M.H. Sayegh is a recipient of the National Kid- required for the immunosuppressive suggesting absence of immunologic tol- ney Foundation Clinician Scientist Award. effects of CTLA4Ig in a mouse heart erance. Second, there is the paradoxical The author would like to thank Charles B. transplant model, adding further to the result showing the divergence of sup- Carpenter, Samia J. Khoury, and Laurence A. complexity of the B7-1/B7-2 costimula- pression of cell-mediated and humoral Turka for their helpful comments and review of the manuscript. tory pathway in regulating immune immune responses at the high-dose responses (22). schedule (50 mg/kg) of CTLA4Ig thera- 1. Janeway, C.A., and Bottomly, K. 1994. Signals and After almost a decade of laboratory py. This latter observation and the recent signs for lymphocyte responses. Cell. 76:275–285. 2. Schwartz, R.H. 1990. A cell culture model for T studies, CTLA4Ig finally “graduates” to studies by Judge et al. (22) make one lymphocyte clonal anergy. Science. 248:1349–1356. the clinic. In this issue, Abrams et al. wonder whether in certain diseases, com- 3. Reiser, H., and Stadecker, M.J. 1996. Costimula- (23) present the results of a phase I clin- plete blockade of B7-1/B7-2 may not be tory B7 molecules in the pathogenesis of infec- tious and autoimmune diseases. N. Engl. J. Med. ical trial describing the immunosup- desirable because it may result in inhibi- 335:1369–1377. pressive effects of CTLA4Ig in the T tion of a beneficial negative regulatory 4. Sayegh, M.H., and Turka, L.A.
Load more

Recommended publications
  • Oral Tolerance: Therapeutic Implications for Autoimmune Diseases
    Clinical & Developmental Immunology, June–December 2006; 13(2–4): 143–157 Oral tolerance: Therapeutic implications for autoimmune diseases ANA M. C. FARIA1 & HOWARD L. WEINER2 1Departamento de Bioquı´mica e Imunologia, Instituto de Cieˆncias Biolo´gicas, Universidade Federal de Minas Gerais, Av. Antonio Carlos, 6627, Belo Horizonte, MG 31270-901, Brazil, and 2Harvard Medical School, Center for Neurologic Diseases, Brigham and Women’s Hospital, 77 Avenue Louis Pasteur, Boston, MA 02115, USA Abstract Oral tolerance is classically defined as the suppression of immune responses to antigens (Ag) that have been administered previously by the oral route. Multiple mechanisms of tolerance are induced by oral Ag. Low doses favor active suppression, whereas higher doses favor clonal anergy/deletion. Oral Ag induces Th2 (IL-4/IL-10) and Th3 (TGF-b) regulatory T cells (Tregs) plus CD4þCD25þ regulatory cells and LAPþT cells. Induction of oral tolerance is enhanced by IL-4, IL-10, anti-IL-12, TGF-b, cholera toxin B subunit (CTB), Flt-3 ligand, anti-CD40 ligand and continuous feeding of Ag. In addition to oral tolerance, nasal tolerance has also been shown to be effective in suppressing inflammatory conditions with the advantage of a lower dose requirement. Oral and nasal tolerance suppress several animal models of autoimmune diseases including experimental allergic encephalomyelitis (EAE), uveitis, thyroiditis, myasthenia, arthritis and diabetes in the nonobese diabetic (NOD) mouse, plus non-autoimmune diseases such as asthma, atherosclerosis, colitis and stroke. Oral tolerance has been tested in human autoimmune diseases including MS, arthritis, uveitis and diabetes and in allergy, contact sensitivity to DNCB, nickel allergy.
    [Show full text]
  • The Distribution of Immune Cells in the Uveal Tract of the Normal Eye
    THE DISTRIBUTION OF IMMUNE CELLS IN THE UVEAL TRACT OF THE NORMAL EYE PAUL G. McMENAMIN Perth, Western Australia SUMMARY function of these cells in the normal iris, ciliary body Inflammatory and immune-mediated diseases of the and choroid. The role of such cell types in ocular eye are not purely the consequence of infiltrating inflammation, which will be discussed by other inflammatory cells but may be initiated or propagated authors in this issue, is not the major focus of this by immune cells which are resident or trafficking review; however, a few issues will be briefly through the normal eye. The uveal tract in particular considered where appropriate. is the major site of many such cells, including resident tissue macro phages, dendritic cells and mast cells. This MACRO PHAGES review considers the distribution and location of these and other cells in the iris, ciliary body and choroid in Mononuclear phagocytes arise from bone marrow the normal eye. The uveal tract contains rich networks precursors and after a brief journey in the blood as of both resident macrophages and MHe class 11+ monocytes immigrate into tissues to become macro­ dendritic cells. The latter appear strategically located to phages. In their mature form they are widely act as sentinels for capturing and sampling blood-borne distributed throughout the body. Macrophages are and intraocular antigens. Large numbers of mast cells professional phagocytes and play a pivotal role as are present in the choroid of most species but are effector cells in cell-mediated immunity and inflam­ virtually absent from the anterior uvea in many mation.1 In addition, due to their active secretion of a laboratory animals; however, the human iris does range of important biologically active molecules such contain mast cells.
    [Show full text]
  • Of T Cell Tolerance
    cells Review Strength and Numbers: The Role of Affinity and Avidity in the ‘Quality’ of T Cell Tolerance Sébastien This 1,2,† , Stefanie F. Valbon 1,2,†, Marie-Ève Lebel 1 and Heather J. Melichar 1,3,* 1 Centre de Recherche de l’Hôpital Maisonneuve-Rosemont, Montréal, QC H1T 2M4, Canada; [email protected] (S.T.); [email protected] (S.F.V.); [email protected] (M.-È.L.) 2 Département de Microbiologie, Immunologie et Infectiologie, Université de Montréal, Montréal, QC H3C 3J7, Canada 3 Département de Médecine, Université de Montréal, Montréal, QC H3T 1J4, Canada * Correspondence: [email protected] † These authors contributed equally to this work. Abstract: The ability of T cells to identify foreign antigens and mount an efficient immune response while limiting activation upon recognition of self and self-associated peptides is critical. Multiple tolerance mechanisms work in concert to prevent the generation and activation of self-reactive T cells. T cell tolerance is tightly regulated, as defects in these processes can lead to devastating disease; a wide variety of autoimmune diseases and, more recently, adverse immune-related events associated with checkpoint blockade immunotherapy have been linked to a breakdown in T cell tolerance. The quantity and quality of antigen receptor signaling depend on a variety of parameters that include T cell receptor affinity and avidity for peptide. Autoreactive T cell fate choices (e.g., deletion, anergy, regulatory T cell development) are highly dependent on the strength of T cell receptor interactions with self-peptide. However, less is known about how differences in the strength Citation: This, S.; Valbon, S.F.; Lebel, of T cell receptor signaling during differentiation influences the ‘function’ and persistence of anergic M.-È.; Melichar, H.J.
    [Show full text]
  • Commentary Clonal Anergy of B Cells
    Commentary Clonal Anergy of B Cells: A Flexible, Reversible, and Quantitative Concept By G.J.V. Nossal From The Walter and Eliza Hall Institute of Medical Research, Post Office, The Royal Melbourne Hospital, Victoria 3050, Australia t the conclusion of the 1986 Immunology Congress in termed clonal anergy (7). Support for clonal anergy among A Toronto, the late Georges K6hler presented a sum- T lymphocytes also gradually emerged (8, 9). mary lecture which was, unfortunately, poorly attended. It Enter transgenic mouse technology. As far as B cell tol- dealt with the impact of the new genetics on immunology, erance was concerned, the first results were disappointing. Downloaded from http://rupress.org/jem/article-pdf/183/5/1953/1108328/1953.pdf by guest on 29 September 2021 and, among other wise things, he said that transgenic tech- Antigen-transgenic mice were either non-tolerant or vari- nology was set to revolutionize the way we studied immu- ably tolerant (10, 11). However, antigen-transgenic animals nologic tolerance (1). The greatest barrier to uncovering were not the main game, as they left the investigator with the details of what happened to anti-self cells in the repertoire the task of studying the minority of (unidentifiable) reactive was the heterogeneity oflymphocytes. Cells potentially re- lymphocytes. Things really took off when B (12, 13) or T active with a given self antigen were so rare that most at- (14) cell receptor transgenic mice were used. From the tempts to study their fate retied on inferential rather than viewpoint of the present story (15), the critical model was direct methods.
    [Show full text]
  • Rat Corneal Allograft Survival Prolonged by the Superantigen Staphylococcal Enterotoxin B
    Rat Corneal Allograft Survival Prolonged by the Superantigen Staphylococcal Enterotoxin B Zhiqiang Pan,1 Yu Chen,2 Wenhua Zhang,1 Ying Jie,1 Na Li,3 and Yuying Wu1 PURPOSE. The purpose of this study was to determine the The term superantigen (SAg) is used to describe those optimal conditions for prolonging corneal allograft survival by microbial products that activate a large portion of the T-cell inducing anergy with the superantigen staphylococcal entero- population (5%–30%), whereas conventional antigens stimu- toxin B (SEB). late only 0.01%. Superantigens differ from conventional anti- METHODS. A rat model of penetrating keratoplasty, whereby gens in that they bind to the outside of the peptide-binding Fisher344 donor corneas are implanted into Lewis recipients, groove of MHC class, thus exerting their effects as an intact was used to evaluate the effects of SEB on inhibiting immune- molecule without being processed. Furthermore, recognition mediated allograft rejection. To induce anergy, SEB was in- of SAgs by the T-cell receptor (TCR) depends only on the jected into the peribulbar space of Lewis rats. Furthermore, variable region of the TCR ␤ chain (V␤). Therefore, SAgs histopathology and immunofluorescent staining were used to stimulate both antigen-presenting cells (APCs) and T lympho- examine the levels of infiltrating CD4ϩ and CD8ϩ T lympho- cytes, which leads to the massive production of cytokines, cytes and NK1.1ϩ lymphocytes. enhanced expression and/or activation of cell adhesion mole- ␮ cules, T-cell proliferation, activation-induced apoptosis, and RESULTS. By administering SEB, at doses of 90 or 120 g/kg 7 4 days before and after keratoplasty, we suppressed the episode T-cell anergy.
    [Show full text]
  • Immunology: Improving on Nature Review in the Twenty-First Century
    CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector Cell, Vol. 100, 129±138, January 7, 2000, Copyright 2000 by Cell Press Immunology: Improving on Nature Review in the Twenty-First Century Abul K. Abbas* and Charles A. Janeway Jr.² notion at the time, one that challenged existing concepts *Department of Pathology of how proteins conformed to the shapes of other inter- University of California San Francisco School acting proteins. Nevertheless, the clonal selection the- of Medicine ory became the foundation for our understanding of the San Francisco, California 94123 specificity and development of immune responses. The ² Section of Immunobiology molecular understanding of how the diverse repertoire Yale University School of Medicine of antigen receptors is generated came with the studies New Haven, Connecticut 06520 of Susumu Tonegawa in the 1970s (Tonegawa et al., 1977). Based on this work, and its many subsequent refinements, it is now known that the antigen receptors Introduction of B and T lymphocytes are encoded by genes that are Immunology is the study of the body's defenses against produced by somatic recombination of gene segments infection. The birth of immunology as an experimental during maturation of the cells. The recombination pro- science dates to Edward Jenner's successful vaccina- cess is initiated by the RAG proteins, and presence of tion against smallpox in 1796 (Jenner, 1798). The world- RAG genes during phylogeny identifies the evolutionary wide acceptance of vaccination led to mankind's great- time of appearance of the adaptive immune system, est achievements in preventing disease, and smallpox which is just past the appearance of vertebrates (Agra- is the first and only human disease that has been eradi- wal et al., 1998; Hiom et al., 1998).
    [Show full text]
  • Usefulness of IL-21, IL-7, and IL-15 Conditioned Media for Expansion of Antigen-Specific CD8+ T Cells from Healthy Donor-Pbmcs Suitable for Immunotherapy
    Cellular Immunology 360 (2021) 104257 Contents lists available at ScienceDirect Cellular Immunology journal homepage: www.elsevier.com/locate/ycimm Research paper Usefulness of IL-21, IL-7, and IL-15 conditioned media for expansion of antigen-specific CD8+ T cells from healthy donor-PBMCs suitable for immunotherapy Julian´ A. Chamucero-Millares a,b, David A. Bernal-Est´evez b, Carlos A. Parra-Lopez´ a,* a Immunology and Translational Medicine Research Group, Department of Microbiology, School of Medicine, Universidad Nacional de Colombia, Carrera 30 No. 45-03, Bogota,´ South-America, Colombia b Immunology and Clinical Oncology Research Group, Fundacion´ Salud de los Andes, Calle 44 #58-05, Bogota,´ South-America, Colombia ARTICLE INFO ABSTRACT Keywords: Clonal anergy and depletion of antigen-specific CD8+ T cells are characteristics of immunosuppressed patients Antigen-specific T cells such as cancer and post-transplant patients. This has promoted translational research on the adoptive transfer of Monocyte-derived dendritic cells T cells to restore the antigen-specific cellular immunity in these patients. In the present work, we compared the Dendritic cell-based immunotherapy capability of PBMCs and two types of mature monocyte-derived DCs (moDCs) to prime and to expand ex-vivo Adoptive cell transfer antigen-specific CD8+ T cells using culture conditioned media supplemented with IL-7, IL-15, and IL-21. The Cancer immunotherapy Viral immunity data obtained suggest that protocols involving moDCs are as efficient as PBMCs-based cultures in expanding CD8 T cell antigen-specific CD8+ T cell to ELA and CMV model epitopes. These three gamma common chain cytokines Immunological memory promote the expansion of naïve-like and central memory CD8+ T cells in PBMCs-based cultures and the expansion of effector memory T cells when moDCs were used.
    [Show full text]
  • Clonal Anergy: the Universally Anergic B Lymphocyte (Immunological Tolerance/Monoclonal Anti-,A/B Cell Differentiation/Fluorescence-Activated Cell Sorter) BEVERLEY L
    Proc. Natt Acad. Sci. USA Vol. 79, pp. 2013-2017, March 1982 Immunology Clonal anergy: The universally anergic B lymphocyte (immunological tolerance/monoclonal anti-,A/B cell differentiation/fluorescence-activated cell sorter) BEVERLEY L. PIKE, ANDREW W. BOYD, AND G. J. V. NOSSAL The Walter and Eliza Hall Institute of Medical Research, Post Office Royal Melbourne Hospital, Victoria 3050, Australia Contributed by G. J. V. Nossal, December 23, 1981 ABSTRACT The clonal anergy theory of induction of immu- to have received some signal rendering it incapable ofrespond- nological tolerance states that differentiating B lymphocytes that ing to appropriate triggering stimuli. We termed this phenom- encounter multivalent antigen at the pre-B to B cell transition enon clonal anergy. stage can receive and store a negative signal, which renders them This conclusion was dependent on a technology that enum- anergic to later triggering stimuli. The theory was tested by using erated and characterized FLU-binding B cells, by counting cells an anti-IL chain monoclonal antibody, E4, as a model tolerogen. adhering specifically to thin layers of haptenated gelatin, and The fluorescence-activated cell sorter was used to select B cell- then analyzing the cells' capacity to bind fluoresceinated pro- free cell populations from adult murine bone marrow or newborn teins by using the fluorescence-activated cell sorter (FACS) (8, spleen, and later, to analyze B cell neogenesis in vitro. The pres- 9). We wished to strengthen the conclusion by using an ex- ence ofE4 at 21 jg/ml was required to impede the development perimental design that avoids the complexities inherent in work of normal numbers of B cells with full receptor status.
    [Show full text]
  • Molecular Mechanisms of CD4+ T-Cell Anergy
    FOCUS ON IMMUNE TOLERANCEREVIEWS Molecular mechanisms of CD4+ T-cell anergy C. Garrison Fathman and Neil B. Lineberry Abstract | Directing both innate and adaptive immune responses against foreign pathogens with correct timing, location and specificity is a fundamental objective for the immune system. Full activation of CD4+ T cells requires the binding of peptide–MHC complexes coupled with accessory signals provided by the antigen-presenting cell. However, aberrant activation of the T-cell receptor alone in mature T cells can produce a long-lived state of functional unresponsiveness, known as anergy. Recent studies probing both immune signalling pathways and the ubiquitin–proteasome system have helped to refine and elaborate current models for the molecular mechanisms underlying T-cell anergy. Controlling anergy induction and maintenance will be a key component in the future to mitigate unwanted T-cell activation that leads to autoimmune disease. Central tolerance ‘The highest result of education is tolerance.’ This cell-intrinsic state of unresponsiveness, subse- The lack of self-responsiveness Helen Keller quently termed clonal T-cell anergy, was shown to be that occurs during lymphocyte long-lived, associated with defects in cell-cycle progres- development in the central In the complex matrix of an immune response, toler- sion and some effector function, and reversible with lymphoid organs. B-cell progenitors in the bone ance to self allows the identification and elimination of strong stimuli. marrow and T-cell progenitors non-self pathogens while simultaneously minimizing Due to the many different experimental conditions in the thymus that strongly bystander damage to the host. To help accomplish this and model systems used, it has been difficult to build recognize self antigen either immense task, the immune system has a series of con- a cohesive mechanistic model of clonal T-cell anergy.
    [Show full text]
  • 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.
    [Show full text]
  • Differentiation of Th1 Cells Expansion but Fails to Prevent the Peripheral
    Peripheral Immune Tolerance Blocks Clonal Expansion but Fails to Prevent the Differentiation of Th1 Cells This information is current as Erika-Nell Malvey, Marc K. Jenkins and Daniel L. Mueller of September 23, 2021. J Immunol 1998; 161:2168-2177; ; http://www.jimmunol.org/content/161/5/2168 Downloaded from References This article cites 55 articles, 29 of which you can access for free at: http://www.jimmunol.org/content/161/5/2168.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • 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 23, 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 © 1998 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Peripheral Immune Tolerance Blocks Clonal Expansion but Fails to Prevent the Differentiation of Th1 Cells1 Erika-Nell Malvey,* Marc K. Jenkins,† and Daniel L. Mueller2* Clonal anergy in Ag-specific CD41 T cells is shown in these experiments to inhibit IL-2 production and clonal expansion in vivo. We also demonstrate that the defect in IL-2 gene inducibility can be achieved in both naive and Th1-like memory T cells when repeatedly exposed to aqueous peptide Ag.
    [Show full text]
  • Human T-Cell Clonal Anergy Is Induced by Antigen Presentation in the Absence of B7 Costimulation CLAUDE D
    Proc. Natl. Acad. Sci. USA Vol. 90, pp. 6586-6590, July 1993 Immunology Human T-cell clonal anergy is induced by antigen presentation in the absence of B7 costimulation CLAUDE D. GIMMItt, GORDON J. FREEMANtt, JOHN G. GRIBBENtt, GARY GRAY§, AND LEE M. NADLERt* tDivision of Tumor Immunology, Dana-Farber Cancer Institute, and tDepartments of Medicine and Pathology, Harvard Medical School, Boston, MA 02115; and §Repligen Corporation, Cambridge, MA 02139 Communicated by Stuart F. Schlossman, April 12, 1993 (receivedfor review February 19, 1993) ABSTRACT The maximal T-cell response to its antigen pathway appears to be central to the induction of peripheral requires presentation of the antigen by a major histocompat- T-cell tolerance. (i) Anti-CD28 mAb could block the induc- ibility complex class II molecule as well as the delivery of one tion of anergy in murine T-cell clones (18). (ii) Blocking the or more costimulatory signals provided by the antigen- CD28/CTLA4-B7 pathway by the in vivo administration of presenting cell (APC). Although a number of candidate mol- the recombinant (r) CTLA4-immunoglobulin (Ig) fusion pro- ecules have been identified that are capable of delivering a tein prolonged xenogeneic pancreatic-islet-cell graft survival costimulatory signal, increasing evidence suggests that one in mice and resulted in the induction of long-term antigen- such critical pathway involves the interaction of the T-cell specific tolerance (19). surface antigen CD28 with its ligand B7, expressed on APCs. In the present report, we demonstrate in an antigen- In view ofthe number ofpotential costimulatory molecules that specific model that antigen presentation by MHC class II might be expressed on the cell surface of APCs, artificial APCs molecules in the absence of B7 costimulation results in were constructed by stable transfection of NIM 3T3 cells with human T-cell clonal anergy.
    [Show full text]