DOCSLIB.ORG

The Tunable Activation Threshold and the Significance of Subthreshold Responses (Context Dis Nation/Autoreavity/Meanr/M Oy Units) Zvi GROSSMAN*T and WILLIAM E

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Tunable Activation Threshold and the Significance of Subthreshold Responses (Context Dis Nation/Autoreavity/Meanr/M Oy Units) Zvi GROSSMAN*T and WILLIAM E Proc. Natl. Acad. Sci. USA Vol. 89, pp. 10365-10369, November 1992 Immunology Adaptive cellular interactions in the immune system: The tunable activation threshold and the significance of subthreshold responses (context dis nation/autoreavity/meanr/m oy units) Zvi GROSSMAN*t AND WILLIAM E. PAULt *Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; and tLaboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 Contributed by William E. Paul, July 21, 1992 ABSTRACT A major challenge for Immunologists is to (iv) Memory: Static or dynamic? Memory cells show signs explain how the immune system adjusts its responses to the of activation but undergo limited division before challenge. microenvironmental context in which antigens are roi. Their inherent longevity has been questioned, but whether We propose that lymphocytes achieve this by tuning and they require continued stimulation by residual antigen re- updating their responsiveness to rcurrent signals. In partic- mains unresolved (6). ular, cellular anergy in vivo is a dynamic state in which the (v) The in vivo/in vitro dichotomy. Recent experiments in threshold for a stereotypic mode of activation has been ele- which animals are rendered deficient in specific genes have vated. Anergy is associated with other formsofcellular activity, provided some surprises. Interleukins 2- and 4-deficient mice not paralysis. Cells engaged in such subthreshold interactions appear surprisingly normal (7, 8). In transgenic mice over- mediate functions such as maintenance ofimmu l mem- expressing major histocompatibility complex (MHC) class II ory and control of infections. In such interactions, patterns of antigens, immune responses were largely unaffected and signals are recognized and ciasied and evoke selective re- there was no indication ofuncontrolled lymphoproliferation, sponses. The robust mechanis proposed for segregation of immunodeficiency, or autoimmunity (9). Finally, anergy as suprathreshold and subthreshold immune responses allows assayed in vitro correlated in some cases in vivo with memory lymphocytes to use recognition of self-antigens in executing (10) and activation (11) rather than tolerance. physiological functions. Autoreactivity is allowed where it is (vi) Complexity ofsignaling. Many peptide factors, includ- dissociated from uncontrolled on. ing lymphokines, are multifunctional, have a broad range of target cells, and the activity of one peptide in a single cell Despite the major contributions of molecular and cellular depends on the other signal molecules present (12). More- immunology, the physiological rules of immunity are poorly over, the existence of bidirectional communication between understood (1). Consequently, progress achieved in autoim- the immune system and the hemopoietic and neuroendocrine mune diseases, transplantation tolerance, allergy, and systems is now established. There is a growing schism (13) chronic infectious diseases has been limited (2). Some of the between the broadening scope of physiologic connections unresolved issues are listed below. and the traditional concept of antigen-oriented lymphocytes (i) The enigma of autoreactivity and anergy. There is that function as the specialized members of a stereotypical benign autoreactivity in healthy individuals, and the presence defense system. Why should lymphocytes, with their clonally of autoreactive lymphocytes is pronounced during infection distributed receptors for antigens, require so rich and so (3). Therefore, self/nonself discrimination may be much intricate communication among themselves and with other more complex than the simple failure of competent lympho- cells? cytes to recognize self-antigens. (vii) How does the immune system discriminate antigens by Cellular unresponsiveness (anergy) has been proposed as a context? There is a rich repertoire of cellular responses, major self-tolerance mechanism in addition to clonal deletion mediated by different molecules and their combinations, (4, 20, 27, 29). Natural autoreactivity could be ascribed to ranging from direct killing of the antigen-bearing cells to the cells that have escaped both mechanisms. However, the activation, or inactivation, of these cells and/or other lym- orderly nature of autoreactivity needs to be explained: the phocytes and accessory cells. The selection of a particular targets of both benign autoreactivity and autoimmunity in response depends not only on the nature and quantity of the different individuals are not random, but restricted and antigen, but also on the tissue and site of encounter and on predictable (5). The very concept ofanergy as a self-tolerance other cofactors. An illustration is provided by the striking mechanism is problematic: one might expect that the number differences in the response to the antigens ofMycobacterium of autoreactive cells, potentially the cause of autoimmunity, leprae in tuberculoid and lepromatous leprosy (14). The should be reduced to a minimum. immune system appears to recognize and classify different (ii) Multiclonal activity. The extensive involvement in patterns ofsignals, even within the same tissue. The respond- specific immune responses of clones that lack receptors for ing cells, in turn, differ in the pattern of cytokines they the immunogen has not been satisfactorily explained. It is secrete and in the effector functions they execute, both often attributed to so-called bystander effects, to progression individually and collectively. The explanation, in terms ofthe of idiotypic signals along a network, or to other pathological properties of individual cells, of how the immune system effects. adjusts its response to the environmental context in which (iii) Suppression. Attempts to formulate the principles antigen is recognized is a major challenge. underlying the interplay of suppression and help have been The unresolved questions listed above are taken as indi- limited. The issue ofthe controversial suppressor cells is still cations that currently accepted hypotheses may be suscep- confusing. tible to modification. The following analysis is an attempt to The publication costs ofthis article were defrayed in part by page charge Abbreviations: TAT, tunable activation threshold; TCR, T-cell re- payment. This article must therefore be hereby marked "advertisement" ceptor; APC, antigen presenting cell; MHC, major histocompatibility in accordance with 18 U.S.C. §1734 solely to indicate this fact. complex. 10365 Downloaded by guest on October 2, 2021 10366 Immunology: Grossman and Paul Proc. Natl. Acad Sci. USA 89 (1992) examine the logical consequences of varying the presuppo- The Tunable Activation Threshold (TAT) Model sitions about the nature of immunological functions by way of deductive reasoning. Let us assume that the direct effect on a cell of an external stimulus is changing the metabolic state of the cell in a way The Adaptable Lymphocyte Hypothesis: Presuppositions that can be expressed in quantitative terms. The metabolic change will be referred to as excitation and it is assumed, for Infection can, in theory, sneak through classical immunolog- simplicity, that there is a (positive) scalar measure, termed ical surveillance if its progression is gradual (15-17). Typical excitation level, of this excitation. of many real-life infections is a fast initial increase in antigen Two classes of models may be proposed: balance-of- concentration. It is this kinetic aspect that leads, partly due growth models (15-17) and cell-tuning models. Both regard to time delays along the feedback loops that regulate the the lymphocyte as a multistate system with alternative state immune response at the cell population level, to an overshoot transition pathways, e.g., (i) maintenance: rest -) excitation in the number of effectors and to effective elimination of the rest; (ii) self-renewal: rest -+ excitation proliferation antigen (15-17). (=self-renewal) -+ rest; (iii) activation: rest excitation On the other hand, a destructive immune response aimed proliferation (=amplification) -* differentiation. at the elimination of all antigen-bearing cells may be unde- Only the third process is defined as activation: induction of sirable in the case ofa slow but widespread infection. In such proliferation and (stepwise) differentiation of at least some cases of chronic infection, or residual infection (when the progeny. Balance-of-growth models are concerned with the initial growth burst of infectious agent has been controlled), balance between processes ii and iii, whereas cell-tuning different modes of resistance are required in which patterns models focus on i and ii and their dynamic segregation from of signals are recognized and classified and selective re- iii. sponses are evoked. We shall loosely refer to this class of While balance-of-growth models emphasize Darwinian- responses as environment regulated to underscore their type selection and the proliferation-differentiation interplay, adaptability. These responses are characterized by a variety more recent evidence has indicated that cell viability can be oflocally applied effector and regulatory functions and a fine promoted independently of growth (19) and that processes discrimination of antigenic stimuli based on the associated such as thymic selection of T lymphocytes, during a critical signals (the context). The functions could be implemented by phase, or memory cell maintenance do not involve
Load more

Recommended publications
  • Pathway in the Thymus by a CD24-Dependent Autoreactive T
    Autoreactive T Cells Escape Clonal Deletion in the Thymus by a CD24-Dependent Pathway This information is current as Joseph W. Carl, Jr., Jin-Qing Liu, Pramod S. Joshi, Hani Y. of September 27, 2021. El-Omrani, Lijie Yin, Xincheng Zheng, Caroline C. Whitacre, Yang Liu and Xue-Feng Bai J Immunol 2008; 181:320-328; ; doi: 10.4049/jimmunol.181.1.320 http://www.jimmunol.org/content/181/1/320 Downloaded from References This article cites 54 articles, 18 of which you can access for free at: http://www.jimmunol.org/content/181/1/320.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 by guest on September 27, 2021 *average 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 © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Autoreactive T Cells Escape Clonal Deletion in the Thymus by a CD24-Dependent Pathway1 Joseph W. Carl, Jr.,* Jin-Qing Liu,* Pramod S.
    [Show full text]
  • Natural Killer T Cells Are Required for the Development of a Superantigen-Driven T Helper Type 2 Immune Response in Mice
    IMMUNOLOGY ORIGINAL ARTICLE Natural killer T cells are required for the development of a superantigen-driven T helper type 2 immune response in mice Auro Nomizo,1 Edilberto Postol,2 Summary Raquel de Alencar,2 Fabı´ola We show, here, that one single injection or weekly injections of staphylo- Cardillo2 and Jose´ Mengel2 coccal enterotoxin B (SEB), starting in 1-day-old newborn mice, induced 1Department of Clinical Analysis, Toxicology a powerful immune response with a T helper type 2 (Th2) pattern, as and Bromatology, Faculty of Pharmaceutical Sciences of Ribeira˜o Preto, University of Sa˜o judged by the isotype and cytokine profile, with the production of large Paulo, Ribeira˜o Preto, and 2Department of amounts of SEB-specific immunoglobulin G1 (IgG1), detectable levels of Immunology, Institute of Biomedical Sciences, SEB-specific IgE and increased production of interleukin-4 by spleen cells. University of Sa˜o Paulo, Sa˜o Paulo, SP, Brazil These protocols also induced an increase in the levels of total IgE in the serum. Memory of SEB was transferred to secondary recipients by using total spleen cells from primed animals. The secondary humoral response in transferred mice was diminished if spleen cells from SEB-treated mice were previously depleted of CD3+ or Vb8+ T cells or NK1.1+ cells. In vivo depletion of NK1.1+ cells in adult mice resulted in a marked reduction in the SEB-specific antibody response in both the primary and secondary doi:10.1111/j.1365-2567.2005.02215.x immune responses. Additionally, purified NK1.1+ T cells were able to per- Received 11 April 2005; revised 23 May 2005; form SEB-specific helper B-cell actions in vitro and in vivo.
    [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]
  • Proapoptotic Protein Bim Is Differentially Required During Thymic Clonal Deletion to Ubiquitous Versus Tissue-Restricted Antigens
    Proapoptotic protein Bim is differentially required during thymic clonal deletion to ubiquitous versus tissue-restricted antigens Alexander Y. W. Suen and Troy A. Baldwin1 Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada T6G 2S2 Edited by Michael J. Bevan, University of Washington, Seattle, WA, and approved December 8, 2011 (received for review September 8, 2011) Positive and negative selection of thymocytes in the thymus are positively selected by high-affinity antigen encounter in the thy- critical for the development of a mature and self-tolerant T-cell mus (6). One such example are T-regulatory (Treg) cells, which repertoire. The proapoptotic Bcl-2 family member Bim is important are believed to require high-affinity interactions to develop in the for negative selection by inducing apoptosis in thymocytes receiv- medulla (7). It remains unknown what drives this distinction ing a strong signal through their antigen receptor. However, in the between negative selection and Treg development, although case of ubiquitous self-antigens (UbA), Bim is not required for the secondary signals, such as TGF-β, may play a role in overcoming clonal deletion of self-reactive thymocytes, suggesting the exis- cell death (8). tence of nonapoptotic clonal deletion mechanisms. Unlike UbA, Although it is unclear how the same TCR can transduce a sig- clonal deletion to tissue-restricted antigens (TRAs) requires posi- nal for positive or negative selection, differential mitogen-acti- tive selection and CCR7-mediated migration to the medulla. This vated protein kinase signaling appears to play a role, ultimately led us to hypothesize that Bim is required for the latter.
    [Show full text]
  • Coordination of T Cell Activation and Migration Through Formation of the Immunological Synapse
    Coordination of T Cell Activation and Migration through Formation of the Immunological Synapse MICHAEL L. DUSTIN Program in Molecular Pathogenesis, Skirball Institute of Biomolecular Medicine and the Department of Pathology, New York University School of Medicine, New York, New York 10016, USA ABSTRACT: T cell activation is based on interactions of T cell antigen receptors with MHC-peptide complexes in a specialized cell–cell junction between the T cell and antigen-presenting cell—the immunological synapse. The immunolog- ical synapse coordinates naïve T cell activation and migration by stopping T cell migration with antigen-presenting cells bearing appropriate major histo- compatibility complex (MHC) peptide complexes. At the same time, the immu- nological synapse allows full T cell activation through sustained signaling over a period of several hours. The immunological synapse supports activation in the absence of continued T cell migration, which is required for T cell activa- tion through serial encounters. Src and Syk family kinases are activated early in immunological synapse formation, but this signaling process returns to the basal level after 30 min; at the same time, the interactions between T cell re- ceptors (TCRs) and MHC peptides are stabilized within the immunological synapse. The molecular pattern of the mature synapse in helper T cells is a self- stabilized structure that is correlated with cytokine production and prolifera- tion. I propose that this molecular pattern and its specific biochemical constit- uents are necessary
    [Show full text]
  • T-Cell Tolerance by Prof. Anand Prakash
    PROF. ANAND PRAKASH Department of Biotechnology Mahatma Gandhi Central University Motihari Bihar • Immature T-Cells enter in the thymus after differentiating in the bone marrow. • These T-cells undergo maturation and develop TCRs through Somatic Recombination. Bone Marrow Precursors of the T-Cells enter from Bone marrow to THYMUS thymus T Cell Maturation starts Expression of TCR s • DEVELOPMENT OF T-CELL RECEPTORS (TCRs) Some of T-Cells in the thymus develop receptors which are useless with no antigen specificity and while others develop TCRs with • specificity for self antigens and non-self antigens. Thymocytes having TCRs with low affinity for auto antigens, displayed in the MHC class I and II, undergo positive selection and further differentiate to become part of adaptive immunity, whereas the one with non-functional receptors die off because of • negligence. Clonal deletion of T-cells with useless TCRs and high affinity receptors along with clonal diversion for development of “Treg”, are the major processes operative in the thymus towards elimination or regulation of self-reactive T cells. INSIDE THE THYMUS THE T-CELLS UNDERGO AN ELABORATE SCREENING PROCEDURE3 THROUGH FOLLOWING MECHANISMS • • • T CELLS RECOGNIZE ANTIGEN DERIVED PEPTIDES PRESENTED BY MHC MOLECULES MHC Class II MHC Class I Antigen Infected or Presenting Tumour Cell Cell CD8 Peptide CD4 CD4+ CD8+ Helper Cell Cytotoxic T Cell T Cell Receptor T Cell Receptor T CELLS RECOGNIZE ANTIGEN DERIVED PEPTIDES PRESENTED BY MHC MOLECULES Inside Thymus THYMIC T -CELL FATE IS DETERMINED BY STRENGTH OF TCR-MHC/PEPTIDE INTERACTION Thymic MHC stromal Cell Thymic T Cell TCR + CD4 CD8 • NEGATIVE SELECTION Negative selection occurs at the Double positive stage in the thymic cortex, or at the Single Positive stage in the thymic medulla.
    [Show full text]
  • The New Aspects of Aminoacyl-Trna Synthetases
    Vol. 47 No. 3/2000 821–834 QUARTERLY Review The new aspects of aminoacyl-tRNA synthetases. Maciej Szymañski, Marzanna Deniziak and Jan Barciszewski½ Institute of Bioorganic Chemistry of the Polish Academy of Sciences, 60-704 Poznañ, Poland Received: 29 December, 1999; revised: 24 May, 2000; accepted: 02 June, 2000 Key words: aminoacylation, aminoacyl-tRNA synthetases, protein biosynthesis, tRNA Aminoacyl-tRNA synthetases (AARS) are essential proteins found in all living organ- isms. They form a diverse group of enzymes that ensure the fidelity of transfer of ge- netic information from the DNA into the protein. AARS catalyse the attachment of amino acids to transfer RNAs and thereby establish the rules of the genetic code by virtue of matching the nucleotide triplet of the anticodon with its cognate amino acid. Here we summarise the effects of recent studies on this interesting family of multifunctional enzymes. The universal genetic code is established in a only components of the gene expression appa- single aminoacylation reaction of transfer ri- ratus that function at the interface between bonucleic acids (tRNAs). The reaction is nucleic acids and proteins. This leads to three catalysed by the family of aminoacyl-tRNA interesting aspects of studies on amino- synthetases (AARS) each of which activates acyl-tRNA synthetases: (i) the mechanism of an amino acid by binding to ATP and trans- amino acid recognition and chemical activa- fers it to the 3¢ end of the cognate tRNA. The tion, (ii) the specificity of tRNA recognition, conservation of the genetic code suggests that and (iii) the origin and evolution of AARS [3].
    [Show full text]
  • Lymphocyte-Activation Gene 3 (LAG-3) Immune Pathway
    Lymphocyte-Activation Gene 3 (LAG-3) About LAG-3 LAG-3 Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint receptor protein found on the cell surface of effector T cells and regulatory T cells (Tregs) and functions to control T cell response, activation and growth.1 TCR T cells are a type of white blood cell that are part of the immune system. Activation of cytotoxic T cells by antigens enables them to 1 kill unhealthy or foreign cells. Inactive T cell Antigen MHC Dendritic cell (APC) LAG-3 and LAG-3 and LAG-3 and Immune Function T Cell Exhaustion Cancer • After a T cell is activated to kill its • However, in certain situations where T • Because of its critical role in regulating target cell, LAG-3 expression is cells experience prolonged exposure to an exhaustion of cytotoxic T cells and Treg increased to turn off the immune antigen, such as cancer or chronic function, LAG-3 has become a target of response, so that the T cell does not go infection, the T cells become desensitized study in the cancer field. on to attack healthy cells.2 and lose their ability to activate and multiply in the presence of the antigen.4 • In cancer, LAG-3 expressing exhausted • Inhibition of the immune response is cytotoxic T cells and Tregs expressing accomplished through activation of • The desensitized T cell will also LAG-3 gather at tumor sites.5,6 the LAG-3 pathway, which can occur progressively fail to produce cytokines via binding of LAG-3 to a type of (proteins that assist in the immune • Preclinical studies suggest that inhibiting antigen-presenting complex called response) and kill the target cells.4 LAG-3 allows T cells to regain their MHC II.
    [Show full text]
  • Understanding the Immune System: How It Works
    Understanding the Immune System How It Works U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES NATIONAL INSTITUTES OF HEALTH National Institute of Allergy and Infectious Diseases National Cancer Institute Understanding the Immune System How It Works U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES NATIONAL INSTITUTES OF HEALTH National Institute of Allergy and Infectious Diseases National Cancer Institute NIH Publication No. 03-5423 September 2003 www.niaid.nih.gov www.nci.nih.gov Contents 1 Introduction 2 Self and Nonself 3 The Structure of the Immune System 7 Immune Cells and Their Products 19 Mounting an Immune Response 24 Immunity: Natural and Acquired 28 Disorders of the Immune System 34 Immunology and Transplants 36 Immunity and Cancer 39 The Immune System and the Nervous System 40 Frontiers in Immunology 45 Summary 47 Glossary Introduction he immune system is a network of Tcells, tissues*, and organs that work together to defend the body against attacks by “foreign” invaders. These are primarily microbes (germs)—tiny, infection-causing Bacteria: organisms such as bacteria, viruses, streptococci parasites, and fungi. Because the human body provides an ideal environment for many microbes, they try to break in. It is the immune system’s job to keep them out or, failing that, to seek out and destroy them. Virus: When the immune system hits the wrong herpes virus target or is crippled, however, it can unleash a torrent of diseases, including allergy, arthritis, or AIDS. The immune system is amazingly complex. It can recognize and remember millions of Parasite: different enemies, and it can produce schistosome secretions and cells to match up with and wipe out each one of them.
    [Show full text]
  • Clonal Deletion of Autoreactive B Lymphocytes in Bone Marrow
    Proc. Nati. Acad. Sci. USA Vol. 86, pp. 8039-8043, October 1989 Immunology Clonal deletion of autoreactive B lymphocytes in bone marrow chimeras (immunological tolerance/transgenic mice/histocompatibility complex) DAVID NEMAZEE*t AND KURT BUERKIt *Basel Institute for Immunology, Postfach CH-4005, Basel, Switzerland; and tPrecinical Research, Sandoz, Ltd., CH-4002, Basel, Switzerland Communicated by Philippa Marrack, July 24, 1989 (receivedfor review June 17, 1989) ABSTRACT To study the fate of developing B cells in the mice that either did or did not bear the H-2k antigens to which presence and absence of the autoantigens to which they react, the transgenic antibody reacts (H-2Kk and H-2Dk). chimeric mice were constructed by ij'ecting bone marrow cells A potential difficulty with studying tolerance to H-2k in our from mice transgenic for rearranged immunoglobulin genes system with genetic crosses was that, because the B cells in encoding an anti-H-2Kk antibody into irradiated recipients that the tolerant animals also bore H-2 class I antigens, it was not did or did not express the H-2Kk antigen. In the presence of clear whether it was necessary for the H-2k antigens to be H-2Kk, the anti-H-2Kk-specific B cells were deleted from the coexpressed on the transgenic B cells themselves to achieve spleen and lymph nodes, whereas in its absence, anti-H-2Kk tolerance. In this report we describe the tolerance phenotype cells were abundant. B cells bearing a low level of membrane of irradiation bone marrow chimeras in which anti-H-2k immunoglobulin with the anti-H-2Kk idiotype were found in the transgenic B cells that lack the H-2k antigens develop in hosts bone marrows of H-2Kk recipients, suggesting that clonal that bear or do not bear H-2k antigens.
    [Show full text]
  • Immune Regulation and Tolerance
    Mechanisms of unresponsiveness: Immunological Ignorance Immune Regulation Normal response and Proliferation and Tolerance differentiation Mechanisms of Antigen/lymphocyte barrier unresponsiveness Mechanisms of Tissue abnormalities contributing to release and Yong-Rui Zou (Oct. 2005) autoimmunity presentation of self antigens. [email protected] Disease models Sympathetic ophthalmia, experimental allergic encephalomyelitis (EAE) Immunoregulation: A balance between activation and Mechanisms of unresponsiveness: suppression of effector cells to achieve an efficient Central tolerance in B and T cells (I): Clonal Deletion immune response without damaging the host. Self antigen presented in generative Activation (immunity) Suppression (tolerance) lymphoid Deletion of immature organs lymphocytes strongly recognizing self antigens autoimmunity immunodeficiency present in generative organs Lymphoid precursor Significance: The induction of tolerance may be Survival of clones which are only moderately exploited to prevent graft rejection, to treat autoimmune responsive to self antigens and allergic diseases, and to prevent immune responses present in generative in gene therapy. organs; forms T/B cell repertoire Important features of immunoregulation: 1. Antigen specific; affects T or B lymphocytes Science 298:1395 (2002) 2. Tolerance vs. activation? Determined by the nature of antigen and associated stimuli, and when and where the antigen is encountered Immunity 23:227 (2005) 1 Mechanisms of unresponsiveness: AIRE: Autoimmune regulator. Peripheral tolerance in B cells (I): Anergy Immunogenic signaling Tolerogenic signaling • Transcription factor. • Expressed at a high level by thymic medullar epithelium Acute Chronic cells. antigens antigens CD40L • Autosomal recessive mutation leads to autoimmune LPS polyendocrine syndrom - type 1 (APS-1). CD40 CD40 TLR4 • Inactivation of aire abolishes expression of some tissue TLR4 BCR BCR Fcγ2b specific genes in the thymic medulla.
    [Show full text]
  • An in Vitro Approach to Detect Metabolite Toxicity Due to CYP3A4
    Toxicology 216 (2005) 154–167 An in vitro approach to detect metabolite toxicity due to CYP3A4-dependent bioactivation of xenobiotics Luisella Vignati ∗, Elisa Turlizzi 1, Sonia Monaci, Pietro Grossi, Ruben de Kanter, Mario Monshouwer 2 Department of Pre-Clinical Development, Nerviano Medical Sciences S.r.l., V.le Pasteur, 10, 20014, Nerviano, MI, Italy Received 22 June 2005; received in revised form 3 August 2005; accepted 3 August 2005 Available online 19 September 2005 Abstract Many adverse drug reactions are caused by the cytochrome P450 (CYP) dependent activation of drugs into reactive metabolites. In order to reduce attrition due to metabolism-mediated toxicity and to improve safety of drug candidates, we developed two in vitro cell-based assays by combining an activating system (human CYP3A4) with target cells (HepG2 cells): in the first method we incubated microsomes containing cDNA-expressed CYP3A4 together with HepG2 cells; in the second approach HepG2 cells were transiently transfected with CYP3A4. In both assay systems, CYP3A4 catalyzed metabolism was found to be comparable to the high levels reported in hepatocytes. Both assay systems were used to study ten CYP3A4 substrates known for their potential to form metabolites that exhibit higher toxicity than the parent compounds. Several endpoints of toxicity were evaluated, and the measurement of MTT reduction and intracellular ATP levels were selected to assess cell viability. Results demonstrated that both assay systems are capable to metabolize the test compounds leading to increased toxicity, compared to their respective control systems. The co-incubation with the CYP3A4 inhibitor ketoconazole confirmed that the formation of reactive metabolites was CYP3A4 dependent.
    [Show full text]