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PubMed1994

New biologic immunosuppressive agents in transplantation.

Antigen-specific immunologic nonresponsiveness (tolerance) to alloantigens is a goal in transplantation. Most successful strategies of tolerance induction target the T cell. Activation of a quiescent T cell requires two different signals. Signal 1 is delivered when the T-cell receptor is engaged by foreign antigen presented by major histocompatibility complex molecules. Several potential pathways exist to deliver signal 2, which is also termed a costimulatory signal, although by far the best characterized pathway is through the T-cell co-receptor CD28. Blockade of either signal 1 or signal 2 may be sufficient to induce tolerance to alloantigens. Recent advances in knowledge of T-cell receptor-major histocompatibility complex interactions, in mechanisms of self-tolerance and in the identity and importance of costimulatory receptors and their ligands, have led to the development of various new strategies to block signals 1 and 2 using biologic agents. This review focuses on the most promising new modalities.

Animals↗
PubMed2004

Induction of tolerance using Fas ligand: a double-edged immunomodulator.

Apoptosis mediated by Fas ligand (FasL) interaction with Fas receptor plays a pivotal regulatory role in immune homeostasis, immune privilege, and self-tolerance. FasL, therefore, has been extensively exploited as an immunomodulatory agent to induce tolerance to both autoimmune and foreign antigens with conflicting results. Difficulties associated with the use of FasL as a tolerogenic factor may arise from (1) its complex posttranslational regulation, (2) the opposing functions of different forms of FasL, (3) different modes of expression, systemic versus localized and transient versus continuous, (4) the level and duration of expression, (5) the sensitivity of target tissues to Fas/FasL-mediated apoptosis and the efficiency of antigen presentation in these tissues, and (6) the types and levels of cytokines, chemokines, and metalloproteinases in the extracellular milieu of the target tissues. Thus, the effective use of FasL as an immunomodulator to achieve durable antigen-specific immune tolerance requires careful consideration of all of these parameters and the design of treatment regimens that maximize tolerogenic efficacy, while minimizing the non-tolerogenic and toxic functions of this molecule. This review summarizes the current status of FasL as a tolerogenic agent, problems associated with its use as an immunomodulator, and new strategies to improve its therapeutic potential.

Animals↗
PubMed1992

Cyclosporine A and peripheral tolerance. Inhibition of veto cell-mediated clonal deletion of postthymic precursor cytotoxic T lymphocytes.

Veto cell-mediated suppression of CTL responses has been proposed as one mechanism by which self tolerance is maintained in mature T cell populations. We have reported that murine bone marrow cells cultured in the presence of high-dose IL-2 (activated bone marrow cells) mediate strong veto suppressor function in vitro and in vivo, and that such veto activity is effected through clonal deletion of cytotoxic T cell precursors. In our studies, we have determined that bone marrow cell populations from athymic NCr-nu mice (H-2d) mediate strong veto cell activity without exposure to exogenous IL-2 in vitro. To examine mechanisms by which these naturally occurring veto cell populations in BM suppress precursor CTL (pCTL) responses, we used as a responding cell population in MLC, spleen cells of transgenic mice expressing at high frequency TCR specific for H-2 Ld encoded Ag with stimulation by H-2d-expressing cells in culture. Flow cytometric analysis was performed by staining the responding MLC cell population with the mAb 1B2 specific for the transgene-encoded TCR and determined changes of 1B2+ T cells. Such experiments demonstrated that the anti-H-2d cytotoxic response by these cell populations was specifically suppressed by NCr-nu (H-2d) bone marrow, and that 1B2+ pCTL were in fact specifically deleted from the responding cell population by incubation with such naturally occurring veto cell populations expressing the appropriate target Ag. In addition, to further understand the interactions of pCTL and veto cells and possible contributions by the latter to peripheral tolerance, we evaluated the effect of cyclosporine A (CsA) on veto cell-mediated suppression of pCTL of the transgenic mice. CsA inhibited veto cell-mediated suppression of cytotoxic T cell responses, and this inhibition correlated with a lack of clonal deletion of pCTL by veto cells in the presence of CsA. Furthermore, CsA exerted its effect through pCTL and not through veto cells, indicating that pCTL may play an active role in their own deletion by veto cells.

Animals↗
PubMed1992

The use of a non-depleting anti-CD4 monoclonal antibody to re-establish tolerance to beta cells in NOD mice.

The use of immunosuppressive drugs in the management of autoimmunity penalizes a large part of the immune system for the misdemeanors of a small minority of T cells. An ideal form of therapy would be one in which it were possible to render the immune system tolerant of the inciting antigens with minimal effects on other responses. We here show that it is possible to re-establish self tolerance in an animal model of insulin-dependent diabetes mellitus without prior deletion of CD4+ T cells using a short course of therapy with a non-lytic monoclonal antibody to the CD4 adhesion receptor on T cells. This tolerance can be achieved even when diabetogenic cells are already in the pancreas. Primary responses to antigens given after therapy has ceased are normal and secondary responses to antigens seen prior to, but not during, the period of antibody therapy can remain unaffected. This suggests that intervention with selected CD4 antibodies may have significant advantages over and above that provided not only by conventional immunosuppression but also over that provided by a depleting antibody.

Animals↗
PubMed2001

T cell-specific loss of Pten leads to defects in central and peripheral tolerance.

PTEN, a tumor suppressor gene, is essential for embryogenesis. We used the Cre-loxP system to generate a T cell-specific deletion of the Pten gene (Pten(flox/-) mice). All Pten(flox/-) mice develop CD4+ T cell lymphomas by 17 weeks. Pten(flox/-) mice show increased thymic cellularity due in part to a defect in thymic negative selection. Pten(flox/-) mice exhibit elevated levels of B cells and CD4+ T cells in the periphery, spontaneous activation of CD4+ T cells, autoantibody production, and hypergammaglobulinemia. Pten(flox/-) T cells hyperproliferate, are autoreactive, secrete increased levels of Th1/Th2 cytokines, resist apoptosis, and show increased phosphorylation of PKB/Akt and ERK. Peripheral tolerance to SEB is also impaired in Pten(flox/-) mice. PTEN is thus an important regulator of T cell homeostasis and self-tolerance.

Animals↗
PubMed1995

Tolerance induction as a therapeutic strategy for the control of autoimmune endocrine disease in mouse models.

This chapter aims to describe ways in which autoimmunity can be prevented or reversed and 'self-tolerance' re-established. To this end we have largely restricted our overview to the two main autoimmune disease models with which we are involved, i.e. IDDM in NOD mice and EAT in H-2k mice although, where appropriate and to demonstrate a particular point, other models are mentioned. The chapter has been divided into sections covering protection afforded by 1) transgenes, 2) autoantigen and 3) by reagents targetting T-cell surface molecules. Where established, the mechanism by which protection or tolerance is achieved is described but where, as in most cases, it is unknown the possibilities are discussed. Investigations using T-cell lines and clones and on islet regeneration which are currently being followed as part of a comprehensive approach to the study of autoimmunity are included as separate sections and their relevance discussed.

Animals↗
PubMed2005

Dendritic cells as pharmacological targets for the generation of regulatory immunosuppressive effectors. New implications for allo-transplantation.

Dendritic cells (DCs) play a central role in the establishment of tolerance/immunity, because they activate naïve T cells (TCs). Therefore, the pharmacological modulation of DCs has become a major field of interest in immunology. A large body of literature has arisen from the studies of DC biology during immunosuppressive drug treatment. Immunosuppressive drugs have improved the therapeutic management of allograft organ transplantation and autoimmune diseases, significantly. There is now strong evidence that, DCs might be the key for antigen specific tolerance induction. Recently, the existence of a population of DCs that migrate to the regional lymph node in the steady state has been identified. Such steady state immature migrating DCs are loaded with tissue antigens and deliver self-antigens towards secondary lymphatic organs and might educate TCs towards self-tolerance. Latest experimental data from rodent solid organ allo-transplantation supports the idea, that DCs might even become regulatory DCs towards foreign antigen specific tolerance induction. Apparently, regulatory donor DCs invade host secondary lymphatic organs where they might eventually educate host TCs towards foreign antigen specific tolerance. Seemingly, it depends on the DC maturation state whether pharmacologically modulated DCs induce antigen specific long-term tolerance in allo-transplantation solid organ transplantation. Several authors reported a positive self-limiting feedback loop between tolerogenic DCs and allo-specific regulatory TCs. Thus, the DC-TC network appears as an exceptionally good target for pharmacological manipulations. Here we review how immunosuppressive agents interfere with DC maturation, migration and homeostasis. We are developing a rational to select different drugs for the generation of regulatory DCs, for allo-transplantation clinical settings.

Animals↗
PubMed2006

Peripheral antigen display by lymph node stroma promotes T cell tolerance to intestinal self.

The intestinal epithelium functions to absorb nutrients and to protect the organism against microbes. To prevent autoimmune attack on this vital tissue, T cell tolerance to intestinal self-antigens must be established. Central tolerance mechanisms involve medullary thymic epithelial cells (mTECs), which use endogenously expressed peripheral-tissue antigens (PTAs) to delete self-reactive thymocytes. The prevailing model for the induction of peripheral tolerance involves cross-presentation of tissue antigens by quiescent dendritic cells. Here we show that lymph node stromal cells present endogenously expressed PTAs to T cells. Moreover, antigen presentation by lymph node stroma is sufficient to induce primary activation and subsequent tolerance among CD8(+) T cells. Thus, lymph node stromal cells are functionally akin to mTECs and provide a direct strategy for purging the peripheral repertoire of self-reactive T cells.

Animals↗
PubMed1999

Self-reported exercise tolerance and the risk of serious perioperative complications.

BACKGROUND: Impaired exercise tolerance during formal testing is predictive of perioperative complications. However, for most patients, formal exercise testing is not indicated, and exercise tolerance is assessed by history. OBJECTIVE: To determine the relationship between self-reported exercise tolerance and serious perioperative complications. METHODS: Our study group consisted of 600 consecutive outpatients referred to a medical consultation clinic at a tertiary care medical center for preoperative evaluation before undergoing 612 major noncardiac procedures. Patients were asked to estimate the number of blocks they could walk and flights of stairs they could climb without experiencing symptomatic limitation. Patients who could not walk 4 blocks and climb 2 flights of stairs were considered to have poor exercise tolerance. All patients were evaluated for the development of 26 serious complications that occurred during hospitalization. RESULTS: Patients reporting poor exercise tolerance had more perioperative complications (20.4% vs 10.4%; P<.001). Specifically, they had more myocardial ischemia (P = .02) and more cardiovascular (P = .04) and neurologic (P = .03) events. Poor exercise tolerance predicted risk for serious complications independent of all other patient characteristics, including age (adjusted odds ratio, 1.94; 95% confidence interval, 1.19-3.17). The likelihood of a serious complication occurring was inversely related to the number blocks that could be walked (P = .006) or flights of stairs that could be climbed (P = .01). Other patient characteristics predicting serious complications in multivariable regression analysis included history of congestive heart failure, dementia, Parkinson disease, and smoking greater than or equal to 20 pack-years. CONCLUSION: Self-reported exercise tolerance can be used to predict in-hospital perioperative risk, even when using relatively simple and familiar measures.

Aged↗
PubMed1998

Nature versus nurture: contributions of developmental programming and the microenvironment to B cell tolerance.

The original Burnet Lederberg and Bretscher Cohn models of immunological tolerance are essentially incompatible, one considering tolerance to be the obligatory outcome of antigen recognition by an immature lymphocyte and the other considering it as one of two possible responses to antigen, the crucial determinant being interaction with a second antigen-reactive cell. The early experimental evidence was confusing, in that it appeared to support both theories. In response to this situation, a hybrid model retaining some of the features of the original models was proposed. In particular, immature B cells were regarded as 'hypersensitive to tolerance induction', but could also make a positive response to antigen under some circumstances. More recent data from B cell transgenic mice have challenged even these hybrid models, stimulating renewed interest in the question of how B cell tolerance is regulated in vivo. This article presents a new interpretation of the data, in which the increased resistance of mature B cells to tolerance induction is postulated to result from partial receptor desensitization in response to environmental antigen, rather than from a developmentally programmed change in B cell signalling. Thus, it is suggested that Burnet's 'window of tolerance induction' is determined by the environment rather than developmental pre-programming. If this postulate is accepted, induction of B cell self-tolerance in both the bone marrow and periphery follows the simple and elegant rules originally laid down by Bretscher and Cohn.

Animals↗
PubMed1988

Split tolerance induced by the intrathymic adoptive transfer of thymocyte stem cells.

The intrathymic transfer of semiallogeneic CD4/CD8 double-negative (DN) thymocyte stem cells into irradiated host mice resulted in a transient state of chimerism in adoptive host thymus, spleen, and lymph nodes. Host-derived T cells, isolated from the thymus and periphery of the chimeric mice, were found to be specifically nonresponsive to the MHC antigens of the semiallogeneic DN donor in cytotoxicity assays. This nonresponsiveness was not permanent, but persisted as long as appreciable numbers of Thy-1 alloantigen-positive progeny of the DN donor cells could be detected in the spleen and lymph nodes of adoptive host mice. FACS sorting of DN donor cells before intrathymic transfer indicated that nonresponsiveness could be induced by Thy-1+ cells and was therefore not attributable to contaminating thymic macrophages, dendritic cells, or B cells. When FACS-sorted Thy-1+ (bm5 x bm12)F1 DN cells were transferred intrathymically into C57BL/6 hosts, nonresponsiveness to DN donor MHC class I but not class II alloantigen (split tolerance) was observed. These experiments were repeated using FACS-sorted Thy-1+ DN donor cells that were semiallogeneic to the irradiated adoptive host at either MHC class I or class II locus with similar results. Limiting dilution analysis showed that host-derived CTL precursors were tolerant of DN donor MHC class I alloantigen and no evidence for the involvement of suppressor T cells was found. The data indicate that murine thymocytes themselves are capable of tolerizing to MHC class I but not class II alloantigen after intrathymic transfer. The implications for intrathymic T cell differentiation and maintenance of self tolerance are discussed.

Animals↗
PubMed1999

Immunological models of type 1 diabetes.

Type 1 diabetes mellitus is a serious health problem that affects several million new people each year. Although it is recognized that type 1 diabetes results from an autoimmune destruction of the insulin-producing beta-cells in the pancreatic islets of Langerhans, its etiopathogenesis is still not well understood. A certain genetic phenotype seems to be required, but it is not sufficient per se to trigger diabetes development. Numerous studies have pointed to the role of infectious agents as important environmental factors in breaking 'self'-tolerance and triggering activation of autoreactive T cells. Activated T cells, in turn, destroy target cells harboring the corresponding tissue-specific self-antigen, causing organ damage and loss of function. Several theories have been proposed to explain how environmental factors can initiate and/or perpetuate autoimmunity towards pancreatic beta-cells.

Amino Acid Sequence↗
PubMed2000

Transplantation tolerance: mechanisms and strategies?

The goal of transplantation is to induce tolerance to the transplanted tissue. We believe that this will only be possible by exploring strategies normally used to endure and maintain self-tolerance. Tolerance can be defined as a state where the immune system does not respond to a specific antigen. This is in sharp contrast with immunosuppression, which decreases the immune response to a myriad of antigens and requires continued medication. T cells play an essential role in the immune response to alloantigens, because animals devoid of T cells do not reject transplanted organs. In this article we will focus on the mechanism of T cell tolerance and how the immune system may be manipulated to achieve tolerance to alloantigens.

Animals↗
PubMed2001

Unanswered questions in arsenic toxicology.

Arsenic (As) is one of the most important environmental global toxicants. In various countries and for decades people have been and currently are exposed to inorganic As through geogenically contaminated drinking water. An increased incidence of diseases mediated by this toxic element is the consequence of long-term exposure. Despite past extensive research on the toxicology of As, many questions remained unanswered, making risk assessment difficult. For instance, it is still not known how the carcinogenicity of As is mechanistically operative. Moreover, there is an increasing debate on whether the metabolic methylation of As has to be considered a detoxification process. Furthermore, it is historically documented that long-term intake of small amounts of As can lead to an acquired increased tolerance to its acute toxicity. It is not known whether this tolerance may be associated with a reduced chronic toxicity as well. In contrast to nonhuman cells, the selection of As-induced self-tolerance in human cells in vitro had been unsuccessful until now. However, we recently selected As-resistant human hepatoma HepG2 sublines that have low-level tolerance to As. Besides an approximately twofold elevated resistance to As cytotoxicity, this tolerance was associated with a significantly suppressed induction of As-mediated genotoxicity, which was evident in the cytokinesis-block micronucleus test. Additional questions arise when we consider several factors suspected to modulate the long-term toxicity of arsenic in vitro, variables that may either enhance or suppress the environmental genotoxicity and carcinogenicity of the metalloid. Besides malnutrition, these are single nutritional factors such as selenium and possible drinking water co-contaminants such as antimony. For instance, in the case of selenium, we could show that antimony (III) is able to suppress As genotoxicity. Taken together, research answers in many fields of As toxicology are needed in order to reduce the uncertainties in risk assessment of environmental As.

Antimony↗
PubMed1991

Induction of tolerance to syngeneic IgE in neonatal mice.

We have previously shown that adult A/J mice are tolerant to syngeneic IgE at the level of T cells, but not B cells. T cells of mice are responsive until the age of 2 to 3 wk, which correlates with the time of appearance of serum IgE. Tolerance can be induced earlier by neonatal administration of IgE in saline. We report here that purified nonimmune adult B cells, but not T cells, can transfer the state of tolerance to neonatal mice. As few as 2 x 10(6) B cells are effective. If IgE-bearing or IgE-secreting cells prove to be responsible, the amount of cell-bound IgE that can induce tolerance must be very small. The results also indicate that suppressor T cells do not have a major role in maintenance of self-tolerance to IgE.

Animals↗
PubMed1997

C1q binds directly and specifically to surface blebs of apoptotic human keratinocytes: complement deficiency and systemic lupus erythematosus revisited.

Complete deficiency of C1q is almost invariably associated with the development of systemic lupus erythematosus. It has been suggested that this association may result from a generalized failure to clear Ag-Ab complexes. However, it has not been demonstrated how such a broad impairment results in this specific and consistent autoimmune phenotype, in which photosensitive skin disease is the most prominent manifestation. We believe there is another role for the classical pathway in maintaining immune tolerance. Surface blebs of apoptotic keratinocytes are concentrated sources of autoantigens, and these packages may define a novel immune context and challenge self-tolerance if not properly cleared and processed. We demonstrate here that when human keratinocytes are rendered apoptotic, they also develop the capacity to specifically and directly bind to C1q in the absence of Ab. C1q may mediate Ab-independent clearance of apoptotic keratinocytes, and prevent immunization with autoantigens of cutaneous origin.

Apoptosis↗
PubMedDate not supplied

Incomplete tolerance induced in Xenopus by larval tissue allografting: evidence from immunohistology and mixed leucocyte culture.

Application of adult skin allografts to Xenopus larvae has been a favoured protocol for probing the development of self-tolerance. A more physiologic approach is presented here that examines the immunologic outcome of grafting semi- or fully allogeneic larval skin or spleen to age-matched, larval Xenopus (X. laevis/X. gilli clonal hybrids). Following such grafting at 2 or 4 weeks-of-age, young froglets (4-5-months-old) are generally unable to reject second-set skin transplants, but destroy third-party skin vigorously, the MHC class II-rich spleen proving especially effective at inducing this tolerance. In contrast, following larval grafting of semiallogeneic tissues, mixed leucocyte culture performed at the end of metamorphosis (6 weeks) and again at 6 months reveals splenocyte reactivity toward donor-strain stimulators. Immunohistological findings extend this observation of anti-donor reactivity (suggesting incomplete tolerance) to the graft site. Thus despite excellent health when viewed externally, apparently tolerated second-set skin transplants display localised infiltration (especially into the epidermis) by CD8+ T cells and increased numbers of MHC class I and II-expressing cells by 3 weeks post-grafting. The immunologic implications of these findings are discussed.

Animals↗