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Lucienne Chatenoud

Publications and source records attributed to Lucienne Chatenoud.

35 records · Page 2Linked to original sources
PubMed2005

Monoclonal antibody-based strategies in autoimmunity and transplantation.

Monoclonal antibodies are homogeneous sets of immunoglobulins with well-defined specificity and biochemical characteristics. They were introduced into clinical practice in the early 1980s, and since then their use has rapidly expanded. Most of the side effects observed with first-generation murine (mouse or rat) antibodies have been successfully overcome with the advent of humanized (chimeric or CDR-grafted) and more recently fully human antibodies. Our aim is to review the major steps in the development of therapeutic monoclonal antibodies in the fields of transplantation and autoimmunity, and discuss the salient features of antibodies presently used in the clinic--notably anti-T-cell and anticytokine antibodies. The discussion will also focus on the unique capacity of some monoclonal antibodies to induce immune tolerance.

Animals↗
PubMed2005

Resetting the functional capacity of regulatory T cells: a novel immunotherapeutic strategy to promote immune tolerance.

Over the last few years, there has been a re-emergence of the concept of suppressor/regulatory T cells among the central players of immune mechanisms controlling a wide variety of immune responses from physiological autoreactivity (i.e., response to self-antigens) to responses to transplants, tumours and infectious antigens. Regulatory T cells are diverse in their phenotypes, antigen specificity, mode of action and immunopathological relevance. This review briefly summarises studies from the authors' group showing that specialised subsets of regulatory T cells are instrumental in the control of autoimmune diseases and more specifically of Type 1 diabetes. In addition, this review will provide evidence supporting the notion that CD3-specific monoclonal antibodies are representatives of a new category of immunotherapeutic agents that possess the unique capacity to promote immunological tolerance (an antigen-specific unresponsiveness in the absence of long-term generalised immunosuppression) through their ability to induce immunoregulatory T cells.

Animals↗
PubMed2005

Treatment with granulocyte colony-stimulating factor prevents diabetes in NOD mice by recruiting plasmacytoid dendritic cells and functional CD4(+)CD25(+) regulatory T-cells.

Accumulating evidence that granulocyte colony-stimulating factor (G-CSF), the key hematopoietic growth factor of the myeloid lineage, not only represents a major component of the endogenous response to infections, but also affects adaptive immune responses, prompted us to investigate the therapeutic potential of G-CSF in autoimmune type 1 diabetes. Treatment with G-CSF protected NOD mice from developing spontaneous diabetes. G-CSF triggered marked recruitment of dendritic cells (DCs), particularly immature CD11c(lo)B220(+) plasmacytoid DCs, with reduced costimulatory signal expression and higher interferon-alpha but lower interleukin-12p70 release capacity than DCs in excipient-treated mice. G-CSF recipients further displayed accumulation of functional CD4(+)CD25(+) regulatory T-cells that produce transforming growth factor-beta1 (TGF-beta1) and actively suppressed diabetes transfer by diabetogenic effector cells in secondary NOD-SCID recipients. G-CSF's ability to promote key tolerogenic interactions between DCs and regulatory T-cells was demonstrated by enhanced recruitment of TGF-beta1-expressing CD4(+)CD25(+) cells after adoptive transfer of DCs isolated from G-CSF- relative to vehicle-treated mice into naive NOD recipients. The present results suggest that G-CSF, a promoter of tolerogenic DCs, may be evaluated for the treatment of human type 1 diabetes, possibly in association with direct inhibitors of T-cell activation. They also provide a rationale for a protective role of the endogenous G-CSF produced during infections in early diabetes.

Aging↗
PubMed2005

Autoimmune diabetes onset results from qualitative rather than quantitative age-dependent changes in pathogenic T-cells.

Diabetogenic T-cells can be detected in pre-diabetic nonobese diabetic (NOD) mice after transfer in NOD-SCID recipients. Here we demonstrate that 6-week-old pre-diabetic NOD mice, >2 months before disease onset, already harbor pathogenic T-cells in equal numbers to overtly diabetic animals. The delay in diabetes appearance is explained by the presence of regulatory CD4+ CD25+ T-cells that control diabetogenic effectors and that are, in our hands, transforming growth factor (TGF)-beta-dependent. Our present results suggest, however, that diabetes onset is only partly explained by a decline in this regulatory T-cell activity. Another major factor appears to be the progressive resistance of diabetogenic cells to TGF-beta-dependent mediated inhibition. We propose that progression to overt disease correlates with the pathogenic T-cell's escape from TGF-beta-dependent T-cell-mediated regulation.

Adoptive Transfer↗
PubMed2004

Unique role of CD4+CD62L+ regulatory T cells in the control of autoimmune diabetes in T cell receptor transgenic mice.

Converging experimental evidence indicates that CD4(+) regulatory T cells control progression of autoimmune insulitis in nonobese diabetic (NOD) mice. Here, we studied the nature of these regulatory T cells and their mode of action in diabetes-prone NOD Rag(-/-) or severe combined immunodeficient (SCID) mice harboring a transgenic T cell receptor derived from the diabetogenic T cell clone BDC2.5. We first show that diabetes onset is prevented in such mice by infusion of polyclonal CD4(+) T cells expressing L-selectin (CD62L) but not prevented or only marginally prevented by CD4(+)CD25(+) T cells. Similarly, we found with a cotransfer model that CD4(+)CD62L(+) T cells but not CD4(+)CD25(+) T cells inhibited diabetes transfer into NOD SCID recipients by transgenic NOD BDC2.5 SCID cells. Unexpectedly, cotransfer of transgenic NOD BDC2.5 SCID cells and spleen cells from WT diabetic NOD mice did not induce diabetes, whereas each individual population did so. Data are presented arguing for the role of CD4(+)CD62L(+) T cells present within the polyclonal diabetogenic population in mediating this apparently paradoxical effect. Collectively, these data confirm the central role of CD4(+)CD62L(+) regulatory T cells in controlling disease onset in a well defined transgenic model of autoimmune diabetes and suggest the intervention of homeostatic mechanisms as part of their mode of action.

Adoptive Transfer↗
PubMed2004

Anti-CD3 antibodies: towards clinical antigen-specific immunomodulation.

Current therapeutic approaches in transplantation and autoimmunity are essentially focused on immunosuppression, which is non-specific (i.e. unrelated to the antigens involved). The major drawback is their relative ineffectiveness in the long term, with the likely risk of recurrence of the pathogenic immune process once the drug is withdrawn necessitating indefinite drug administration; this has attendant problems of recurrent infections and drug toxicity. Instead, CD3-specific monoclonal antibodies possess the unique capacity to induce immunological tolerance: an antigen-specific unresponsiveness in the absence of long-term generalised immunosuppression, as is well-established in experimental models. Clinical application using humanised non-mitogenic CD3-specific antibodies is presently underway. The future challenge will be to define the modalities allowing the widespread application of this strategy through a better understanding of the underlying immune mechanisms.

Animals↗
PubMed2003

Diversity of regulatory CD4+T cells controlling distinct organ-specific autoimmune diseases.

Depletion of selected regulatory CD4+ T cell subsets induces the spontaneous onset of various immune or autoimmune disorders. It is not clear, however, whether a given subset, notably CD4+CD25+ regulatory T cells, protects from a wide spectrum of immune disorders, or whether specialized subsets of regulatory T cells control each given disease or group of diseases. We report here, using diabetes prone nonobese diabetic (NOD) mice, that depending on the regulatory T cells that are depleted, i.e., CD25+, CD62L+, or CD45RB(low), distinct immune diseases appear after transfer into NOD severe combined immunodeficiency (SCID) recipients. Thus, reconstitution of NOD SCID mice with CD25- T cells induces major gastritis and late-onset diabetes, but no or mild colitis. Reconstitution with CD62L- T cells induces fulminant diabetes with no colitis or gastritis. Reconstitution with CD45RB(high) T cells induces major colitis with wasting disease and no or very moderate gastritis and diabetes. Major differences among the three regulatory T cell subsets are also seen in vitro. The bulk of suppressor cells inhibiting the proliferation of CD4+CD25- T cells in coculture is concentrated within the CD25+ but not the CD62L+ or CD45RB(low) T cell subsets. Similarly, cytokine production patterns are significantly different for each regulatory T cell subset. Collectively, these data point to the diversity and organ selectivity of regulatory T cells controlling distinct autoimmune diseases whatever the underlying mechanisms.

Animals↗
PubMed2003

TGF-beta-dependent mechanisms mediate restoration of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes.

CD3-specific antibodies have the unique capacity to restore self-tolerance in established autoimmunity. They induce long-term remission of overt diabetes in nonobese diabetic (NOD) mice and in human type I diabetes. The underlying mechanisms had been unclear until now. Here we report that treatment with CD3epsilon-specific antibodies induces transferable T-cell-mediated tolerance involving CD4+CD25+ cells. However, these CD4+CD25+ T cells are distinct from naturally occurring regulatory T cells that control physiological autoreactivity. CD3-specific antibody treatment induced remission in NOD Cd28-/- mice that were devoid of such regulatory cells. Remission of diabetes was abrogated by coadministration of a neutralizing transforming growth factor (TGF)-beta-specific antibody. The central role of TGF-beta was further suggested by its increased, long-lasting production by CD4+ T cells from tolerant mice. These data explain the intriguing tolerogenic effect of CD3-specific antibodies and position them as the first clinically applicable pharmacological stimulant of TGF-beta-producing regulatory CD4+ T cells.

Animals↗
PubMed2003

CD3-specific antibody-induced active tolerance: from bench to bedside.

Although they were used initially as non-specific immunosuppressants in transplantation, CD3-specific monoclonal antibodies have elicited renewed interest owing to their capacity to induce immune tolerance. In mouse models of autoimmune diabetes, CD3-specific antibodies induce stable disease remission by restoring tolerance to pancreatic beta-cells. This phenomenon was extended recently to the clinic--preservation of beta-cell function in recently diagnosed patients with diabetes was achieved by short-term administration of a CD3-specific antibody. CD3-specific antibodies arrest ongoing disease by rapidly clearing pathogenic T cells from the target. Subsequently, they promote long-term T-cell-mediated active tolerance. Recent data indicate that transforming growth factor-beta-dependent CD4+CD25+ regulatory T cells might have a central role in this effect.

Animals↗
PubMed2003

CD3 antibody treatment stimulates the functional capability of regulatory T cells.

Autoimmune diabetes progression in NOD mice is under the control of CD4+ regulatory T cells. In the thymus these regulatory cells are CD25+-like CD4+ cells shown to control physiologic organ-specific autoimmunity. In contrast, in the periphery, both CD4+CD25+ and CD4+CD25- cells exhibit regulatory capacities. We have accumulated evidence showing an important role of transforming growth factor beta (TGFbeta) in this T cell-mediated regulation in vivo. Additionally, onset of autoimmune diabetes was preceded by a functional abnormality of CD4+CD25+ regulatory T cells as assessed by their inability to suppress in vitro the proliferation of polyclonally activated CD25- T cells. Antibodies to CD3 are potent immunosuppressants now generally applied as non Fc-receptor (FcR) binding monoclonals (F(ab')2 fragments in mice and humanized Fc-mutated monoclonals in humans). They were shown to induce durable regression of overt diabetes in NOD mice by restoring self-tolerance. The data from our laboratory were the first to show that in NOD mice anti-CD3 antibodies could reverse recent onset of disease by restoring tolerance to beta cell antigens. Thus in NOD mice presenting full-blown diabetes, a five consecutive day treatment with low doses of the hamster anti-CD3 monoclonal antibody 145 2C11 induced complete and durable disease remission, within 2-4 weeks in the absence of insulin treatment. This result has led to clinical trials, presently ongoing, in recent onset type 1 diabetic patients using non FcR binding monoclonal antibodies to CD3 that are well tolerated since they are devoid of the mitogenic activity that was a hallmark of first generation CD3 antibodies such as OKT3. Concerning the mechanistic aspects, data from the NOD mouse model indicate that CD3 antibodies promote (1) immediate clearance of insulitis, followed by (2) 'resetting' of specialized subsets of immunoregulatory CD4+ T cells mediating active tolerance similar to those that control the onset of spontaneous diabetes. Our recent data show that in CD3-treated NOD mice, these immunoregulatory T cells concentrate in the CD4-CD62L+ compartment and part of the population shares the CD25 marker. Furthermore, we also obtained evidence in CD3-treated NOD for a significant increase (in the pancreatic and mesenteric lymph nodes but not in the spleen) in the proportion of CD4+CD25+CTLA4+ T cells which produce TGFbeta.

Animals↗
PubMed2002

Long-term reversal of established autoimmunity upon transient blockade of the LFA-1/intercellular adhesion molecule-1 pathway.

Transgenic models and administration of mAbs directed against the LFA-1/intercellular adhesion molecule 1 (ICAM-1) pathway have shown that these costimulatory molecules play a key role in generating effector cells mediating inflammatory responses. In this report, durable remission of recent diabetes in nonobese diabetic (NOD) mice was induced by transient expression of an immunoadhesin gene encoding the soluble form of ICAM-1 (sICAM-1/Ig). A single i.v. injection of an adenovirus vector encoding the immunoadhesin gene led to 70% diabetes remission as opposed to 0% in mice injected with a control adenovirus vector. Despite the rapid decline of sICAM-1/Ig serum levels, diabetes remission remained stable in 50% of NOD mice for >6 mo. sICAM-1/Ig expression also led to long-term protection against diabetes in prediabetic NOD mice. sICAM-1/Ig in vitro induced an agonistic effect of T cell activation in a TCR-transgenic model, increasing T cell proliferation and IL-2 secretion. Importantly, protected mice were not immunosuppressed because they rejected skin allografts normally and developed immunity against the adenovirus vector. Rather, sICAM-1/Ig induced active tolerance, as assessed by the persistence of diabetogenic T cells in protected mice and the reversal of protection by immunosuppression with cyclophosphamide.

Adenoviridae↗
PubMed2002

Nonmitogenic CD3 antibody reverses virally induced (rat insulin promoter-lymphocytic choriomeningitis virus) autoimmune diabetes without impeding viral clearance.

Treatment with nonmitogenic CD3 Ab reverses established autoimmune diabetes in nonobese diabetic mice by restoring self-tolerance, and is currently under clinical evaluation in patients presenting recent onset type I diabetes. Due to the immunosuppressive potential of this strategy, it was relevant to explore how this treatment would influence the outcome of concomitant viral infections. In this study, we used a transgenic model of virally induced autoimmune diabetes (rat insulin promoter-lymphocytic choriomeningitis virus) that allows for more precise tracking of the autoaggressive response and choice of the time point for initiation of autoimmunity. CD3 was most effective during a clearly defined prediabetic phase and prevented up to 100% of diabetes by drastically lowering activation of autoaggressive CD8 lymphocytes and their production of inflammatory cytokines. Interestingly, reversion of established disease could be achieved as well, when nonmitogenic CD3 was administered late during pathogenesis to overtly diabetic recipients. Most importantly, competence to clear viral infections was maintained. Thus, administration of nonmitogenic CD3 prevents diabetes by sufficient systemic reduction of (auto)aggressive lymphocytes, but without compromising antiviral immune competence.

Adjuvants, Immunologic↗
PubMed2002

The use of monoclonal antibodies to restore self-tolerance in established autoimmunity.

The author hopes to convince the reader that the data presented argue for a stage during the development of IDDM when beta-cell destruction can be counteracted and tolerance to beta cells restored, provided the immune aggression is arrested. This argument constitutes a solid rationale for immunointervention in established IDDM, especially by using potent agents such as CD3. The future for the application of monoclonal antibodies not only in autoimmunity but also in transplantation is exiting. With the development of humanized monoclonal antibodies, therapeutic uses for them are likely to expand. Enormous progress has been made in the last 15 years, and it is likely that before a similar time period has elapsed, monoclonal antibodies will have become standard tools that will dispense the need for long-term immunosuppression and its inherent dangers in various clinical arenas.

Animals↗
PubMed2002

A view on beta cell transplantation in diabetes.

Organ donors also offer a source of insulin-producing tissue that might be used for the treatment of diabetes. Clinical protocols for transplantation of this tissue aim for the prevention of chronic diabetes complications without introducing new serious side effects. Pancreas and islet cell transplantation are discussed in this perspective. The future of islet cell implants looks favorable but depends on finding ways to induce immune tolerance to the donor beta cells. Clinical trials can take advantage of relevant progress in animal models. In a limited study, recipient treatment with antilymphocyte antibodies and culture of donor cell preparations appeared useful to induce a state of operational immune tolerance in type 1 diabetic patients, as indirectly judged by graft survival and by analysis of auto- and alloreactivities in recipients. Use of cultured beta cell preparations also allows donor cell recruitment from suboptimal donor organs and increases the degree of standardization and quality control of islet cell grafts. The future of these grafts will depend on the development of techniques for the neogenesis of beta cells.

Animals↗
PubMedDate not supplied

Regulatory T cells in the control of autoimmune diabetes: the case of the NOD mouse.

Over the last few years, there has been a revival of the concept of suppressor/regulatory T cells being central players in the control of various immune responses, including autoimmune responses and immune response to transplants, tumors, and infectious agents. It appears that regulatory T cells are diverse in their phenotypes, antigen specificity, and modes of action. Here we summarize studies from various groups, including our own, demonstrating that specialized subsets of regulatory T cells are pivotal in the control of autoimmune diabetes as well shown by the compelling evidence accumulated using the non-obese diabetic (NOD) mouse model. We also provide a discussion of the evidence showing that some biological products (such as CD3-specific monoclonal antibodies) are representatives of a new category of immunotherapeutic agents endowed with unique capacities to promote immunological tolerance (an antigen-specific unresponsiveness in the absence of long-term generalized immunosuppression) through their ability to induce immunoregulatory T cells.

Animals↗
PubMedDate not supplied

CD3-specific antibodies as promising tools to aim at immune tolerance in the clinic.

Currently, therapies applied in transplantation and autoimmunity are essentially based on the use of immunosuppressants. These agents depress all immune responses and expose individuals to the recurrence of the pathogenic immune process once they are withdrawn, thus necessitating a chronic administration leading to the risk of recurrent infections and increased frequency of tumors. At variance, CD3 monoclonal antibodies appear unique in their capacity to induce immunological tolerance that is an antigen-specific unresponsiveness in the absence of chronic immunosuppression. This has been well-established in experimental models, and recent data show successful clinical translation using humanized anti-CD3 antibodies. The aim of this brief review is to discuss the main characteristics of these very promising tools and to present the experimental and clinical results arguing for their unique tolerogenic ability.

Animals↗