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Luis Graca

Publications and source records attributed to Luis Graca.

At least 19 recordsLinked to original sources
PubMed2006

Regulatory T cell maintenance of dominant tolerance: induction of tissue self-defense?

In the last decade there has been an increasing interest for the action of regulatory T cells (Treg) in preventing transplant rejection, autoimmunity and other inflammatory diseases and in maintaining dominant tolerance. It is becoming clear that such regulatory function does not rely simply on direct inhibition of "aggressive" T cells. In fact, several studies suggest that Treg cells may induce changes in the target tissue, promoting a state of "immune privilege" where protective genes such as heme oxygenase-1 (HO-1) and indolamine 2,3 dioxygenase (IDO) may have a critical role.

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PubMed2006

Co-receptor and co-stimulation blockade for mixed chimerism and tolerance without myelosuppressive conditioning.

BACKGROUND: A major challenge in the application of marrow transplantation as a route to immunological tolerance of a transplanted organ is to achieve hematopoietic stem cell (HSC) engraftment with minimal myelosuppressive treatments. RESULTS: We here describe a combined antibody protocol which can achieve long-term engraftment with clinically relevant doses of MHC-mismatched bone marrow, without the need for myelosuppressive drugs. Although not universally applicable in all strains, we achieved reliable engraftment in permissive strains with a two-stage strategy: involving first, treatment with anti-CD8 and anti-CD4 in advance of transplantation; and second, treatment with antibodies targeting CD4, CD8 and CD40L (CD154) at the time of marrow transplantation. Long-term mixed chimerism through co-receptor and co-stimulation blockade facilitated tolerance to donor-type skin grafts, without any evidence of donor-antigen driven regulatory T cells. CONCLUSION: We conclude that antibodies targeting co-receptor and co-stimulatory molecules synergise to enable mixed hematopoietic chimerism and central tolerance, showing that neither cytoreductive conditioning nor 'megadoses' of donor bone marrow are required for donor HSC to engraft in permissive strains.

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PubMed2006

Regulatory T cells in transplantation.

Our ability to harness tolerance mechanisms will have a major impact in organ transplantation. It should enable drug minimization, and eventually, the elimination of all immunosuppressive drugs. An improved understanding of the biology of regulatory T cells will make it possible to replace current induction regimens with those favouring the selective vaccination of T cells that prevent graft rejection. Once regulation is established, the continued supply of graft antigens should empower T cell regulation to become the dominant natural mechanism to prevent graft rejection.

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PubMed2006

Immune privilege induced by regulatory T cells in transplantation tolerance.

Immune privilege was originally believed to be associated with particular organs, such as the testes, brain, the anterior chamber of the eye, and the placenta, which need to be protected from any excessive inflammatory activity. It is now becoming clear, however, that immune privilege can be acquired locally in many different tissues in response to inflammation, but particularly due to the action of regulatory T cells (Tregs) induced by the deliberate therapeutic manipulation of the immune system toward tolerance. In this review, we consider the interplay between Tregs, dendritic cells, and the graft itself and the resulting local protective mechanisms that are coordinated to maintain the tolerant state. We discuss how both anti-inflammatory cytokines and negative costimulatory interactions can elicit a number of interrelated mechanisms to regulate both T-cell and antigen-presenting cell activity, for example, by catabolism of the amino acids tryptophan and arginine and the induction of hemoxygenase and carbon monoxide. The induction of local immune privilege has implications for the design of therapeutic regimens and the monitoring of the tolerant status of patients being weaned off immunosuppression.

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PubMed2006

Reprogramming the immune system using antibodies.

Tolerance induction induced by monoclonal antibodies or co-receptor blockade is robust enough to resist breakdown by adoptive transfer of lymphocytes. Such resistance, the hallmark of dominant tolerance, is mediated by CD4+ regulatory T cells. CD4+CD25+ T cells inhibit lymphopenia-mediated accumulation of T cells in vivo, but caution should be exerted when investigating antigen-specific regulation in replete mice. A number of different deletional and tolerogenic processes following antibody-induced tolerance are discussed in this chapter, including activation-induced cell death, immunosuppressive cytokines, and immunoprivileged sites. The possibility of spreading tolerance to other cells, including parenchymal cells, is also discussed. This chapter emphasizes recent evidence that shows that self-tolerance does not rely on several mechanisms running independently, but rather a continuum of synergistic and overlapping mechanisms.

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PubMed2005

Critical influence of natural regulatory CD25+ T cells on the fate of allografts in the absence of immunosuppression.

BACKGROUND: Allografts are occasionally accepted in the absence of immunosuppression. Because naturally occurring CD4(+)CD25(+) regulatory T cells (natural CD25(+) Treg cells) have been shown to inhibit allograft rejection, we investigated their influence on the outcome of allografts in nonimmunosuppressed mouse recipients. METHODS: We compared survival times of male CBA/Ca skin grafts in female CBA/Ca recipients expressing a transgenic anti-HY T-cell receptor on a RAG-1(+/+) (A1[M]RAG+) or a RAG-1(-/-) (A1[M]RAG-) background. Depletion of natural CD25(+) Treg cells in A1[M]RAG+ mice was achieved by in vivo administration of the PC61 monoclonal antibody. The influence of natural CD25(+) Treg cells on the fate of major histocompatibility complex class II-mismatched (C57BL/6X bm12)F1 skin or bm12 heart transplants in C57BL/6 recipients was also assessed. Finally, we investigated the impact of natural CD25(+) Treg cells on the production of T-helper (Th)1 and Th2 cytokines in mixed lymphocyte cultures between C57BL/6 CD4(+) CD25(-) T cells as responders and bm12 or (C57BL/6X bm12)F1 antigen-presenting cells as stimulators. RESULTS: Male allografts were spontaneously accepted by female A1(M)RAG+ mice but readily rejected by female A1(M)RAG+ mice depleted of natural CD25(+) Treg cells by pretreatment with the PC61 monoclonal antibody. Depletion of CD25(+) Treg cells also enhanced eosinophil-determined rejection of (C57BL/6X bm12)F1 skin grafts or bm12 cardiac grafts in C57BL/6 recipients. Finally, natural CD25(+) Treg cells inhibited the production of interleukin (IL)-2, interferon-gamma, IL-5, and IL-13 in mixed lymphocyte culture in a dose-dependent manner. CONCLUSION: Natural CD25(+) Treg cells control Th1- and Th2-type allohelper T-cell responses and thereby influence the fate of allografts in nonimmunosuppressed recipients.

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PubMed2005

New tools to identify regulatory T cells.

The lack of tools for direct identification of regulatory T cells (T(reg) cells) at the single-cell level has been one of the major hurdles for the study of T(reg) cells and their involvement in human disease. The identification of the transcription factor Foxp3 as a molecular correlate for T(reg) function offered the opportunity to directly identify T(reg) cells, but until recently adequate reagents were not available. The tools promising the solution for this problem have emerged through the development of transgenic mice in which Foxp3 expression drives the production of fluorescent proteins, as well as the development of mAb that are able to identify Foxp3(+) cells by histology or flow cytometry. With these new tools, the mAb in particular, it will become possible for the first time to directly probe the participation of Foxp3(+) T(reg) cells in human pathology in a quantitative fashion.

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PubMed2004

Donor-specific transplantation tolerance: the paradoxical behavior of CD4+CD25+ T cells.

To investigate the antigen specificity of regulatory T cells capable of preventing transplant rejection, we have developed two different strategies to achieve tolerance to fully mismatched skin grafts in euthymic mice. A combination of nondepleting Abs targeting CD4, CD8, and CD154 (CD40 ligand) induces dominant transplantation tolerance to fully mismatched skin allografts. Such tolerance is antigen-specific, mediated by regulatory T cells, and can be extended through linked suppression to naïve lymphocytes. The same protocol, when combined with allogeneic bone marrow, enables the development of mixed hematopoietic chimerism and deletional tolerance. Although we cannot exclude that some regulatory T cells may persist in chimeric mice, these cells are insufficient to mediate linked suppression. CD4(+)CD25(+) T cells, whether taken from naïve mice or from mice tolerized through either treatment protocol, were always able to prevent rejection of skin grafts by naïve CD4(+) T cells, and did so with no demonstrable specificity for the tolerizing donor antigens. Such data question whether CD4(+)CD25(+) regulatory T cells alone can account for the antigen specificity of dominant transplantation tolerance.

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PubMed2004

Induction of foxP3+ regulatory T cells in the periphery of T cell receptor transgenic mice tolerized to transplants.

Transplantation tolerance can be induced in mice by grafting under the cover of nondepleting CD4 plus CD8 or CD154 mAbs. This tolerance is donor Ag specific and depends on a population of CD4(+) regulatory T cells that, as yet, remain poorly defined in terms of their specificity, origin, and phenotype. Blocking of the Ag-specific response in vitro with an anti-CD4 mAb allowed T cells from monospecific female TCR-transgenic mice against the male Ag Dby, presented by H-2E(k), to express high levels of foxP3 mRNA. foxP3 induction was dependent on TGF-beta. The nondepleting anti-CD4 mAb was also able to induce tolerance in vivo in such monospecific TCR-transgenic mice, and this too was dependent on TGF-beta. As in conventional mice, acquired tolerance was dominant, such that naive monospecific T cells were not able to override tolerance. Splenic T cells from tolerant mice proliferated normally in response to Ag, and secreted IFN-gamma and some IL-4, similar to control mice undergoing primary or secondary graft rejection. High levels of foxP3 mRNA, and glucocorticoid-induced TNFR superfamily member 18 (GITR)(+) CD25(+) T cells were found within the tolerated skin grafts of long-term tolerant recipients. These data suggest that regulatory T cells maintaining transplantation tolerance after CD4 Ab blockade can be induced de novo through a TGF-beta-dependent mechanism, and come to accumulate in tolerated grafts.

Amino Acid Sequence↗
PubMed2004

Regulatory T cells and organ transplantation.

Empirical studies attempting to explain tolerance to transplanted tissues have demonstrated a regulatory role for CD4+ T-cells. We here propose that regulatory T-cells mediating transplantion tolerance comprise two sets which can functionally complement each other. The CD4+CD25+ "natural regulator" arises in the thymus, and is preoccupied with self-antigens expressed at sites of inflammation. The second, comprising both CD4+CD25+ (FoxP3+) and CD4+CD25- Tr1-like cells are induced by persistent danger-free antigen in the periphery. The role of these cells is to moderate immune responses to prevent tissue destruction while allowing microbial elimination.

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PubMed2003

Regulatory T cells in the induction and maintenance of peripheral transplantation tolerance.

It is now possible to induce donor-specific transplantation tolerance in adult rodents using non-depleting monoclonal antibodies against T cell co-receptor and co-stimulation molecules or by immunisation with tolerogenic antigen-presenting cells. It is a common finding of all these models of peripheral tolerance, as well as of various mouse models of autoimmune disease, that regulatory CD4(+) T cells are the principal mediators. There are currently no specific markers for regulatory T cells, but in some autoimmune models their activity has been associated with the expression of activation markers such as CD25 and CTLA4, or anti-inflammatory cytokines such as IL-10 and TGF-beta. CD4(+)CD25(+) T cells from both naïve and tolerised donors are able to transfer tolerance to grafts in lymphopenic recipients, and this may be directly applicable to bone-marrow transplantation. The challenge is now to understand the biological principles that allow such immune re-programming so that they can be safely applied to clinical organ grafting.

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PubMed2003

Dominant transplantation tolerance. Opinion.

Long-term allograft survival in the absence of continuous immunosuppression can be induced following a short treatment of nondepleting antibodies, such as those that target CD4 or CD154 (CD40 ligand). It is now established that this may involve dominant tolerance mechanisms that are maintained by CD4+ regulatory T cells present within the lymphoid tissue and the tolerated graft. The phenotype of these cells, their relationship to CD4+CD25+ T cells, and the mechanism of action are still controversial.

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PubMed2003

Serial analysis of gene expression provides new insights into regulatory T cells.

It is now possible to induce donor-specific transplantation tolerance in adult rodents using a number of therapeutic strategies. Such peripheral tolerance is maintained by regulatory CD4+ T cells, not only in transplantation models, but also in autoimmunity. Differential gene expression analyses have been used to identify potential new markers for regulatory T cells, aiming to reveal new insights into their mechanisms of action, and to find novel targets for therapeutic manipulation of the immune system.

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PubMed2003

Regulatory T cells and dendritic cells in transplantation tolerance: molecular markers and mechanisms.

Transplantation tolerance can be induced in adult rodents using monoclonal antibodies against coreceptor or costimulation molecules on the surface of T cells. There are currently two well-characterized populations of T cells, demonstrating regulatory capacity: the "natural" CD4+CD25+ T cells and the interleukin (IL)-10-producing Tr1 cells. Although both types of regulatory T cells can induce transplantation tolerance under appropriate conditions, it is not clear whether either one plays any role in drug-induced dominant tolerance, primarily due to a lack of clear-cut molecular or functional markers. Similarly, although dendritic cells (DCs) can be pharmacologically manipulated to promote tolerance, the phenotype of such populations remains poorly defined. We have used serial analysis of gene expression (SAGE) with 29 different T-cell and antigen-presenting cell libraries to identify gene-expression signatures associated with immune regulation. We found that independently derived, regulatory Tr1-like clones were highly concordant in their patterns of gene expression but were quite distinct from CD4+CD25+ regulatory T cells from the spleen. DCs that were treated with the tolerance-enhancing agents IL-10 or vitamin D3 expressed a gene signature reflecting a functional specification in common with the most immature DCs derived from embryonic stem cells.

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PubMed2003

Antibody-induced transplantation tolerance: the role of dominant regulation.

A short-treatment with nondepleting antibodies, such as those targeting CD4 or CD154 (CD40 ligand), allows long-term graft survival without the need for continuous immunosuppression. This state of immune tolerance is maintained by regulatory CD4+ T cells present within both the lymphoid tissue and the tolerated graft. The nature of such regulatory T cells, their relationship to CD4+CD25+ T cells, and their mode of action have all been the subjects of much attention recently. Here, we review recent progress on understanding the nature, specificity, and mechanisms of action of T cells mediating dominant tolerance brought about by antibody therapy.

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PubMed2002

Dominant transplantation tolerance impairs CD8+ T cell function but not expansion.

Alloreactive CD8+ T cells may persist in animals made tolerant of transplanted tissues; their function is controlled through continuous censorship by regulatory CD4+ T cells. We sought to establish the stage at which such censorship operates. We found that monospecific CD8+ T cells introduced into tolerant animals responded to the tolerated tissue antigen as if they had received CD4+ T cell "help": they proliferated and accumulated normally. However, they did show compromised graft rejection, interferon-gamma production and cell-mediated cytotoxicity. These findings suggest that tolerance mediated by regulatory T cells acts by censoring immune effector functions rather than by limiting the induction of T cell responses.

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PubMed2002

Identification of regulatory T cells in tolerated allografts.

Induction of transplantation tolerance with certain therapeutic nondepleting monoclonal antibodies can lead to a robust state of peripheral "dominant" tolerance. Regulatory CD4+ T cells, which mediate this form of "dominant" tolerance, can be isolated from spleens of tolerant animals. To determine whether there were any extra-lymphoid sites that might harbor regulatory T cells we sought their presence in tolerated skin allografts and in normal skin. When tolerated skin grafts are retransplanted onto T cell-depleted hosts, graft-infiltrating T cells exit the graft and recolonize the new host. These colonizing T cells can be shown to contain members with regulatory function, as they can prevent nontolerant lymphocytes from rejecting fresh skin allografts, without hindrance of rejection of third party skin. Our results suggest that T cell suppression of graft rejection is an active process that operates beyond secondary lymphoid tissue, and involves the persistent presence of regulatory T cells at the site of the tolerated transplant.

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